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SARS-CoV-2 was initially reported in 2019 in China and spread rapidly worldwide, causing the COVID-19 pandemic in humans. Since the pandemic unfolded, the role of animals as amplifying or reservoir [...]

Rodents are widespread, opportunistic, and competent host reservoirs involved in the maintenance, circulation, and transmission of a wide panel of zoonotic pathogens (1). Rodent-related zoonoses cause up to 400 million [...]

In Valencia, Spain, permanent rodent control campaigns are the responsibility of The Pest Control Section of the Health Service of Valencia City Council. As part of its tasks, the Section [...]

Exposure of adult female rats (Rattus norvegicus (Berkenhout, 1769)) to restraint (1 h) and after a gap of 4 h to forced swimming exercise for 15 min daily for 12 weeks resulted in a significant decrease in (i) weight of the body and lymphoid organs (spleen, thymus, and axillary lymph node), (ii) counts of total leukocytes and their subpopulation (lymphocytes, neutrophils, monocytes, eosinophils, and basophils), and (iii) healthy cells of all lymphoid organs and a significant increase in the count of apoptotic cells in all the lymphoid organs. One month after cessation of exposure to stressors (recovery group), all the parameters did not significantly differ from stress-group rats. The results may indicate that either deleterious effects of long- term chronic exposure to stress are not reversible or the 4-week recovery period is not sufficient to restore normalcy. Key words: apoptosis, blood, immunity, stress, rat, Rattus norvegicus. L'exposition de rats (Rattus norvegicus (Berkenhout, 1769)) femelles adultes a la contention (1 h) et, apres un intervalle de 4 h, a un exercice de nage force pendant 15 min chaque jour, pour une periode de 12 semaines a entrame des reductions significatives (i) de la masse du corps et des organes lymphoides (rate, thymus et nreud lymphatique axillaire), (ii) du nombre de leucocytes totaux et de leurs sous-populations (lymphocytes, neutrophiles, monocytes eosinophiles et basophiles) et (iii) des cellules saines de tous les organes lymphoides, et une augmentation significative du nombre de cellules apoptotiques dans tous les organes lymphoides. Un mois apres la cessation de l'exposition aux facteurs de stress (groupe en recuperation), tous les parametres ne montraient aucune difference significative par rapport aux rats du groupe expose aux facteurs de stress. Ces resultats pourraient indiquer soit que les effets deleteres de l'exposition chronique au stress sur une longue periode sont irreversibles ou qu'une periode de recuperation de 4 semaines n'est pas suffisante pour retablir l'etat normal. [Traduit par la Redaction] Mots-cles: apoptose, sang, immunite, stress, rat, Rattus norvegicus., Introduction Stress has long been known to alter the homeostatic state of the organisms and elicit behavioral and physiological changes (Silberman et al. 2003). Chronic stress adversely affects different physiological [...]

[sup.3]H-tetracycline ([sup.3]H-TC) is thought to be superior to calcium (Ca) isotopic tracers for estimating bone resorption rates due to the less redeposition upon release in animal models. However, these 2 tracers have not been compared directly using complete kinetic studies with sampling of blood, urine, feces, and bone. Our goal was to compare the 2 isotopes for evaluating bone turnover. We firstly developed a model for [sup.3]H-TC kinetics in 4-mo-old female rats (n = 3) by measuring the tracer in serum, urine, and feces over 4 d. Then, 9-mo-old ovariectomized (OVX) rats (n = 6) were given both [sup.45]Ca and [sup.3]H-TC subcutaneously. Urine was collected in 24-h pools and assayed for both tracers. Rats were killed 7 and 46 d after the dose and whole skeleton was harvested. We calculated bone resorption rates by modeling the [sup.45]Ca and [sup.3]H-TC data in urine and bone. [sup.3]H-TC kinetics revealed that, like Ca, there are 2 exchangeable compartments between serum and bone. An additional pool was required to account for bone mass of Ca. Bone resorption rates determined from urinary [sup.45]Ca and [sup.3]H-TC did not differ significantly. The tracers [sup.45]Ca and [sup.3]H-TC can be used interchangeably to determine bone resorption rates in OVX rats. Thus, both labels can be used to screen dietary and other interventions for beneficial effects on bone. J. Nutr. 140: 1704-1709, 2010. doi: 10.3945/jn.110.121301.

Adult rats chronically fed a high-fat (HF) diet maintain reduced sensitivity to cholecystokinin (CCK). We hypothesized that, similar to adult rats, pups fed a HF diet would also exhibit reduced sensitivity to CCK. To test this, male pups fed low-fat (LF) and HF isoenergetic (16.2 k J/g) diets were administered CCK intraperitoneally (0.125-1 g/kg) 1 wk following dietary adaptation. After receiving 0.5 g/kg CCK, pups fed the HF diet suppressed food intake less (8.9 [+ or -] 5.0%) than pups fed the LF diet (28.9 [+ or -] 4.7%; P < 0.05) relative to intakes after saline administration. We then assessed the development and extinction of changes in CCK sensitivity by switching the diets between the groups. The HF-fed group, when switched to the LF diet, regained sensitivity by wk 4 and suppressed food intake following administration of 0.25 g/kg CCK (33.1 [+ or -] 5.7%; P < 0.05). The LF-fed group, when switched to the HF diet, lost sensitivity by wk 2 and did not suppress food intake after administrations of CCK compared with saline. Finally, we examined if HF-fed rats have an increased sensitivity to corn oil during brief access tests using a multibottle gustometer. At oil concentrations of 25, 75, and 100%, rats fed the HF diet sampled more oil than LF-fed rats (P < 0.05). These findings demonstrate that male rat pups fed a HF diet exhibit reduced sensitivity to CCK, the development of this reduced sensitivity is quicker than its extinction, and rats consuming a HF diet have increased oral sensitivity to oils. J. Nutr. 140: 1698-1703, 2010. doi: 10.3945/jn.110.124149.

The purpose of the present study was to assess whether resolvin E1 (RvE1), an anti-inflammatory mediator derived from eicosapentaenoic acid, would limit myocardial infarct size in the rat. The H9c2 cell line was used to assess whether RvE1 has direct protective effects on cardiomyocytes. In in vivo experiments, Male Sprague-Dawley rats underwent 30 min of ischemia/4 h of reperfusion. Before reperfusion, rats received intravenous RvE1 (0, 0.03, 0.1, or 0.3mg/kg). In in vitro experiments, H9c2 cells were incubated with RvE1 (0, 1, 10, 100, or 1000 nM). Cells were subjected to 18 h of incubation under normoxic conditions, 16 h of hypoxia, or 16 h of hypoxia and 2 h of reoxygenation. In vivo, RvE1 dose dependently reduced infarct size (30.7 [+ or -] 1.7% of the area at risk in the control group and 29.1 [+ or -] 1.6%, 14.7 [+ or -] 1.3%, and 9.0 [+ or -] 0.6% in the 0.03, 0.1, and 0.3 mg/kg groups, respectively, P < 0.001). In vitro, RvE1 increased viability and decreased apoptosis in a dose-dependent fashion in cells exposed to hypoxia or hypoxia/reoxygenation. A maximal effect was achieved at a concentration of 100 nM. RvE1 augmented phosphoinositide 3-kinase activity, attenuated caspase-3 activity, and augmented calciumdependent nitric oxide synthase activity in cells exposed to hypoxia or hypoxia/reoxygenation. RvE1 increased Akt, ERK1/2, and endothelial nitric oxide synthase phosphorylation and attenuated the levels of activated caspase-3 and phosphorylated p38 levels. AG-1478, an EGF receptor tyrosine kinase inhibitor, blocked the protective effect of RvE1 both in vivo and in vitro and attenuated the RvE1-induced increase in Akt and ERK1/2 phosphorylation. In conclusion, RvE1, an anti-inflammatory mediator derived from eicosapentaenoic acid, has a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion. infarct size; ischemia-reperfusion injury; apoptosis; epidermal growth factor receptor doi: 10.1152/ajpheart.01057.2009.

Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% [O.sub.2]-90% [N.sub.2] gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-L-arginine methyl ester (L-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in L-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase. pulmonary vasodilation; systemic vasodilation; hypoxic pulmonary vasoconstriction; nitric oxide release; BAY 41-8543 doi: 10.1152/ajpheart.00181.2009.

Obesity is a risk factor for stroke, but the determinants of increased stroke risk in obesity are unknown. We have previously reported that obese Zucker rats (OZRs) have a worse stroke outcome and display evidence of remodeling of the middle cerebral artery (MCA), in parallel with hypertension, compared with lean controls. This study tested the hypothesis that hypertension is an essential determinant of cerebral vascular remodeling and increased stroke damage in OZRs. Blood pressure was measured by telemetery in lean and obese rats with and without hydrochlorthiazide (HCT; 2 mg x [kg.sup.-1] x [day.sup.-1]) from 8 to 15 wk of age. A separate group of rats was also chronically fed a low-sodium (LS) diet. Vessel structure was assessed in isolated, pressurized MCAs. Cerebral ischemia was induced for 60 rain using an intralumenal suture technique, followed by 24 h of reperfusion. HCT treatment effectively prevented the increase in blood pressure in obese rats; however, the LS diet did not lower pressure. Importantly, infarct size was normalized by HCT after ischemia-reperfusion injury. Additionally, HCT improved the changes in MCA structure observed in untreated OZRs. There were no benefits of the LS diet on stroke injury or vessel structure. These results indicate that increased pressure is essential for driving the changes in infarct size in OZRs. hypertension; vascular remodeling; hydrochlorothiazide doi: 10.1152/ajpheart.01111.2009.

Genetic absence epilepsy rats from Strasbourg are a strain of Wistar rats in which all animals exhibit spontaneous occurrences of spike and wave discharges (SWDs) in the EEG. In this paper, we propose a novel method for the detection of SWDs, based on the key observation that SWDs are quasi-periodic signals. The method consists of the following steps: 1) calculation of the spectrogram; 2) estimation of the background spectrum and detection of stimulation artifacts; 3) harmonic analysis with continuity analysis to estimate the fundamental frequency; and 4) classification based on the percentage of power in the harmonics to the total power of the spectrum. We evaluated the performance of the novel detection method and six SWD/seizure detection methods from literature on a large database of labeled EEG data consisting of two datasets running to a total duration of more than 26 days of recording. The method outperforms all tested SWD/seizure detection methods, showing a sensitivity and selectivity of 96% and 97%, respectively, on the first test set, and a sensitivity and selectivity of 94% and 92%, respectively, on the second test set. The detection performance is less satisfactory (as for all other methods) for EEG fragments showing more irregular and less periodic SWDs. Index Terms--Automatic detection, detection, epilepsy, experimental animal models, genetic absence epilepsy rats from Strasbourg (GAERS), pitch detection, spike and wave discharges (SWDs), time-frequency analysis.

Recent work has suggested that inflammation is a common component of a number of age-related diseases. The hypothesis of the present study was that normal aging of the retina and choroid would increase levels of inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and tumor necrosis factor alpha (TNF-[alpha]). To investigate this hypothesis, gene expression and protein analyses were completed on retinal and choroidal samples from Fischer 344 x Brown Norway F1 hybrid rats at 8, 22, and 32 months of age. Aging of the choroid produced significant increases in PGE2, with decreased TNF-[alpha] protein. Protein levels and messenger RNA of iNOS and TNF-[alpha] protein levels were significantly decreased in the aging retina in contrast to PGE2 protein activity, which was increased with age in the retina. These results suggest that PGE2 is likely involved in the aging process in both the retina and choroid, whereas iNOS plays a role predominantly in the retina. Key Words: Inflammatory markers--Retina--Choroid--Aging.

In this study, our aim was to determine whether orally administered ovine serum Ig improved growth performance, organ weights, and gut morphology in growing rats and whether the method of manufacture of ovine serum Ig affected its bioactivity. Ninety Sprague-Dawley male rats were used in a 21-d growth study and were fed a basal control diet (BD; no Ig) and 5 test diets: spray-dried porcine plasma (SDPP), freeze-dried ovine Ig (FDOI), 2 concentrations of spray-dried ovine Ig ([SDO.sub.100] and [SDOI.sub.150]), and inactivated ovine Ig (IOI). Diets were isocaloric and contained the same amount of the first limiting amino acids, methionine plus cysteine. The body weight gain:feed ratio was higher (P < 0.05) for the FDOI-fed rats than for the BD- and IOI-fed groups. FDOI rats had higher jejunum (P < 0.05) and colon weights (P < 0.05) at the end of the study than rats in the BD group. Compared with the [SDOI.sub.100]-fed group, the FDOI group supported higher (P < 0.05) duodenum and colon weights. For gut morphology, the FDOI and the BD and IOI groups differed (P < 0.05). The FDOI-fed rats had longer (P < 0.05) villi and greater villi surface areas in the duodenum, jejunum, and ileum than the rats fed [SDOI.sub.100]. An ovine Ig fraction selectively improved growth performance, organ weight, and gut morphology in growing rats. Compared with spray-drying, a freeze-drying procedure appears to preserve a higher degree of immunological activity.

