Variabilité des concentrations plasmatiques de l'angiotensinogène et risque d'hypertension artérielle chez le rat transgénique [Variability of plasma angiotensinogen levels and risk of hypertension in a transgenic rat model].

AIM: Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors. METHODS: Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction). RESULTS: At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05). CONCLUSION: Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Limited role of the c-Jun N-terminal kinase pathway in a neonatal rat model of cerebral hypoxia-ischemia

D-JNKI1, a cell-permeable peptide inhibitor of the c-Jun N-terminal kinase (JNK) pathway, has been shown to be a powerful neuroprotective agent after focal cerebral ischemia in adult mice and young rats. We have investigated the potential neuroprotective effect of D-JNKI1 and the involvement of the JNK pathway in a neonatal rat model of cerebral hypoxia-ischemia. Seven-day-old rats underwent a permanent ligation of the right common carotid artery followed by 2h of hypoxia (8% oxygen). Treatment with D-JNKI1 (0.3mg/kg intraperitoneally) significantly reduced early calpain activation, late caspase-3 activation and, in the thalamus, autophagosome formation, indicating an involvement of JNK in different types of cell death: necrotic, apoptotic and autophagic. However the size of the lesion was unchanged. Further analysis showed that neonatal hypoxia-ischemia induced an immediate decrease in JNK phosphorylation (reflecting mainly P-JNK1) followed by a slow progressive increase (including P-JNK3 54kDa), whereas c-jun and c-fos expression were both strongly activated immediately after hypoxia-ischemia. In conclusion, unlike in adult ischemic models, JNK is only moderately activated after severe cerebral hypoxia-ischemia in neonatal rats and the observed positive effects of D-JNKI1 are insufficient to give neuroprotection. Thus, for perinatal asphyxia, D-JNKI1 can only be considered in association with other therapies.

Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure.

Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed.

Impact of body tilt on the central aortic pressure pulse.

The present work was undertaken to investigate, in young healthy volunteers, the relationships between the forward propagation times of arterial pressure waves and the timing of reflected waves observable on the aortic pulse, in the course of rapid changes in body position. 20 young healthy subjects, 10 men, and 10 women, were examined on a tilt table at two different tilt angles, -10° (Head-down) and + 45° (Head-up). In each position, carotid-femoral (Tcf) and carotid-tibial forward propagation times (Tct) were measured with the Complior device. In each position also, the central aortic pressure pulse was recorded with radial tonometry, using the SphygmoCor device and a generalized transfer function, so as to evaluate the timing of reflected waves reaching the aorta in systole (onset of systolic reflected wave, sT1r) and diastole (mean transit time of diastolic reflected wave, dMTT). The position shift from Head-up to Head-down caused a massive increase in both Tct (women from 130 ± 10 to 185 ± 18 msec P < 0.001, men from 136 ± 9 to 204 ± 18 msec P < 0.001) and dMTT (women from 364 ± 35 to 499 ± 33 msec P < 0.001, men from 406 ± 22 to 553 ± 21 msec P < 0.001). Mixed model regression showed that the changes in Tct and dMTT observed between Head-up and Head-down were tightly coupled (regression coefficient 2.1, 95% confidence interval 1.9-2.3, P < 0.001). These results strongly suggest that the diastolic waves observed on central aortic pulses reconstructed from radial tonometric correspond at least in part to reflections generated in the lower limbs.

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Fingermarks and Other Impressions Left by the Human Body - A Review (August 2007-July 2010)

The purpose of this paper is to review the scientific literature from August 2007 to July 2010. The review is focused on more than 420 published papers. The review will not cover information coming from international meetings available only in abstract form. Fingermarks constitute an important chapter with coverage of the identification process as well as detection techniques on various surfaces. We note that the research has been very dense both at exploring and understanding current detection methods as well as bringing groundbreaking techniques to increase the number of marks detected from various objects. The recent report from the US National Research Council (NRC) is a milestone that has promoted a critical discussion on the state of forensic science and its associated research. We can expect a surge of interest in research in relation to cognitive aspect of mark and print comparison, establishment of relevant forensic error rates and statistical modelling of the selectivity of marks' attributes. Other biometric means of forensic identification such as footmarks or earmarks are also covered in the report. Compared to previous years, we noted a decrease in the number of submission in these areas. No doubt that the NRC report has set the seed for further investigation of these fields as well.

Immunocytochemical localisation of microtubule-associated proteins 1b and 2 in the developing rat spinal cord.

The straightforward anatomical organisation of the developing and mature rat spinal cord was used to determine and interpret the time of appearance and expression patterns of microtubule-associated proteins (MAP) 1b and 2. Immunoblots revealed the presence of MAP1b and 2 in the early embryonic rat spinal cord and confirmed the specificity of the used anti-MAP mouse monoclonal antibodies. The immunocytochemical data demonstrated a rostral-to-caudal and ventral-to-dorsal gradient in the expression of MAP1b/2 within the developing spinal cord. In the matrix layer, MAP1b was found in a distinct radial pattern distributed between the membrana limitans interna and externa between embryonal day (E)12 and E15. Immunostaining for vimentin revealed that this MAP1b pattern was morphologically and topographically different from the radial glial pattern which was present in the matrix layer between E13 and E19. The ventral-to-dorsal developmental gradient of the MAP1b staining in the spinal cord matrix layer indicates a close involvement of MAP1b either in the organisation of the microtubules in the cytoplasmatic extensions of the proliferating neuroblasts or neuroblast mitosis. MAP2 could not be detected in the developing matrix layer. In the mantle and marginal layer, MAP1b was abundantly present between E12 and postnatal day (P)0. After birth, the staining intensity for MAP1b gradually decreased in both layers towards a faint appearance at maturity. The distribution patterns suggest an involvement of MAP1b in the maturation of the motor neurons, the contralaterally and ipsilaterally projecting axons and the ascending and descending long axons of the rat spinal cord. MAP2 was present in the spinal cord grey matter between E12 and maturity, which reflects a role for MAP2 in the development as well as in the maintenance of microtubules. The present description of the expression patterns of MAP1b and 2 in the developing spinal cord suggests important roles of the two proteins in various morphogenetic events. The findings may serve as the basis for future studies on the function of MAP1b and 2 in the development of the central nervous system.

Intraseasonal variation in immune defence, body mass and hematocrit in adult house martins Delichon urbica

The intensity of parasite infections often increases during the reproductive season of the host as a result of parasite reproduction, increased parasite transmission and increased host susceptibility. We report within-individual variation in immune parameters, hematocrit and body mass in adult house martins Delichon urbica rearing nestlings in nests experimentally infested with house martin bugs Oeciacus hirundinis and birds rearing nestlings in initially parasite-free nests. From first to second broods body mass and hematocrit of breeding adult house martins decreased. In contrast leucocytes and immunoglobulins became more abundant. When their nests were infested with ectoparasites adults lost more weight compared with birds raising nestlings in nests treated with pyrethrin, whereas the decrease in hematocrit was more pronounced during infection with blood parasites. Neither experimental infestation with house martin bugs nor blood parasites had a significant effect on the amount of immune defences.

Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia.

A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.

Relationship of physical activity with motor skills, aerobic fitness and body fat in preschool children: a cross-sectional and longitudinal study (Ballabeina).

Adiposity, low aerobic fitness and low levels of activity are all associated with clustered cardiovascular disease risk in children and their high prevalence represents a major public health concern. The aim of this study is to investigate the relationship of objectively measured physical activity (PA) with motor skills (agility and balance), aerobic fitness and %body fat in young children. This study is a cross-sectional and longitudinal analyses using mixed linear models. Longitudinal data were adjusted for baseline outcome parameters. In all, 217 healthy preschool children (age 4-6 years, 48% boys) participated in this study. PA (accelerometers), agility (obstacle course), dynamic balance (balance beam), aerobic fitness (20-m shuttle run) and %body fat (bioelectric impedance) at baseline and 9 months later. PA was positively associated with both motor skills and aerobic fitness at baseline as well as with their longitudinal changes. Specifically, only vigorous, but not total or moderate PA, was related to changes in aerobic fitness. Higher PA was associated with less %body fat at baseline, but not with its change. Conversely, baseline motor skills, aerobic fitness or %body fat were not related to changes in PA. In young children, baseline PA was associated with improvements in motor skills and in aerobic fitness, an important determinant of cardiovascular risk.

Cells with neuronal characteristics differentiate and persist for one year in rat optic nerve explants cultures.

Evidence concerning the presence or absence of common neuronglia lineages in the postnatal mammalian central nervous system is still a matter of speculation. We address this problem using optic nerve explants, which show an extremely long survival in culture. Morphological, immunocytochemical and immunochemical methods were applied. The results obtained from in vitro tissue were compared with optic nerves (ONs) and whole-brain samples from animals of different ages. Newborn rat ONs represented the starting material of our tissue culture; they are composed of unmyelinated axons, astrocytes and progenitor cells but devoid of neuronal cell bodies. At this age, Western blots of ONs were positively stained by neurofilament and synapsin I specific antibodies. These bands increased in intensity during postnatal in situ development. In explant cultures, the glia cells reach a stage of functional differentiation and they maintain, together with undifferentiated cells, a complex histotypic organization. After 6 days in vitro, neurofilaments and synapsin I could not be detected on immunoblots, indicating that 1) axonal degeneration was completed, and 2) neuronal somata were absent at the time. Surprisingly, after about 4-5 weeks in culture, a new cell type appeared, which showed characteristics typical of neurons. After 406 days in vitro, neurofilaments and synapsin I were unequivocally detectable on Western blots. Furthermore, both immunocytochemical staining and light and electron microscopic examinations corroborated the presence of this earlier-observed cell type. These in vitro results clearly show the high developmental plasticity of ON progenitor cells, even late in development. The existence of a common neuron-glia precursor, which never gives rise to neurons in situ, is suggested.

Morphogenesis of the ureterovesical junction:a histologic and microanatomic study in the rat.

OBJECTIVES: To investigate the development of the ureterovesical junction in rats. METHODS: A total of 110 albino rats (50 prenatal and 60 newborn) with a gestation of 21 days were studied at the age of 17 days after conception until 5 days after birth. The lower urinary tract was microdissected. Microphotography (110 animals), histologic examination (44 animals), and scanning electron microscopy (66 animals) of the ureterovesical junction were performed. Urea and creatinine from the amniotic fluid of 20 fetuses and from the urine of 10 neonates were measured. RESULTS: At day 17 after conception, separate penetration of the mesonephric duct and ureter into the wall of the urogenital sinus was observed. Continuity between the lumen of the ureter and the urogenital sinus was established on day 19 after conception. The straight passage of the intramural ureter into the urogenital sinus at day 17 after conception changed to the definitive L-shape with a vertical entry into the bladder on day 5 after birth. In the distal ureter, the change of the mesenchymal tissue into immature smooth muscle was first observed at birth, and the muscle became mature on the fifth postnatal day. At birth, Waldeyer's sheath was recognized. The creatinine and urea levels were stable prenatally (average 22.4 micromol/L and 6.88 mmol/L, respectively) and rose significantly postnatally (average 133 micromol/L and 32.65 mmol/L, respectively). CONCLUSIONS: The attachment of the ureter to the urogenital sinus and later to the bladder, the modification of its passage, and its mobility within Waldeyer's sheath may be essential in preventing vesicoureteral reflux. The production of urine and its flow does not seem to be the trigger of ureteral smooth muscle formation.

Metoprolol prevents sodium retention induced by lower body negative pressure in healthy men.

BACKGROUND: Lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal systems, and a renal tubular and hemodynamic response that mimics the renal adaptation observed in congestive heart failure (CHF). As beta-blockers play an important role in the management of CHF patients, the effects of metoprolol on the renal response were examined in healthy subjects during sustained LBNP. METHODS: Twenty healthy male subjects were randomized in this double blind, placebo versus metoprolol 200 mg once daily, study. After 10 days of treatment, each subject was exposed to 3 levels of LBNP (0, -10, and -20 mbar) for 1 hour, each level of LBNP being separated by 2 days. Neurohormonal profiles, systemic and renal hemodynamics, as well as renal sodium handling were measured before, during, and after LBNP. RESULTS: Blood pressure and heart rate were significantly lower in the metoprolol group throughout the study (P < 0.01). GFR and RPF were similar in both groups at baseline, and no change in renal hemodynamic values was detected at any level of LBNP. However, a reduction in sodium excretion was observed in the placebo group at -20 mbar, whereas no change was detected in the metoprolol group. An increase in plasma renin activity was also observed at -20 mbar in the placebo group that was not observed with metoprolol. CONCLUSION: The beta-blocker metoprolol prevents the sodium retention induced by lower body negative pressure in healthy subjects despite a lower blood pressure. The prevention of sodium retention may be due to a blunting of the neurohormonal response. These effects of metoprolol on the renal response to LBNP may in part explain the beneficial effects of this agent in heart failure patients.

Neuroendocrine, metabolic, and immune functions during the acute phase response of inflammatory stress in monosodium L-glutamate-damaged, hyperadipose male rat.

In rats, neonatal treatment with monosodium L-glutamate (MSG) induces several metabolic and neuroendocrine abnormalities, which result in hyperadiposity. No data exist, however, regarding neuroendocrine, immune and metabolic responses to acute endotoxemia in the MSG-damaged rat. We studied the consequences of MSG treatment during the acute phase response of inflammatory stress. Neonatal male rats were treated with MSG or vehicle (controls, CTR) and studied at age 90 days. Pituitary, adrenal, adipo-insular axis, immune, metabolic and gonadal functions were explored before and up to 5 h after single sub-lethal i.p. injection of bacterial lipopolysaccharide (LPS; 150 microg/kg). Our results showed that, during the acute phase response of inflammatory stress in MSG rats: (1) the corticotrope-adrenal, leptin, insulin and triglyceride responses were higher than in CTR rats, (2) pro-inflammatory (TNFalpha) cytokine response was impaired and anti-inflammatory (IL-10) cytokine response was normal, and (3) changes in peripheral estradiol and testosterone levels after LPS varied as in CTR rats. These data indicate that metabolic and neroendocrine-immune functions are altered in MSG-damaged rats. Our study also suggests that the enhanced corticotrope-corticoadrenal activity in MSG animals could be responsible, at least in part, for the immune and metabolic derangements characterizing hypothalamic obesity.

Body-mass index and mortality.

Comment on: Prospective Studies Collaboration, Whitlock G, Lewington S et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083-96. PMID: 19299006.