Inhibitory effect of neuropeptide Y on stimulated renin secretion of awake rats.

1. (1-36)-NPY is a vasoconstrictor peptide widely distributed in sympathetic nerve terminals. This peptide exerts an inhibitory action on renin release induced by various stimuli. Post-synaptic neuropeptide Y (NPY) receptors show a high affinity for (1-36)-NPY as well as for the agonist (Pro34)-NPY, while presynaptic receptors bind preferentially (13-36)-NPY. 2. This study was undertaken to assess whether the NPY induced renin suppression in awake normotensive rats infused with the beta-adrenoceptor stimulant isoproterenol is mediated by activation of pre- or post-synaptic receptors. 3. Non-pressor doses of (1-36)-NPY and (Pro34)-NPY markedly attenuated the renin secretion triggered by isoproterenol whereas (13-36)-NPY had no effect. This suggests that the effect of NPY on renin release is due to the stimulation of post-synaptic receptors. However it remains unknown whether NPY acts directly on juxtaglomerular cells or indirectly by modifying intraglomerular haemodynamics.

rKv1.2 overexpression in the central medial thalamic area decreases caffeine-induced arousal.

The voltage-gated potassium channel Kv1.2 belongs to the shaker-related family and has recently been implicated in the control of sleep profile on the basis of clinical and experimental evidence in rodents. To further investigate whether increasing Kv1.2 activity would promote sleep occurrence in rats, we developed an adeno-associated viral vector that induces overexpression of rat Kv1.2 protein. The viral vector was first evaluated in vitro for its ability to overexpress rat Kv1.2 protein and to produce functional currents in infected U2OS cells. Next, the adeno-associated Kv1.2 vector was injected stereotaxically into the central medial thalamic area of rats and overexpression of Kv1.2 was showed by in situ hybridization, ex vivo electrophysiology and immunohistochemistry. Finally, the functional effect of Kv1.2 overexpression on sleep facilitation was investigated using telemetry system under normal conditions and following administration of the arousing agent caffeine, during the light phase. While no differences in sleep profile were observed between the control and the treated animals under normal conditions, a decrease in the pro-arousal effect of caffeine was seen only in the animals injected with the adeno-associated virus-Kv1.2 vector. Overall, our data further support a role of the Kv1.2 channel in the control of sleep profile, particularly under conditions of sleep disturbance.

Iridocyclectomy for neovascular glaucoma caused by proton-beam radiotherapy of pigmented ciliary adenocarcinoma.

PURPOSE: To report neovascular glaucoma after proton-beam radiotherapy of an adenocarcinoma of the pigmented ciliary epithelium and its successful treatment by iridocyclectomy. PATIENT AND METHODS: A 65-year-old man developed neovascular glaucoma 10 months after proton-beam radiotherapy of a small pigmented iridociliary tumour with a clinical differential diagnosis of uveal melanoma or adenocarcinoma. The diagnosis of 'toxic tumour syndrome' was made, and iridocyclectomy performed. RESULTS: Histopathology and immunohistochemistry of the specimen diagnosed an adenocarcinoma of the pigmented ciliary epithelium, with the presence of mitoses suggesting residual viable tumour cells. The rubeosis regressed, with normalization of the intraocular pressure. Phacoemulsification for radiation-induced cataract restored VA to 6/9, which was better than that recorded at initial referral, the patient having longstanding cellophane maculopathy. CONCLUSIONS: Neovascular glaucoma after radiotherapy of a small, pigmented, ciliary body tumour raises the possibility of adenocarcinoma. This 'toxic tumour syndrome' may respond to iridocyclectomy of the irradiated tumour.

Experience with angiotensin II antagonists in hypertensive patients.

1. The availability of orally active specific angiotensin receptor antagonists (AT1 antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT1 antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.

Impaired glucose tolerance and diabetes in obesity: a 6-year follow-up study of glucose metabolism.