Whether the lusitropic potential of short-term exercise in aged rats is linked to an augmentation in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and an alteration in the cardiac renin angiotensin system (RAS) is unknown. Old (28-month-old) male, Fischer 344xBrown Norway rats were randomized to 4 weeks of GH supplementation (300 [micro]g subcutaneous, twice daily) or 4 weeks of treadmill running, or were used as sedentary controls. Six-month-old rats, sedentary or exercised, were used as young controls. Training improved exercise capacity in old animals. Exercise and GH attenuated age-related declines in myocardial relaxation despite an exercise-induced suppression of IGF-1. The regulatory protein, sarcoplasmic [Ca.sup.2+] adenosine triphosphatase (SERCA2), increased with exercise but not GH. Among aged rats, the cardiac RAS was not altered by training or GH. Thus, the signaling pathway underlying the lusitropic benefit of short-term habitual exercise in the aged rat may be distinct from GH-mediated benefits and independent of the cardiac RAS. Key Words: Aging--Diastolic function--Growth hormone--Insulin-like growth factor-1--Treadmill training.

Epidermal growth factor (EGF) stimulates freshly plated adult hepatocytes to synthesize DNA, but only after they pass through a lag phase of 40 h following EGF exposure. The longer the cells are maintained, they become more responsive to EGF and the lag phase shortens. Maximal EGF-mediated stimulation of DNA synthesis requires the induction of ErbB2, which is not normally expressed in adult hepatocytes. We used immunological methods to demonstrate increased expression during culture of two gene families required for EGF to stimulate hepatocyte DNA synthesis: Akt and ERK 1/2. Both families showed hyperexpression in culture particularly when cells were exposed to insulin and EGF. Unlike CDK-2 and cyclin D1, integral mediators of the G1/S phase transition, ERK 1/2 and Akt appeared in the absence of EGF, particularly when insulin was present. This hyperexpression, which high concentrations of dexamethasone reversed, increased basal and growth factor-stimulated phosphorylation of Akt and ERK 1/2. Pharmacological blockade of phosphatidylinositol kinase suppressed the Akt increase whereas pharmacological blockade or small interfering RNA downregulation of ErbB2 inhibited both Akt and ERK 1/2 expression. All three Akt isoforms contributed to the increase in total Akt. EGF but not insulin specifically upregulated Akt 2 and 3. Since Akt and ERK 1/2 are also hyperexpressed in poorly differentiated hepatomas, their dysregulation in cancer may involve transcriptional mechanisms normally operative in cultured hepatocytes. We hypothesize that the induction and activation of ErbB2 increases the expression of these kinases, enhancing the responsiveness of hepatocytes to EGF as they adapt to culture. cell culture; liver; signaling; EGF; insulin

Androgen exposure during intrauterine life in nonhuman primates and in sheep results in a phenocopy of the reproductive and metabolic features of polycystic ovary syndrome (PCOS). Such exposure also results in reproductive features of PCOS in rodents. We investigated whether transient prenatal androgen treatment produced metabolic abnormalities in adult female rats and the mechanisms of these changes. Pregnant dams received free testosterone or vehicle injections during late gestation, and their female offspring were fed regular or high-fat diet (HFD). At 60 days of age, prenatally androgenized (PA) rats exhibited significantly increased body weight; parametrial and subcutaneous fat; serum insulin, cholesterol and triglyceride levels; and hepatic triglyceride content (all P < 0.0125). There were no significant differences in insulin sensitivity by intraperitoneal insulin tolerance test or insulin signaling in liver or skeletal muscle. HFD had similar effects to PA on body weight and composition as well as on circulating triglyceride levels. HFD further increased hepatic triglyceride content to a similar extent in both PA and control rats. In PA rats, HFD did not further increase circulating insulin, triglyceride, or cholesterol levels. In control rats, HFD increased insulin levels, but to a lesser extent than PA alone (~2.5-vs. ~12-fold, respectively). We conclude that transient prenatal androgen exposure produces features of the metabolic syndrome in adult female rats. Dyslipidemia and hepatic steatosis appear to be mediated by PA-induced increases in adiposity, whereas hyperinsulinemia appears to be a direct result of PA. prenatal androgen exposure; metabolic syndrome; polycystic ovary syndrome; hepatic steatosis

For investigation of possible bio-effects of the 2-GHz wideband code division multiple access cellular system on pregnant and newborn rats, we have developed an unrestrained whole-body exposure setup, which employs two dipole antennas to induce a circularly polarized field at the location of the rats. The dosimetric results, by using the finite-difference time-domain method in conjunction with anatomical rat models, have confirmed the realization of a circular polarization in the exposure space, and have also revealed that the exposure setup can maintain a relative variation of the whole-body average specific absorption rate (SAR) within [+ or -]60% of the designed average level for various positions of rats. These findings show that the exposure setup is reasonable and acceptable in view of the actual SAR variation in a human body due to RF exposure from base stations. Index Terms--Bio-effect of electromagnetic field, circular polarization, pregnant rat, RF, whole-body exposure setup.

It has been reported previously that the offspring of rat dams consuming low dietary copper (Cu) during pregnancy and lactation experience a deficiency in cardiac cytochrome c oxidase (CCO) characterized by reduced catalytic activity and mitochondrial and nuclear subunit content after postnatal d 10. The present study was undertaken to determine whether the cardiac CCO deficiency was caused directly by low postnatal Cu intake or whether it was a prenatal effect of low Cu intake by the dams that became manifest postnatally. Dams were fed either a Cu-adequate diet (6 mg Cu/kg) or Cu- deficient diet (1 mg Cu/kg) beginning 3 wk before conception and throughout gestation and lactation. One day following parturition, several litters from Cu-adequate dams were cross fostered to Cu-deficient dams and several litters from Cu-deficient dams were cross fostered to Cu-adequate dams. Litters that remained with their birth dams served as controls. CCO activity, the content of the mitochondrial-encoded CCO subunit 1 (COX1), and the content of the nuclear- encoded subunit COX4 in cardiac mitochondria were reduced in the 21-d-old offspring of Cu-deficient dams. COX1 content was normal in the 21-d-old cross-fostered offspring of Cu-deficient dams, but CCO activity and COX4 were reduced. Cross fostering the offspring of Cu-adequate dams to Cu-deficient dams did not significantly affect CCO activity, COX1 content, or COX4 content in cardiac mitochondria of 21-d-old offspring. These data indicate that low prenatal Cu intake by dams was the determinant of CCO activity in cardiac mitochondria of the 21-d-old offspring and may have led to the assembly of a less-than-fully active holoenzyme.

Iron deficiency during early growth and development adversely affects multiple facets of cognition and behavior in adult rats. The purpose of this study was to assess the nature of the learning and locomotor behavioral deficits observed in male and female rats in the absence of depressed brain iron levels at the time of testing. Adult female Wistar rats were fed either an iron-enriched diet (>225 mg/kg Fe) or an iron-restricted diet (3 mg/kg Fe) for 2 wk prior to and throughout gestation, and a nonpurified diet (270 mg/kg Fe) thereafter. Open-field (OF) and Morris water maze (MWM) testing began when the offspring reached early adulthood (12 wk). At birth, perinatal iron-deficient (PID) offspring had reduced (P < 0.001) hematocrits (-33%), liver iron stores (-83%), and brain iron concentrations (-38%) compared with controls. Although there were no differences in iron status in adults, the PID males and females exhibited reduced OF exploratory behavior, albeit only PID males had an aversion to the center of the apparatus (2.5 vs. 6.9% in controls, P < 0.001). Additionally, PID males required greater path lengths to reach the hidden platform in the MWM, had reduced spatial bias for the target quadrant, and had a tendency for greater thigmotactic behavior in the probe trials (16.5 vs. 13.0% in controls; P= 0.06). PID females had slower swim speeds in all testing phases (-6.2%; P< 0.001). These results suggest that PID has detrimental programming effects in both male and female rats, although the behaviors suggest different mechanisms may be involved in each sex.

It was hypothesized that renal sympathetic nerve activity (RSNA) and neuronal nitric oxide synthase (nNOS) are involved in the acute inhibition of renin secretion and the natriuresis following slow NaCl loading (NaLoad) and that RSNA participates in the regulation of arterial blood pressure (MABP). This was tested by NaLoad after chronic renal denervation with and without inhibition of nNOS by S-methyl-thiocitrulline (SMTC). In addition, the acute effects of renal denervation on MABP and sodium balance were assessed. Rats were investigated in the conscious, catheterized state, in metabolic cages, and acutely during anesthesia. NaLoad was performed over 2 h by intravenous infusion of hypertonic solution (50 [micro]mol*[min.sup.-1]*kg body [mass.sup.-1]) at constant body volume conditions. SMTC was coinfused in amounts (20 [micro]g*[min.sup.-1]*[kg.sup-1]) reported to selectively inhibit nNOS . Directly measured MABPs of acutely and chronically denervated rats were less than control (15% and 9%, respectively, P < 0.005). Plasma renin concentration (PRC) was reduced by renal denervation (14.5 [+ or -] 0.2 vs. 19.3 [+ or -] 1.3 mIU/l, P < 0.005) and by nNOS inhibition (12.4 [+ or -] 2.3 vs. 19.6 [+ or -] 1.6 mlU/l, P < 0.005). NaLoad reduced PRC (P < 0.05) and elevated MABP modestly (P < 0.05) and increased sodium excretion six-fold, irrespective of renal denervation and SMTC. The metabolic data demonstrated that renal denervation lowered sodium balance during the first days after denervation (P < 0.001). These data show that renal denervation decreases MABP and renin secretion. However, neither renal denervation nor nNOS inhibition affects either the renin downregulation or the natriuretic response to acute sodium loading. Acute sodium-driven renin regulation seems independent of RSNA and nNOS under the present conditions. plasma renin concentration; total body sodium; blood pressure; sodium excretion

A major hurdle for current xenogenic-based and other approaches aimed at engineering kidney tissues is reproducing the complex three-dimensional structure of the kidney. Here, a stepwise, in vitro method of engineering rat kidney-like tissue capable of being implanted is described, Based on the fact that the stages of kidney development are separable into in vitro modules, an approach was devised that sequentially induces an epithelial tubule (the Wolffian duct) to undergo in vitro budding, followed by branching of a single isolated bud and its recombination with metanephric mesenchyme. Implantation of the recombined tissue results in apparent early vascularization. Thus, in principle, an unbranched epithelial tubular structure (potentially constructed from cultured cells) can be induced to form kidney tissue such that this in vitro engineered tissue is capable of being implanted in host rats and developing glomeruli with evidence of early vascularization. Optimization studies (of growth factor and matrix) indicate multiple suitable combinations and suggest both a most robust and a minimal system. A whole-genome microarray analysis suggested that recombined tissue recapitulated gene expression changes that occur in vivo during later stages of kidney development, and a functional assay demonstrated that the recombined tissue was capable of transport characteristic of the differentiating nephron. The approach includes several points where tissue can be propagated. The data also show how functional, 3D kidney tissue can assemble by means of interactions of independent modules separable in vitro, potentially facilitating systems-level analyses of kidney development. kidney development | systems biology | tissue engineering

Various antenatal events impair nephrogenesis in humans as well as in several animal models. The consecutive low nephron endowment may contribute to an increased risk for cardiovascular and renal diseases in adulthood. However, little knowledge is available on the influence of the postnatal environment, especially nutrition, on nephrogenesis. Moreover, the consequences of early postnatal nutrition in late adulthood are not clear. We used a model of early postnatal overfeeding (OF) induced by reduction of litter size (3 pups/litter) in rats. Systolic blood pressure (SBP; plethysmography), glomerular filtration rate (clearance of creatinine), glomerular number and volume, and glomerulosclerosis were evaluated in 22-mo-old aging offspring. Early postnatal OF was associated with increased weight gain during the suckling period (+40%, P < 0.01) and a 20% increase in glomerular number (P < 0.05). However, an increase in SBP at 12 mo by an average of 18 mmHg and an increase in proteinuria (2.6-fold) and glomerulosclerosis at 22 mo of age were observed in OF male offspring compared with controls. In conclusion, early postnatal OF in the rat enhances postnatal nephrogenesis, but elevated blood pressure and glomerulosclerosis are still observed in male adults. Factors other than glomerular number reduction are likely to contribute to the arterial hypertension induced by early postnatal OF. nephrogenesis; glomerular number; overfeeding; arterial blood pressure; infant; newborn; developmental origins of adult diseases

