Preliminary evidence for reduced preoperative cerebral blood flow velocity as a risk factor for cognitive decline three months after cardiac surgery: an extension study.

This extension study investigated the association between preoperative cerebral blood flow (CBF) velocity and postoperative cognitive decline (POCD) at a three-month follow-up in patients who underwent cardiac surgery. Continuous transcranial Doppler ultrasound on both middle cerebral arteries (MCAs) was used preoperatively in 31 right-handed cardiac surgery patients at rest. Each patient performed a neuropsychological evaluation to assess cognitive performance before surgery, at discharge and at three-month follow-up. Patients with POCD at the three-month follow-up had a marginally significantly lower preoperative CBF velocity in the left MCA than patients without POCD. Moreover, the group with POCD had a significantly lower CBF velocity in the left than in the right MCA, whereas no difference between the left and right CBF velocity was found in the group without POCD. These preliminary findings suggest that reduced preoperative CBF velocity in the left MCA may represent an independent risk factor for cognitive decline in patients three months after surgery.

The role of asymmetry and the nature of microembolization in cognitive decline after heart valve surgery: a pilot study.

Our objective was to determine the role of asymmetry and the nature of microembolization on postoperative cognitive decline in patients who had undergone heart valve surgery. Continuous transcranial Doppler ultrasound was intraoperatively used for both middle cerebral arteries in 13 right-handed heart valve surgery patients to detect microembolization. The Trail Making Test A and B, Memory with 10/30 s interference, the Digit Span Test and Phonemic Fluency were performed preoperatively, at discharge and three months after surgery. Our data suggest that early and late postoperative psychomotor and executive functions may be sensitive to microemboli in the left, but not in the right middle cerebral artery. Moreover, solid and gaseous microemboli are both similarly associated with early postoperative cognitive decline while, surprisingly, late postoperative cognitive decline is more likely to be associated with gaseous than solid microemboli.

Sequence specific peptidomimetic molecules inhibitors of a protein-protein interaction at the helix 1 level of c-Myc.

Our work is focused in the broad area of strategies and efforts to inhibit protein-protein interactions. The possible strategies in this field are definitely much more varied than in the case of ATP-pocket inhibitors. In our previous work (10), we reported that a retro-inverso (RI) form of Helix1 (H1) of c-Myc, linked to an RI-internalization sequence arising from the third alpha-helix of Antennapedia (Int) was endowed with an antiproliferative and proapoptotic activity toward the cancer cell lines MCF-7 and HCT-116. The activity apparently was dependent upon the presence of the Myc motif. In this work, by ala-scan mapping of the H1 portion of our molecules with D-aa, we found two amino acids necessary for antiproliferative activity: D-Lys in 4 and D-Arg in 5 (numbers refer to L-forms). In the natural hetero-dimer, these two side chains project to the outside of the four alpha-helix bundle. Moreover, we were able to obtain three peptides more active than the original lead. They strongly reduced cell proliferation and survival (RI-Int-VV-H1-E2A,S6A,F8A; RI-Int-VV-H1-S6A,F8A,R11A; RI-Int-VV-H1-S6A,F8A,Q13A): after 8 days at 10 muM total cell number was approximately 1% of the number of cells initially seeded. In these more potent molecules, the ablated side chains project to the inside in the corresponding natural four alpha-helix bundle. In the present work, we also investigated the behavior of our molecules at the biochemical level. Using both a circular dichroism (CD) and a fluorescence anisotropy approach, we noted that side chains projecting at the interior of the four alpha-helix bundle are needed for inducing the partial unfolding of Myc-H2, without an opening of the leucine zipper. Side chains projecting at the outside are not required for this biochemical effect. However, antiproliferative activity had the opposite requirements: side chains projecting at the outside of the bundle were essential, and, on the contrary, ablation of one side chain at a time projecting at the inside increased rather than decreased biological activity. We conclude that our active molecules probably interfere at the level of a protein-protein interaction between Myc-Max and a third protein of the transcription complex. Finally, CD and nuclear magnetic resonance (NMR) data, plus dynamic simulations, suggest a prevalent random coil conformation of the H1 portion of our molecules, at least in diluted solutions. The introduction of a kink (substitution with proline in positions 5 or 7) led to an important reduction of biological activity. We have also synthesized a longer peptido-mimetic molecule (RI-Int-H1-S6A,F8A-loop-H2) with the intent of obtaining a wider zone of interaction and a stronger interference at the level of the higher-order structure (enhanceosome). RI-Int-H1-S6A,F8A-loop-H2 was less active rather than more active in respect to RI-Int-VV-H1-S6A,F8A, apparently because it has a clear bent to form a beta-sheet (CD and NMR data).