To investigate the time course of glucose metabolism in obesity 33 patients (21 to 69 years old; body mass index [BMI], 25.7 to 53.3 kg/m2) with different degrees of glucose intolerance or diabetes who had been studied initially and 6 years later were submitted to the same 100-g oral glucose tolerance test (OGTT) with indirect calorimetry. From a group of 13 obese subjects with normal glucose tolerance (NGT), four developed impaired glucose tolerance (IGT); from a group of nine patients with IGT, three developed non-insulin-dependent diabetes mellitus (NIDDM); five of six obese NIDDM subjects with high insulin response developed NIDDM with low insulin response. Five patients had diabetes with hypoinsulinemia initially. As previously seen in a cross-sectional study, the 3-hour glucose storage measured by continuous indirect calorimetry remained unaltered in patients with IGT, whereas it decreased in NIDDM patients. A further decrease in glucose storage was observed with the lowering of the insulin response in the previously hyperinsulinemic diabetics. These results confirm cross-sectional studies that suggest successive phases in the evolution of obesity to diabetes: A, NGT; B, IGT (the hyperglycemia normalizing the glucose storage over 3 hours); C, diabetes with increased insulin response, where hyperglycemia does not correct the resistance to glucose storage anymore; and D, diabetes with low insulin response, with a low glucose storage and an elevated fasting and postload glycemia.

Developing psychosis and its risk States through the lens of schizotypy.

Starting from the early descriptions of Kraepelin and Bleuler, the construct of schizotypy was developed from observations of aberrations in nonpsychotic family members of schizophrenia patients. In contemporary diagnostic manuals, the positive symptoms of schizotypal personality disorder were included in the ultra high-risk (UHR) criteria 20 years ago, and nowadays are broadly employed in clinical early detection of psychosis. The schizotypy construct, now dissociated from strict familial risk, also informed research on the liability to develop any psychotic disorder, and in particular schizophrenia-spectrum disorders, even outside clinical settings. Against the historical background of schizotypy it is surprising that evidence from longitudinal studies linking schizotypy, UHR, and conversion to psychosis has only recently emerged; and it still remains unclear how schizotypy may be positioned in high-risk research. Following a comprehensive literature search, we review 18 prospective studies on 15 samples examining the evidence for a link between trait schizotypy and conversion to psychosis in 4 different types of samples: general population, clinical risk samples according to UHR and/or basic symptom criteria, genetic (familial) risk, and clinical samples at-risk for a nonpsychotic schizophrenia-spectrum diagnosis. These prospective studies underline the value of schizotypy in high-risk research, but also point to the lack of evidence needed to better define the position of the construct of schizotypy within a developmental psychopathology perspective of emerging psychosis and schizophrenia-spectrum disorders.

Double-blind comparison of indapamide with a placebo in hypertensive patients treated by practicing physicians.

The antihypertensive effect of indapamide (2.5 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by 11 physicians in their private practice. Thirty-one patients with uncomplicated essential hypertension were included. After a run-in period of 3 weeks without any treatment, either indapamide (n = 16) or a placebo (n = 15) were administered for 8 weeks in double-blind fashion. Blood pressure decreased in both groups. In patients treated with indapamide, systolic pressure was significantly lower than in those given the placebo at 3 out of the 4 follow-up visits; diastolic pressure, however, was significantly lower only at the end of the trial. Both the active drug and the placebo were well tolerated. No significant change in body weight, plasma potassium and uric acid occurred during the study in either group of patients. It appears therefore that indapamide, at a dose which apparently has no major diuretic effect, may be useful for practitioners in managing patients with mild to moderate hypertension.

Association of moderate alcohol use and binge drinking during pregnancy with neonatal health.

Background:  Heavy drinking and smoking during pregnancy are known to have a negative impact on the unborn child. However, the impact of low-to-moderate alcohol consumption and binge drinking has been debated recently. The aim of this study was to examine the relationship of moderate prenatal drinking and binge drinking with birthweight, being small for gestational age (SGA) at birth, preterm birth, and neonatal asphyxia. Methods:  Moderate alcohol drinking, binge drinking, and several possible confounders were assessed in 1,258 pregnant women; information on neonatal health was obtained at birth. Results:  Results indicate that 30.8% of the women drank at low levels (<2 glasses/wk), 7.9% drank moderately (2 to 4 glasses/wk), and 0.9% showed higher levels of drinking (≥5 glasses/wk); 4.7% reported binge drinking (defined as ≥3 glasses/occasion). 6.4% of the children were SGA (<10th percentile of birthweight adjusted for gestational age), 4.6% were preterm (<37th week of gestation), and 13.0% showed asphyxia (arterial cord pH <7.10 and/or arterial cord lactate >6.35 mmol and/or Apgar score <7 at 5 minutes). When controlling for maternal age, citizenship, occupational status, parity, smoking, use of prescription/over-the-counter drugs, illicit drug use, and child gender moderate drinking was related to lower birthweight (p < 0.01), and moderate drinking and binge drinking were associated with neonatal asphyxia at trend level (p = 0.06 and p = 0.09). Moderate drinking and binge drinking were not related to length of gestation. Conclusions:  In contrast to recent reviews in the field, our results assume that moderate drinking and binge drinking are risk factors for neonatal health.

Effect of amino acids and glucose on exercise-induced gut and skeletal muscle proteolysis in dogs.

The effect of amino acid and/or glucose administration before and during exercise on protein metabolism in visceral tissues and skeletal muscle was examined in mongrel dogs. The dogs were subjected to treadmill running (150 minutes at 10 km/h and 12% incline) and intravenously infused with a solution containing amino acids and glucose (AAG), amino acids (AA), glucose (G) or saline (S) in randomized order. The infusion was started 60 minutes before exercise and continued until the end of the exercise period. An arteriovenous-difference technique was used to estimate both tissue protein degradation and synthesis. When S was infused, the release of leucine (Leu) from the gut and phenylalanine (Phe) from the hindlimb significantly increased during exercise, thus indicating that exercise augmented proteolysis in these tissues. The balance of Leu across the gut during exercise demonstrated a net uptake with both AAG and AA, whereas a net release was observed for G and S. In addition, Leu uptake in the gut during the last 90 minutes of the exercise period tended to be greater with AAG versus AA (P = .06). Phe balance across the hindlimb during the late exercise period showed a significant release with S, AA, and G, whereas the balance with AAG did not show a significant release. These results suggest that exercise-induced proteolysis in the gut may be reduced by supplementation with AA, and this effect may be enhanced by concomitant G administration. However, in skeletal muscle, both AA and G may be required to prevent net protein degradation during exercise. G provided without AA did not achieve net protein synthesis in either tissue.

Angiotensin II antagonists.

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Les antagonistes du récepteur minératocorticoïde

Mineralocorticoid signaling pathway plays a pivotal role in cardiovascular physiopathology. Evidences from clinical and experimental studies have linked mineralocorticoid hormones with cardiovascular morbiditiy and mortality. Thus, antagonist of the mineralocorticoid receptor (AMR) has reappeared. In addition, a novel mineralocorticoid receptor antagonist has been developped, named eplerenone, which lack the side effect of former ARMs as gynecomastia. Based on two studies named RALES et EPHESUS, guidelines of the european and american societies of cardiology recommend the use of ARMs as a treatment for cardiac failure NYHA III and IV, and post-infarct cardiac failure (ejection fraction < 40%).

Gut permeability and food allergies.

Intestinal permeability is a critical feature of the gastrointestinal epithelium as it must allow an efficient passage of nutrients and restrict the entry of larger molecules, such as protein antigen, in order to facilitate appropriate immune responses towards food antigens. The proper regulation of the epithelial barrier relies on multiple, intricate physiological and immunologic mechanisms, in terms of which recent progresses regarding the cellular and molecular components have been unravelled. In genetically predisposed individuals, breakdown of oral tolerance can occur, leading to the inadequate production of allergen-specific IgE and the recruitment of mast cells in the gastrointestinal mucosa. Under such conditions, the intestinal permeability towards allergen is altered via different mechanisms, with IgE-CD23-mediated transport across the mucosa playing an important amplification role. Additionally, during the effector phase of the allergic reaction, when mast cells degranulate, a series of inflammatory mediators, such as proteases and cytokines, are released and further affects intestinal permeability. This leads to an increase in the passage of allergens and hence contributes to perpetuate the inflammatory reaction. In this review, we describe the importance of properly balanced intestinal permeability in oral tolerance induction and address the processes involved in damaging the intestinal barrier in the sensitized epithelium and during allergic reactions. We conclude by speculating on the effect of increased intestinal permeability on the onset of sensitization towards dietary antigens.

Angiotensin II as an Inducer of Atherosclerosis: Evidence from Mouse Studies

Mechanisms responsible for atherosclerotic plaque development, destabilization, and rupture are still largely unknown. Angiotensin II, the main bioactive peptide of renin angiotensin system, has been shown to be critically involved in the pathogenesis of atherosclerosis and vulnerable plaque. Experimental studies in hypercholesterolemic mouse models with high circulating Angiotensin II levels, provide direct evidence that Angiotensin II induces plaque vulnerability partly by 1/ downregulating vascular expression of anti-atherosclerotic genes and/or upregulating expression of pro-atherosclerotic genes, and 2/ skewing the systemic lymphocyte Th1/Th2 balance towards a proinflammatory Th1 response in early disease phase. Further understanding the pro-atherosclerotic mechanisms of Angiotensin II and associated signaling pathways will help to design better therapeutic strategies for reducing the burden of atherosclerotic cardiovascular disease.