Mast cells and other cells such as macrophages have been shown to mediate systemic anaphylaxis. We determined the roles of mast cells and Kupffer ceils in hepatic and systemic anaphylaxis of rats. Roles of mast cells were examined by using the mast cell-deficient white spotting (Ws/Ws) rat; the Ws/Ws and wild type (+/+) rats were sensitized with ovalbumin (1 mg). Roles of Kupffer cells were examined by depleting Kupffer cells using gadolinium chloride or liposome-encapsulated dichloromethylene diphosphonate in the Ws/Ws and Sprague-Dawley rats. An intravenous injection of 0.6 mg ovalbumin caused substantial anaphylactic hypotension in both the Ws/Ws and +/+ rats; however, the occurrence was delayed in the Ws/Ws rats. After antigen, portal venous pressure increased by 13.1 cm[H.sub.2]O in the +/+ rats, while it increased only by 5.7 cm[H.sub.2]O in the Ws/Ws rats. In response to antigen, the isolated perfused liver of the Ws/Ws rats also showed weak venoconstriction, the magnitude of which was one tenth as large as that of the +/+ rats, indicating that hepatic anaphylaxis was primarily due to mast cells. In contrast, Kupffer cell depletion did not attenuate anaphylactic hepatic venoconstriction in isolated perfused livers. In conclusion, mast cells are involved mainly in anaphylactic hepatic presinusoidal portal venoconstriction but only in the early Stage of anaphylactic systemic hypotension in rats. Macrophages, including Kupffer ceils, do not participate in rat hepatic anaphylactic venoconstriction. blood pressure; hemodynamics; macrophages; anaphylactic shock; hepatic circulation

The aim of the present study was to determine characteristics of fast oscillations in the juvenile rat phrenic nerve (Ph) and to establish their temperature and state dependence. Two different age-matched decerebrate, baro- and chemodenervated rat preparations, in vivo and in situ arterially perfused models, were used to examine three systemic properties: 1) generation and dynamics of fast oscillations in Ph activity (both preparations), 2) responses to anoxia (both preparations), and 3) the effects of temperature on fast oscillations (in situ only). Both juvenile preparations generated power and coherence in two major bands analogous to adult medium- and high-frequency oscillations (HFO) at frequencies that increased with temperature but were lower than in adults. At < 28[degrees]C, however, Ph oscillations were confined primarily to one low-frequency band (20-45 Hz). During sustained anoxia, both preparations produced stereotypical state changes from eupnea to hyperpnea to transition bursting (a behavior present only in vivo during incomplete ischemia) to gasping. Thus the juvenile rat produces a sequential pattern of responses to anoxia that are intermediate forms between those produced by neonates and those produced by adults. Time-frequency analysis determined that fast oscillations demonstrated dynamics over the course of the inspiratory burst and a state dependence similar to that of adults in vivo in which hyperpnea (and transition) bursts are associated with increases in HFO, while gasping contains no HFO. Our results confirm that both the fast oscillations in Ph activity and the coherence between Ph pairs produced by the juvenile rat are profoundly state- and temperature-dependent. respiratory control; zero interval subtraction; motor synchrony; diaphragm

In this paper, we present novel algorithms for statistically robust interpolation and approximation of diffusion tensors--which are symmetric positive definite (SPD) matrices--and use them in developing a significant extension to an existing probabilistic algorithm for scalar field segmentation, in order to segment diffusion tensor magnetic resonance imaging (DT-MRI) datasets. Using the Riemannian metric on the space of SPD matrices, we present a novel and robust higher order (cubic) continuous tensor product of B-splines algorithm to approximate the SPD diffusion tensor fields. The resulting approximations are appropriately dubbed tensor splines. Next, we segment the diffusion tensor field by jointly estimating the label (assigned to each voxel) field, which is modeled by a Gauss Markov measure field (GMMF) and the parameters of each smooth tensor spline model representing the labeled regions. Results of interpolation, approximation, and segmentation are presented for synthetic data and real diffusion tensor fields from an isolated rat hippocampus, along with validation. We also present comparisons of our algorithms with existing methods and show significantly improved results in the presence of noise as well as outfiers. Index Terms--Affine invariance, approximation, diffusion tensors, interpolation, segmentation.

BACKGROUND: In a previous study conducted at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation (CMCRC/ERF), we demonstrated for the first time that aspartame (APM) is a multipotent carcinogenic agent when various doses are administered with feed to Sprague-Dawley rats from 8 weeks of age throughout the life span. OBJECTIVE: The aim of this second study is to better quantify the carcinogenic risk of APM, beginning treatment during fetal life. METHODS: We studied groups of 70-95 male and female Sprague-Dawley rats administered APM (2,000, 400, or 0 ppm) with feed from the 12th day of fetal life until natural death. RESULTS: Our results show a) a significant dose-related increase of malignant tumor-bearing animals in males (p < 0.01), particularly in the group treated with 2,000 ppm APM (p < 0.01); b) a significant increase in incidence of lymphomas/leukemias in males treated with 2,000 ppm (p < 0.05) and a significant dose-related increase in incidence of lymphomas/leukemias in females (p < 0.01), particularly in the 2,000-ppm group (p < 0.01); and c) a significant dose-related increase in incidence of mammary cancer in females (p < 0.05), particularly in the 2,000-ppm group (p < 0.05). CONCLUSIONS: The results of this carcinogenicity bioassay confirm and reinforce the first experimental demonstration of APM&apos;s multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. Furthermore, the study demonstrates that when life-span exposure to APM begins during fetal life, its carcinogenic effects are increased. KEY WORDS: artificial sweeteners, aspartame, carcinogenicity, lymphomas/leukemias, mammary cancers, prenatal exposure, Sprague-Dawley. Environ Health Perspect 115:1293-1297 (2007). doi:10.1289/ehp.10271 available via http://dx.doi.org/ [Online 13 June 2007], Aspartame (APM) is one of the most widely used artificial sweeteners in the world. First approved by the U.S. Food and Drug Administration (FDA) for limited use in solid food [...]

Intrauterine growth restriction can lead to significant long-term health consequences such as metabolic and cardiovascular disorders, but less is known about its effects on choice and behavioral adaptation in later life. Virgin Wistar rats were time mated and randomly assigned to receive either ad-libitum access to chow or 30% of that level of nutrition during pregnancy to generate growth-restricted offspring. At 60 days of age, 6 female offspring from each group were trained on concurrent variable-interval schedules. Sessions consisted of seven randomly arranged concurrent-schedule components, each with a different reinforcer ratio that varied from 27:1 to 1:27, and each component lasting for 10 reinforcer deliveries. Behavioral change across reinforcers in components, measured by sensitivity to reinforcement, was consistently lower for offspring of undernourished mothers, showing that their behavior was less adaptable to environmental change. These results provide direct experimental evidence for a link between prenatal environmental conditions and reduced behavioral adaptability--learning--in later life.

The knowledge about consequences of marginal zinc (Zn) deficiency and Zn supplementation during pregnancy on immune function in the offspring is limited. The aim of this study was to examine whether effects of mild Zn deficiency and subsequent Zn supplementation during pregnancy persist after weaning and affect immune function of the offspring. Adult female rats were fed a Zn-adequate diet (ZC, n = 8) or a Zn-deficient diet (ZD, n = 8) from preconception through lactation. Pregnant rats were supplemented with either Zn (1.5 mg Zn in water) or placebo (water) 3 times/wk throughout pregnancy. Pups were orally immunized with cholera toxin and bovine serum albumin-dinitrophenol (DNP) 3 times at weekly intervals and killed 1 wk after the last dose. Proliferation and cytokine responses in lymphocytes from Payer's patches and spleen, and antigen specific antibodies in serum were studied. Zn supplementation of ZD dams led to enhanced lymphocyte proliferation and IFN-[gamma] responses in pups ZDZ+. In contrast, Zn supplementation of ZC dams suppressed these responses in pups ZCZ+. Total and DNP-specific IgA responses were lower in pups of the Zn-deficient group compared with the Zn-adequate group. Relative thymus weight was greater in the pups (ZDZ-) of ZD placebosupplemented dams compared with the other groups at 31 d of age. Prepregnancy and early in utero Zn deficiency affected IgA responses in pups that could not be restored with Zn supplementation during pregnancy. Zn supplementation of ZC dams induced immunosuppressive effects in utero that may also be mediated through milk and persist in the offspring after weaning.

The effects of an acute increase in intraureteral pressure (IUP) on pelvic-urethra reflex potentiation were examined in urethane-anesthetized rats by recording the external urethral sphincter electromyogram activities evoked by the pelvic afferent stimulation. Compared with a single action potential elicited by the test stimulation (TS; characterized by an intensity that evoked a constant reflex response without facilitation, 1/30 Hz, 1.03 [+ or -] 0.12 spikes/stimulation, n = 7), the repetitive stimulation [RS; identical stimulation intensity as the TS (1 Hz)] significantly induced spinal reflex potentiation (SRP; 16.90 [+ or -] 2.00 spikes/stimulation, P < 0.01, n = 7). Such SRP was significantly attenuated by intrathecal 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline [NBQX; a glutamatergic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazoleproprionat (AMPA) receptor antagonist] and D-2-amino-5-phosphonovalerate [APV; a glutamatergic N-methyl-D-aspartate (NMDA) antagonist; the spike number per stimulation: 11.0 [+ or -] 0.70 for NBQX, 1.01 [+ or -] 0.30 for APV, and 16.90 [+ or -] 2.0 for RS, respectively, n = 7, P < 0.01]. Acute stepwise elevations of IUP gradually attenuated and eventually abolished the RS-induced SRP (16.80 [+ or -] 1.30, 17.00 [+ or -] 1.30, 16.30 [+ or -] 1.30, 10.50 [+ or -] 1.80, 8.80 [+ or -] 1.90, 3.50 [+ or -] 1.60, 0.80 [+ or -] 0.20, 0.70 [+ or -] 0.20, and 0.20 [+ or -] 0.10 spikes/stimulation at intraureteral pressure of 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 cm[H.sub.2]O, respectively, n = 7). Intrathecal NMDA (a glutamatergic NMDA receptor agonist) and bicuculline (a GABA receptor antagonist) both reversed the abolition of RS-induced SRP caused by unilateral ureteral distension (14.0 + or -] 4.04 and 8.00 [+ or -] 1.53 spikes/stimulation, respectively, n = 7, P < 0.01). All the results suggested unilateral ureteral distension might compensatorily relax the urethra via GABAergic inhibition of NMDA-dependent SRP. intraureteral pressure; unilateral ureteral obstruction; spinal reflex potentiation; N-methyl-D-aspartic acid

Prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. Although an increase in tubular sodium reabsorption has been postulated to be a factor programming hypertension, this has never been directly demonstrated. The purpose of this study was to examine whether prenatal programming by dexamethasone affected postnatal proximal tubular transport. Pregnant Sprague-Dawley rats were injected with intraperitoneal dexamethasone (0.2 mg/kg) daily for 4 days between the 15th and 18th days of gestation. Prenatal dexamethasone resulted in an elevation in systolic blood pressure when the rats were studied at 7-8 wk of age compared with vehicle-treated controls: 131 [+ or -] 3 vs. 115 [+ or -] 3 mmHg (P < 0.001). The rate of proximal convoluted tubule volume absorption, measured using in vitro microperfusion, was 0.61 + 0.07 nl * [mm.sup.-1] * [min.sup.-1] in control rats and 0.93+ 0.07 nl * [mm-.sup.-1] * [min.sup.-1] in rats that received prenatal dexamethasone (P < 0.05). [Na.sup.+]/[H.sup.+] exchanger activity measured in perfused tubules in vitro using the pH-sensitive dye BCECF showed a similar 50% increase in activity in proximal convoluted tubules from rats treated with prenatal dexamethasone. Although there was no change in abundance of NHE3 mRNA, the predominant luminal proximal tubule [Na.sup.+]/[H.sup.+] exchanger, there was an increase in NHE3 protein abundance on brush-border membrane vesicles in 7- to 8-wk-old rats receiving prenatal dexamethasone. In conclusion, prenatal administration of dexamethasone in rats increases proximal tubule transport when rats are studied at 7-8 wk old, in part by stimulating [Na.sup.+]/[H.sup.+] exchanger activity. The increase in proximal tubule transport may be a factor mediating the hypertension by prenatal programming with dexamethasone. NHE3; in vitro microperfusion; volume absorption; acidification

Activation of the hypothalamic-pituitary-adrenal (HPA) axis and augmented plasma and tissue levels of IL-6 are hallmarks of heart failure (HF). Within the forebrain, cardiovascular homeostasis is mediated in part by the paraventricular nucleus (PVN) of the hypothalamus. IL-6, via binding to the IL-6 receptor (IL-6R)/glycoprotein 130 (gp130) complex influences cellular and physiological responses. Thus, in the current study, we hypothesized that PVN IL-6R protein and gene expression are upregulated in HF vs. sham-operated rats, whereas gp130 levels in the same tissues remain stable. Six weeks after coronary ligation surgery, hemodynamic measurements were obtained, and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices. Plasma IL-6 levels were determined and changes in gene and protein expression of IL-6R and gp130 between sham-operated and HF rats were determined via real-time PCR and Western blot analyses, respectively. Plasma levels of IL-6 were elevated in rats with severe, but not moderate, HF compared with sham-operated controls. In both moderate and severe HF rats, protein but not gene expression of IL-6R was significantly increased in PVN tissue but not in non-PVN tissue, compared with sham-operated controls. Gene and protein levels of the gp130 subunit were not altered by HF in either tissue analyzed. Collectively, these data suggest that within the brain of HF rats, IL-6R expression is not a global change. Rather the increased IL-6 levels characteristic of HF may alter PVN-mediated physiological responses via enhanced expression of the IL-6R. signal transduction; gp130; hypothalamic-pituitary axis

We reported previously that glycerol is a substrate for energy production in cardiomyocytes. Increasing glycerol availability results in increased glycerol uptake and its involvement in complex lipid biosynthesis and energy production. This study evaluated the relationship between glycerol supply, energy demand, and intermediary metabolism leading to energy production. The work was performed on isolated rat heart perfused in the working mode. Glycerol concentrations modeled the fasting (0.33 mM) and fed (3.33 mM) states. Cardiac energy demand was modeled by increasing heart rate from 350 to 450 beats/min (bpm). Increasing glycerol supply increased glycerol uptake from 1.4 (350 bpm) to 3.8 (450 bpm) and from 9.7 (350 bpm) to 34.2 (450 bpm) [micro]mol glycerol/heart in 30 min at 0.33 and 3.33 mM glycerol, respectively. At low glycerol supply, increasing heart rate did not influence the complex lipid synthesis. Conversely, high glycerol concentration increased the complex lipid synthesis by 5- and 30-fold at 350 and 450 bpm, respectively. Increasing glycerol supply and heart rate significantly increased glycerol oxidation rate. Moreover, increasing glycerol supply did not affect glucose oxidation but increased palmitate uptake and significantly decreased its [beta]-oxidation. Physiological concentrations of glycerol contribute to the cardiac intermediary metabolism, both for energy production and glycerolipid synthesis. Increasing energy demand enhances the requirement and use of glycerol. Glycerol contributes to the regulation of cardiac metabolism and energy balance, mainly by decreasing the contribution of fatty acid oxidation, and may thus represent a new factor in cardiac protection through the reduction of oxygen demand. [beta]-oxidation; phospholipids; glucose; palmitate; energy metabolism

Estrogen deficiency impairs intestinal Ca absorption and induces bone loss, but its effects on the vitamin D-endocrine system are unclear. In the present study, calciotropic hormones levels, renal vitamin D metabolism, 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]]-dependent intestinal calcium absorption, and bone properties in 3-too-old sham-operated (sham) or ovariectomized (OVX) rats fed either a normal-Ca (NCD; 0.6% Ca, 0.65% P) or a low-Ca (LCD; 0.1% Ca, 0.65% P) diet for 2 wk were determined. LCD increased serum 1,25[(OH).sub.2][D.sub.3] levels in both sham and OVX rats. Serum parathyroid hormone [PTH(1-84)] levels were highest in OVX rats fed LCD. Renal 25-hydroxyvitamin D1[alpha]-hydroxylase (1-OHase) protein expression was induced in both sham and OVX rats during LCD, while renal 1-OHase mRNA expression was highest in OVX rats fed LCD. Renal vitamin D receptor (VDR) and mRNA expressions in rats were induced by ovariectomy in rats fed NCD but suppressed by ovariectomy in rats fed LCD. The induction of intestinal calcium transporter-1 and calbindin-D9k mRNA expressions by LCD were not altered by ovariectomy. As expected, bone Ca content, cancellous bone mineral density, and bone strength index in proximal metaphysis of rat tibia were reduced by both ovariectomy and LCD (P < 0.05) as analyzed by two-way ANOVA. Taken together, the data demonstrate that ovariectomy alters the responses of circulating PTH levels, renal 1-OHase mRNA expression, and renal VDR expression to LCD. These results suggest that estrogen is necessary for the full adaptive response to LCD mediated by both PTH and 1,25[(OH).sub.2][D.sub.3]. parathyroid hormone ; renal vitamin D receptor; renal 25-hydroxyvitamin D1[alpha]-hydroxylase; dietary Ca restriction

Angiotensin II (ANG II) plays an important role in the development of obstructive nephropathy. Here, we examined the effects of the ANG II receptor type 1 (AT1R) blockade using candesartan on long-term renal molecular and functional changes in response to partial unilateral ureteral obstruction (PUUO). Newborn rats were subjected to severe PUUO or sham operation (Sham) within the first 48 h of life. Candesartan was provided in the drinking water (10 mg*[kg.sup.-1]*[day.sup.-1]) from day 21 of life until 10 wk of age. Renal blood flow (RBF) was evaluated by MRI, glomerular filtration rate (GFR) was measured using the renal clearance of [.sup.51]Cr-EDTA, and the renal expression of Na-K-ATPase and the collecting duct water channel aquaporin-2 (AQP2) was examined by immunoblotting and immunocytochemistry. At 10 wk of age, PUUO significantly reduced RBF (0.8 [+ or -] 0.1 vs. 1.6 [+ or -] 0.1 ml*[min.sup.-1]*100 g body [wt.sup.-1]; p < 0.05) and GFR (37 [+ or -] 16 vs. 448 [+ or -] 111 [micro]l*[min.sup.-1]*100 g body [wt.sup.-1]; P < 0.05) compared with Sham. Candesartan prevented the RBF reduction (PUUO+CAN: 1.6 [+ or -] 0.2 vs. PUUO: 0.8 [+ or -] 0.1 ml*[min.sup.-1]*100 g body [wt.sup.-1]; p < 0.05) and attenuated the GFR reduction (PUUO+CAN: 265 [+ or -] 68 vs. PUUO: 37 [+ or -] 16 [micro]l*[min.sup.-1]*100 g body [wt.sup.-1]; P < 0.05). PUUO was also associated with a significant downregulation in the expression of Na-K-ATPase (75 [+ or -] 12 vs. 100 [+ or -] 5%, P < 0.05) and AQP2 (52 [+ or -] 15 vs. 100 [+ or -] 4%, P < 0.05), which were also prevented by candesartan (Na-K-ATPase: 103 [+ or -] 8 vs. 100 [+ or -] 5% and AQP2: 74 [+ or -] 13 vs. 100 [+ or -] 4%). These findings were confirmed by immunocytochemistry. Consistent with this, candesartan treatment partly prevented the reduction in solute free water reabsorption and attenuated fractional sodium excretion in rats with PUUO. In conclusion, candesartan prevents or attenuates the reduction in RBF, GFR and dysregulation of AQP2 and Na-K-ATPase in response to congenital PUUO in rats, suggesting that AT1R blockade may protect the neonatally obstructed kidney against development of obstructive nephropathy. congenital ureteral obstruction; newborn rat; aquaporin water channels; sodium transporter; A[T.sub.1] receptor blockage

The rat streptozotocin (STZ)-induced diabetes model is widely used to investigate the pathogenesis of diabetic nephropathy. However, overt nephropathy is inexplicably slow to develop in this model compared with renal mass reduction (RMR) models. To examine whether blood pressure (BP) differences correlated with the time course of glomerulosclerosis (GS), BP was measured continuously throughout the course by radiotelemetry in control (n = 17), partially insulin-treated STZ-diabetes (average blood glucose 364 [+ or -] 15 mg/dl; n = 15), and two normotensive RMR models (systolic BP < 140 mmHg)--uninephrectomy (UNX; n = 16) and 3/4 RMR by surgical excision [right nephrectomy + excision of both poles of left kidney (RK-NX); n = 12] in Sprague-Dawley rats. Proteinuria and GS were assessed at ~16-20 wk (all groups) and at 36-40 wk (all groups except RK-NX). At 16 wk, significantly greater proteinuria and GS had developed in the RK-NX group compared with the other three groups (not different from each other). By 36-40 wk, substantial proteinuria and GS had also developed in the UNX group, but both the control and the STZ-diabetic rats exhibited comparable modest proteinuria and minimal GS. Systolic BP (mmHg) was significantly reduced in the STZ-diabetic rats (116 [+ or -] 1.1) compared with both control (124 [+ or -] 1.0) and RMR (128 [+ or -] 1.2 and 130 [+ or -] 3.0) groups (P < 0.01). Similarly, 'BP load' as estimated by BP power spectral analysis was also lower in the STZ-diabetic rats. Given the known protective effects of BP reductions on the progression of diabetic nephropathy, it is likely that this spontaneous reduction in ambient BP contributes to the slow development of GS in the STZ-diabetes model compared with the normotensive RMR models. radiotelemetry; glomerulosclerosis; remnant kidney; hyperfiltration

Normal rat pregnancy is characterized by plasma volume expansion due to renal sodium retention and is associated with a blunted response to natriuretic stimuli, such as atrial natriuretic peptide (ANP). ANP signals via cGMP, and phosphodiesterases (PDE) inactivate cGMP and terminate the natriuretic response. We previously repotted that increased medullary PDE-5 activity occurs in rat pregnancy, which may be the mechanism of the blunted natriuretic effect of ANP. Here, we used anesthetized 16-day pregnant and virgin rats to investigate whether intrarenal infusion of a selective PDE-5 inhibitor, sildenafil, would reverse the blunted response to ANP in pregnancy. We measured blood pressure, renal clearances using inulin and p-aminohippuric acid, and electrolyte excretion at baseline and during an ANP infusion. ANP caused a fall in mean arterial pressure in all groups, and sildenafil induced a further reduction. We observed an increase in sodium excretion with ANP in all rats, but this was blunted in the vehicle-infused pregnant rats. This could not be explained by differences in renal hemodynamics and was of tubular origin, as reflected by the reduced rise in fractional excretion of sodium with ANP in the pregnant rat given vehicle (45 [+ or -] 11 vs. 204 [+ or -] 49%; P < 0.05). However, intrarenal sildenafil increased the natriuretic response and the rise in fractional excretion of sodium to the virgin value (226 [+ or -] 23 vs. 245 [+ or -] 73%; not significant), whereas the blunting persisted in the contralateral kidney. This demonstrates that increased intrarenal PDE-5 mediates the blunted natriuretic response to ANP during pregnancy and may contribute to the physiological volume expansion. plasma volume; sodium retention; cGMP; hormone signaling; hormone resistance

Female mice lacking AR display alterations in ovarian and uterine function. However, the biology of AR in the fallopian tube is not fully understood. To gain an insight into potential roles of AR in this tissue, we demonstrated that eCG treatment increased AR expression in a time-dependent manner and subsequent treatment with hCG decreased AR expression in mouse fallopian tubes. This expression pattern was positively associated with 17[beta]-estradiol and testosterone levels in vivo. Immunohistochemical analysis of fallopian tube epithelial cells revealed that nuclear localization of AR increased in parallel with decreased AR in the cytoplasm following eCG treatment. Moreover, we found that treatment with flutamide upregulated AR expression in immature mice in association with a decrease in serum testosterone levels, whereas the same treatment resulted in downregulation of AR expression in gonadotropin-stimulated mice with concomitant decreases in serum 17[beta]-estradiol concentrations, suggesting that androgen differs from estrogen in the regulation of AR expression. Furthermore, we demonstrated that DES increased both AR protein expression and nuclear location over a 48-h time course. DHT had rapid effects, with induction of AR expression and translocation at 6 h after injection, but unlike DES it had prolonged efficacy. In addition, we provided direct in vivo evidence that nuclear protein interaction between AR and [p21.sup.Cip1], a previously reported AR-regulated gene, was enhanced by gonadotropin stimulation. To our knowledge, this study provides the first demonstration to illustrate that estrogen as a principal regulator may contribute to regulate and activate AR in the fallopian tubes in vivo. androgen receptor; gonadotropins

ABSTRACT Background Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established [...]