Behavioural, biochemical and histochemical effects of locus coeruleus transplantation in rats with neurotoxic lesions of the catecholaminergic system

Exploratory activity in the open field and noradrenaline concentration in the neocortex and brain stem were investigated in intact rats (n = 10) and in the following groups of rats with early postnatal neurotoxic (6-hydroxydopamine) lesion of the catecholaminergic system: (i) rats with embryonal locus coeruleus grafts in the frontal neocortex (n = 5); (ii) rats with the same grafts in lateral ventricles (n = 4); (iii) a control group with intracortical hippocampal tissue grafts (n = 3); (iv) sham-operated rats (n = 3). Experiments were performed by four independent groups of investigators using a double-blind method. In sham-operated rats as well as in rats with hippocampal grafts, and with locus coeruleus grafts in the ventricles, both exploratory activity and noradrenaline content of the forebrain were significantly lowered. In the rats with intracortical locus coeruleus grafts the level of exploratory activity was much higher (almost as in intact controls). This improvement of exploratory behaviour correlated highly with increased noradrenaline concentration in the forebrain. In all animals with locus coeruleus in lateral ventricles a significant increase in noradrenaline level of the brain stem was present, but no change of exploratory behaviour was observed. The grafts with the 3-mm-thick slabs of the adjacent tissue were dissected from the brain and used for histological analysis. The presence of typical locus coeruleus cells was shown in neocortex of all animals which received the grafts of corresponding tissue. The data show the possibility of stable compensation of the forebrain noradrenaline level and exploratory behaviour by embryonic noradrenergic neurons grafted into the neocortex, but not into lateral ventricles.     

Intestinal malrotation in Trinidad.

Fifty-one children under the age of 10 years admitted to a general hospital in Trinidad had a confirmed diagnosis of malrotation of the intestines. This was the primary diagnosis in 20 cases. Analysis of the records of these 20 revealed that one-half were less than 1 month of age at first presentation. Vomiting was a universal complaint, and nearly two-thirds were malnourished. Disturbed bowel habit, anorexia and abdominal pain were also reported. In 30% (six of 20) there were signs of dehydration; an equal number had features of intestinal obstruction. Radiological investigation provided the diagnosis in all but one child, who underwent surgical exploration with a provisional diagnosis of appendicitis. Although a volvulus was found in 35% of cases, no resections were necessary. A high rate of morbidity and a mortality rate of 15% highlight the problems involved in the surgical care of young infants.     

Vestibular contribution to combined arm and trunk motion

Recent studies have shown that the hand-pointing movements within arm's reach remain invariant whether the trunk is recruited or not or its motion is unexpectedly prevented. This suggests the presence of compensatory arm-trunk coordination minimizing the deflections of the hand from the intended trajectory. It has been postulated that vestibular signals elicited by the trunk motion and transmitted to the arm motor system play a major role in the compensation. One prediction of this hypothesis is that vestibular stimulation should influence arm posture and movement during reaching. It has been demonstrated that galvanic vestibular stimulation (GVS) can influence the direction of pointing movements when body motion is restrained. In the present study, we analyzed the effects of GVS on trunk-assisted pointing movements. Subjects either moved the hand to a target or maintained a steady-state posture near the target, while moving the trunk forward with the eyes closed. When GVS was applied, the final position of the hand was deviated in the lateral and sagittal direction in both tasks. This was the result of two independent effects: a deviation of the trunk trajectory and a modification of the arm position relative to the trunk. Thus, the vestibular system might be directly involved not only in the control of trunk motion but also in the arm-trunk coordination during trunk-assisted reaching movements. Electronic Publication     

Spotlight on HDL-raising therapies: insights from the torcetrapib trials

Subnormal levels of HDL cholesterol constitute a major cardiovascular risk factor. Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent HDL-raising agents. Torcetrapib was the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial, which was prematurely terminated in December 2006 because of excess cardiovascular and noncardiovascular mortality in the active treatment group. Therapy with torcetrapib was associated with considerable increases in aldosterone level and blood pressure and changes in serum electrolytes indicative of mineralocorticoid excess. These findings indicate that torcetrapib has off-target toxic effects unrelated to HDL raising that involve the activation of mineralocorticoid receptors by aldosterone and result in the induction of hypertension. In contrast with torcetrapib, other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation which discounts a class effect. The available data do not, however, exclude potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL raising in future studies.     

Adverse effects of nitroglycerin treatment on endothelial function,vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits

OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity.