Inhibition of matrix metalloproteinases prevents the potentiation of nondeprived-eye responses after monocular deprivation in juvenile rats.

The ocular dominance (OD) shift induced by monocular deprivation (MD) during the critical period is mediated by an initial depression of deprived-eye responses followed by an increased responsiveness to the nondeprived eye. It is not fully clear to what extent these 2 events are correlated and which are their physiological and molecular mediators. The extracellular synaptic environment plays an important role in regulating visual cortical plasticity. Matrix metalloproteinases (MMPs) are a family of activity-dependent zinc-dependent extracellular endopeptidases mediating extracellular matrix remodeling. We investigated the effects of MMP inhibition on OD plasticity in juvenile monocularly deprived rats. By using electrophysiological recordings, we found that MMP inhibition selectively prevented the potentiation of neuronal responses to nondeprived-eye stimulation occurring after 7 days of MD and potentiation of deprived-eye responses occurring after eye reopening. Three days of MD only resulted in a depression of deprived-eye responses insensitive to MMP inhibition. MMP inhibition did not influence homeostatic plasticity tested in the monocular cortex but significantly prevented an increase in dendritic spine density present after 7 days MD in layer II-III pyramids.

Ageing, lifestyle modifications, and cardiovascular disease in developing countries.

Developing countries face the double menace of still prevalent infectious diseases and increasing cardiovascular disease (CVD) with epidemic proportions in the near future, linked to demographic changes (expansion and ageing), and to urbanisation and lifestyle modifications. It is estimated that the elderly population will increase globally (over 80% during the next 25 years), with a large share of this rise in the developing world because of expanding populations. Increasing longevity prolongs the time exposure to risk factors, resulting in a greater probability of CVD. As a paradox, increased longevity due to improved social and economical conditions associated with lifestyle changes in the direction of a rich diet and sedentary habits in the last century, is one of the main contributors to the incremental trend in CVD. The variable increase rate of CVD in different nations may reflect different stages of "epidemiological transition" and it is probable that the relatively slow changes seen in developing populations through the epidemiological transition may occur at an accelerated pace in individuals migrating from nations in need to affluent societies (i.e. Hispanics to the USA, Africans to Europe). Because of restrained economic conditions in the developing world, the greatest gains in controlling the CVD epidemic lies in its prevention. Healthy foods should be widely available and affordable, and healthy dietary practices such as increased consumption of fresh fruits and vegetables, reduced consumption of saturated fat, salt, and simple sugars, may be promoted in all populations. Specific strategies for smoking and overweight control may be regulation of marketed tobacco and unhealthy fast food and promotion of an active lifestyle. Greater longevity and economic progress are accompanied by an increasing burden of CVD and other chronic diseases with an important decrease in quality of life, which should question the benefit of these additional years without quality.

Requirement of ERK activation for visual cortical plasticity.

Experience-dependent plasticity in the developing visual cortex depends on electrical activity and molecular signals involved in stabilization or removal of inputs. Extracellular signal-regulated kinase 1,2 (also called p42/44 mitogen-activated protein kinase) activation in the cortex is regulated by both factors. We show that two different inhibitors of the ERK pathway suppress the induction of two forms of long-term potentiation (LTP) in rat cortical slices and that their intracortical administration to monocularly deprived rats prevents the shift in ocular dominance towards the nondeprived eye. These results demonstrate that the ERK pathway is necessary for experience-dependent plasticity and for LTP of synaptic transmission in the developing visual cortex.

Brain-derived neurotrophic factor causes cAMP response element-binding protein phosphorylation in absence of calcium increases in slices and cultured neurons from rat visual cortex.

Neurotrophins play a crucial role in the developmental plasticity of the visual cortex, but very little is known about the cellular mechanisms involved in their action. In many models of synaptic plasticity, increases in cytosolic calcium concentration and activation of the transcription factor cAMP response element-binding protein (CREB) are crucial factors for the induction and maintenance of long-lasting changes of synaptic efficacy. Whether BDNF modulates intracellular calcium levels in visual cortical neurons and the significance of this action for BDNF signal transduction is still controversial. We investigated whether CREB phosphorylation and calcium changes are elicited by acute BDNF presentation in postnatal visual cortical slices and cultures. We found that BDNF did not cause any calcium increase, but it induced robust CREB phosphorylation in neurons from both preparations. We further analyzed signal transduction and its dependency on calcium changes in cultured neurons. CREB phosphorylation required trkB activation because treatment with the trk inhibitor k252a completely blocked CREB phosphorylation. In agreement with the imaging experiments, we verified that calcium changes were not necessary for CREB activation because preincubation with BAPTA-AM did not diminish the level of CREB phosphorylation induced by BDNF stimulation. CREB phosphorylation was accompanied by gene expression, because we observed the upregulation of c-fos expression, which was also not affected by preincubation with BAPTA-AM. Finally, BDNF caused phosphorylation of mitogen-activated protein kinase (MAPK), and because the treatment with the MAPK inhibitor U0126 completely abolished CREB activation and c-fos upregulation, it is likely that both processes depend mainly on the MAP kinase pathway. These results indicate that MAPK and CREB, but not intracellular calcium, are important mediators of neurotrophin actions in the visual cortex.

Effect of aging on intracellular divalent cation metabolism: a link to the increased incidence of hypertension and non-insulin dependent diabetes mellitus in the elderly?

Aging is epidemiologically linked to an increased incidence of hypertension, impaired glucose tolerance and overt non-insulin dependent diabetes mellitus type II (NIDDM). The cellular basis underlying this clinical and epidemiological linkage, cytosolic free calcium (Ca(2+)(i)) and cytosolic free magnesium (Mg(2+)(i)) levels were investigated in elderly subjects and in subjects with essential hypertension (EH) and metabolic diseases. It has been observed that normal aging, as well as hypertension and NIDDM, is characterized by elevated Ca(2+)(i) and suppressed Mg(2+)(i) levels. Furthermore, the divalent ionic defect displayed in EH and NIDDM resembled the normal aging process, i.e., ionic levels in both young and elderly subjects with EH or NIDDM were indistinguishable from those in healthy elderly subjects. The ionic levels predict quantitatively also the extent of elevated blood pressure, and hyperinsulinemic response to oral glucose challenge. Altogether, we suggest that the missing link, responsible for the frequent and increasing clinical coexistence of hypertension, insulin resistance, impaired glucose tolerance, and NIDDM with age, may be ionic in nature, and intrinsic to the normal aging process in Western man.

Multicenter, randomized, placebo-controlled, double-blind study of the safety and efficacy of oral delapril in patients with congestive heart failure.

A total of 101 patients (67 delapril, 34 placebo) with congestive heart failure, New York Heart Association (NYHA) classes II and III, entered a multicenter, randomized (2:1), double-blind, placebo-controlled study to determine the minimum effective and maximum tolerated doses of delapril. Patients received placebo or increasing doses of delapril. After a 2-week run-in period on placebo, patients were randomly assigned to delapril or placebo. The dose of delapril was 7.5 mg twice daily for 2 weeks, 15 mg twice daily for another 2 weeks, followed by 30 mg twice daily for 4 weeks. The dose was increased only if the patient did not present any symptoms of orthostatic hypotension. If such symptoms developed, the code was broken and an open treatment was continued on the minimum effective dose (delapril group). Patients with symptoms of orthostatic hypotension in the placebo group were withdrawn. At the end of the 8-week treatment, 36 (54.5%) patients in the delapril group completed the study on 30 mg twice daily, 12 (18.2%) on 15 mg twice daily, and 18 (27.3%) on 7.5 mg twice daily. Seven patients on placebo were withdrawn because of insufficient therapeutic response; one patient on delapril was lost to follow-up. There was a significant improvement (p < 0.01) in bicycle ergometric performance involving an increase in the exercise duration and the maximum workload tolerated in those patients completing the study on delapril 30 mg twice daily and those finishing on 15 mg twice daily.(ABSTRACT TRUNCATED AT 250 WORDS)

[Allergy in pregnancy]. / L'allergia in gravidanza.

During pregnancy, the ideal would be to abstain from the use of any drug, at least during the first three months. In fact, none of the drugs currently used for the therapy of allergies has been classified by the FDA and European Commission on the basis of controlled human and animal studies as completely negative from the point of view of untoward effects in pregnancy. The following are considered comparatively safe: disodium cromoglycate, diphenhydramine, chlorpheniramine, hydroxyzine, mebhydroline, brompheniramine, inhaled beta 2-agonists, xanthine bronchodilators, pseudoephedrine, and topical nasal treatment with beclomethasone dipropionate in the last trimenon. On the contrary, specific immunotherapy is inadvisable. In the case of anaphylaxis, epinephrine and ephedrine are drugs of choice, while in asthma monitoring of PEFR is essential for appropriate management. For rhinitis, DSCG and beclomethasone diproprionate appear to he comparatively safe. For urticaria, hydroxyzine or possibly ephedrine should be preferred. In case of a history of untoward drug effects, oral antibiotics should be preferred (erythromycin or micamycin); for atopic dermatitis the preference is for topical treatment with hydrocortisone.

[The noninvasive evaluation of the cardiovascular changes in physiological aging]. / Valutazione non invasiva delle alterazioni cardiovascolari nell'invecchiamento fisiologico.

The physiological aging is frequently associated with structural alterations determining a loss of elasticity both of left ventricular wall (that goes towards hypertrophy), and of great and small arteries and arterioles (that have their compliance reduced). In fact, in our experience, the elderly have, in comparison with younger people, greater values of end diastolic thickness of the septum and of the posterior wall (respectively 10.7 +/- 1.5 vs 9.4 +/- 1 and 10.4 +/- 1.7 vs 9.0 +/- 0.9), of the aortic index, that is inversely related to arterial compliance (0.74 +/- 0.06 vs 0.66 +/- 0.05) as well as of minimal vascular resistances, expression of an impaired maximal vasodilation capacity of the arteriolar bed (4.27 +/- 1.08 vs 3.68 +/- 0.91). At cardiac level the global effect of these changes is a remodelling able to maintain a normal function both at rest and after exercise, i.e., a greater intervention of Frank-Starling mechanisms with increase of the end diastolic volume, in order to counteract the lower chronotropic response to catecholamines. At peripheral level the structural changes in the arterial tree (consequent to an increased collagen content in the intimal and medial components of the vessel walls) lead to an increase in blood pressure with aging: in our study by non-invasive blood pressure monitoring mean 24-hours blood pressure values have been the following ones: 116.4 +/- 3.8/72.1 +/- 7.2 mmHg in 25-35 years aged; 121.8 +/- 9.1/75.9 +/- 5.3 mmHg in 45-55 years aged; and 128.4 +/- 10.1/76.4 +/- 7.8 mmHg in aged more than 60 years. On the other hand, the greater cardiac output during stress, together with the lower arterial vasodilation (consequent also to the impaired function of the baroceptor reflexes) determines an exaggerated systolic blood pressure increase after exercise.

Increased plasminogen activator inhibitor antigen levels in diabetic patients with stable angina.

PAI-1 antigen, tPA antigen and thrombin - antithrombin III complexes (TAT) levels were measured in 10 males with stable angina and type-II diabetes mellitus and in 16 males with stable angina without diabetes or other risk factors (hyperfibrinogenaemia, hyperlipidaemia, diabetes, hypertension, smoking and obesity) known to increase PAI levels. Ten healthy men of equivalent age served as controls. Because only diabetics with coronary artery disease (CAD) showed a decreased fibrinolytic capacity, a second study was performed on the 16 non-diabetic CAD patients to determine whether submaximal workload induces significant changes of tPA and PAI levels. TAT levels were increased in CAD, and significantly so in the diabetic group. tPA levels were increased only in the CAD patients without diabetes. PAI levels were significantly increased in diabetic CAD patients (5.26 +/- 1.96 ng/ml) but not in the stable angina patients without diabetes (2.97 +/- 1.44 ng/ml). Immunologically-reactive tPA released after exercise was higher in the 16 CAD patients without diabetes than in controls. Our data could indicate that in stable angina without diabetes there is no chronic latent activation of the clotting system, with no impairment of fibrinolytic activity. On the other hand, the presence of diabetes mellitus seems to influence the fibrinolytic capacity in CAD, particularly increasing PAI levels.

[Caloric intake and bone mineral content in obese and normal weight subjects]. / Apporto calorico e contenuto minerale osseo nei soggetti obesi e nei normopeso.

Bearing in mind the reports which clearly document the constant dissociation between daily calorie intake from diet, obesity and the positive effects of the mechanical load on bone trophism, the possible correlation between total daily calorie intake of some nutrients (Ca, P and vitamin D) on the one hand, and bone mineral density (BMD) on the other was evaluated in 61 obese women. The results appear to indicate that the higher BMD in obese compared to normal weight subjects may largely depend on the presence of notoriously high estrogen levels which allow a better efficacy and use of dietary calcium.