Auditory event-related potentials and reaction times in migraine children.

Cognitive processing was investigated interictally in 18 children with migraine without aura and 18 age-matched controls by measuring event-related potentials (ERPs) and reaction times (RTs) during an acoustic oddball paradigm. Results showed that N100 amplitude evoked by frequent stimuli was significantly smaller in patients compared with controls. Habituation of target P300 amplitude was observed in patients but not in controls. Mean RTs were equivalent in the two groups, but migraine children made more errors than controls.

Electrophysiological evidence of visual encoding deficits in a cross-modal attentional blink paradigm.

Two experiments are reported in which two target stimuli, T1 and T2, were presented at variable stimulus onset asynchronies (SOAs). In Experiment 1, T1 and T2 were visual stimuli embedded in a rapid serial visual presentation (RSVP) stream of distractors. Participants were asked to report T1 and T2 at the end of the stream. In Experiment 2, T1 was an auditory stimulus, and T2 a visual stimulus embedded in an RSVP stream. Participants made a speeded discriminative response to T1, and reported T2 at the end of the stream. An attentional blink (AB) effect was observed in both experiments: T2 report suffered at short SOA compared to long SOA. During the AB, the amplitude of the P300 component of the event-related potential (ERP) locked to T2 onset was sensibly reduced in both experiments. Behavioral and ERP results were very similar across the two experiments. Implications for models of the AB effect are discussed.

Different response of intracerebroventricular cadmium administration on blood pressure in normal and low urinary kallikrein rats.

Cadmium intracerebroventricular (i.c.v.) administration, at definite concentrations, induces a dose-dependent increase in the systemic blood pressure. Kallikreins are suggested to be important regulators of cardiovascular function. We evaluated the effects of 10 microg i.c.v. cadmium on mean blood pressure (MBP) and several urinary parameters such as 24h urine volume, sodium and potassium excretion and osmolality in a rat strain inbred for low urinary kallikrein and in normal-kallikrein Wistar rats. Low-kallikrein rats (LKR) showed an increase in MBP that, after an initial peak (27% from baseline), persisted higher than basal levels (10%) over 24h. In normal-kallikrein rats (NKR) a different reaction of blood pressure to cadmium was observed, causing a temporary increase (26% from baseline) of the systemic blood pressure, that returned to normal values within 2h. In addition, LKR showed a considerable reduction in the urinary volume (UV; 43.0+/-20 ml/24h versus 13.2+/-6 ml/24h, P<0.006), with an increase in the urinary osmolality (U(Osm); 500+/-210 mOsm/l versus 1391+/-245 mOsm/l, P<0.0002). Sodium (U(Na); 1761+/-432 microEq/24h versus 1156+/-522 microEq/24h, P<0.03) and potassium excretion (U(K); 2186+/-482 microEq/24h versus 936+/-299 microEq/24h, P<0.0006) were both significantly reduced. No changes in UV, U(Osm) and U(K) were observed in normal urinary kallikrein rats with the exception of U(Na) excretion that was significantly increased (667+/-274 microEq/24h versus 1725+/-300 microEq/24h, P<0.03). These results suggest that a genetically determined defect in urinary kallikrein excretion leads to a different hypertensive response to i.c.v. cadmium and to a different renal excretion of electrolytes. Perhaps the differences of blood pressure response could be due, at least in part, to a different sensitivity of LKR to cadmium: this implies a complex and articulate hypertensive effect of cadmium involving more systems than those supposed so far.

Novel anthracycline oligosaccharides: influence of chemical modifications of the carbohydrate moiety on biological activity.

Several observations highlight the importance of the carbohydrate moiety for the biological activity of antitumoural anthracyclines. Here is reported the synthesis, cytotoxicity and topoisomerase II-mediated DNA cleavage intensity of the new oligosaccharide anthracyclines 1--4 modified in the sugar residue. Evaluation of cytotoxic potency on different cell lines, resulted in quite similar values among the different analogues. On the other hand, topoisomerase II-mediated DNA breaks level was different for the various compounds, and was not related to cytotoxicity, thus supporting previous observations reported for some monosaccharide anthracyclines modified in the carbohydrate portion.

Studies toward the synthesis of pinolidoxin, a phytotoxic nonenolide from the fungus Ascochyta pinodes. Determination of the configuration at the C-7, C-8, and C-9 chiral centers and stereoselective synthesis of the C(6)-C(18) fragment.

The absolute stereochemistry at the C-7, C-8, and C-9 chiral centers of pinolidoxin (1) has been determined by chemical and spectral methods. First, the synthesis of four stereoisomeric fully benzoylated 2,3-erythro-1,2,3,4-heptanetetrols, corresponding to the C(6)-C(18) portion of the natural substance, has been accomplished starting from meso-tartaric acid. As next step, the selection of the synthetic tetrabenzoate possessing "natural" stereochemistry (10a'), suitable for absolute configuration determination, has been carried out by correlation with its "natural" homologue derived from degradation of pinolidoxin. Determination of the stereochemistry at the title chiral centers has been carried out by application of the Mosher's method both to 7a', a compound stereochemically related to 10a', and to pinolidoxin itself. The stereoselective synthesis of a protected form of the C(6)-C(18) portion of pinolidoxin, to be used in its total synthesis, has also been accomplished starting from commercially available D-erythronolactone.

Cardiac responses associated with affective processing of unpleasant film stimuli.

The autonomic basis of cardiac reactions to unpleasant film stimuli was investigated. Film clips depicting major surgery, threats of violence, and neutral material were presented to 46 subjects. Self-report measures of emotion were obtained, as well as heart rate, respiration rate, respiratory sinus arrhythmia, T-wave amplitude and skin conductance level. Resting vagal tone was estimated in a paced breathing task prior to film viewing. Spontaneous blink rate was also taken as a measure of visual engagement during film viewing. Coherent increases in sympathetic activation accompanied the film containing violent threats, whereas the surgery film yielded greater electrodermal activation, as well as heart rate deceleration and T-wave increase. These data support the hypothesis of differential autonomic response patterns to specifically unpleasant material. As compared with threat and neutral films, greater blink rate inhibition was observed during the surgery film. Individual differences in parasympathetic cardiac control measured at rest were able to discriminate cardiac response patterns during film viewing.

Emotional impairment after right orbitofrontal lesion in a patient without cognitive deficits.

The present study describes a patient, M.L., with right orbitofrontal lesion, who showed no impairment on main neuropsychological tests, including those measuring frontal functions. Nevertheless, he had deeply affected emotional responses. In line with Damasio's work, the patient had lower skin conductance during the projection of a standardized set of emotional slides. Furthermore, he showed altered facial expressions to unpleasant emotions, displaying low corrugator supercilii electromyographical activity associated with reduced recall of unpleasant stimuli. During a task focusing on imagery of emotional situations, M.L.'s heart rate and skin conductance responses were affected during both pleasant and unpleasant conditions. Facial expressions to unpleasant imagery scripts were also impaired. Thus, the orbitofrontal cortex proved to play a critical role in retrieval of psychophysiological emotional patterns, particularly to unpleasant material. These results provide the first evidence that orbitofrontal lesions are associated with emotional impairment at several psychophysiological levels.

Relationship between cerebrospinal fluid pressure and plasmatic ADH.

In a healthy human being, the extracellular volume is kept constant by homeostatic systems. One of these is represented by the antidiuretic hormone (ADH). ADH release is modulated by osmoreceptors and baroreceptors which respond to an increase in osmolality of extracellular fluid and a decrease in blood volume, respectively. In previous studies we investigated the existence of additional structures sensitive to plasma volume modifications. We found evidence of the presence of such receptors in the inner ear, with nervous connections to supraoptic and paraventricular nuclei. However, the possibility that the cerebral ventricle wall contained stretch sensors could not be excluded. To test our hypothesis, we studied 19 rats divided into three groups: Group 1 (n =7), Group 2 (n =7) and Group 3 (control group n =5). In each rat, under total anaesthesia, a femoral cannula was inserted into the left artery and a 22 gauge stainless steel cannula was implanted into the left cerebral ventricle. In the first group an isotonic fluid, similar to the animal's cerebrospinal fluid (CSF), was infused intracerebroventricularly (ICV) at a rate of 0.6 microl min-1 continuously for 6 h. In the second group, under the same conditions, CSF was aspirated; the third group was used as the control. In all animals, plasma modifications of ADH (pADH), osmolality (pOSM), Na+(pNa+) and K+(pK+) were evaluated before and after the experimental procedures. Mean arterial pressure (MAP) and heart rate (HR) were recorded throughout the experiment. At the end of the experiment no significant changes in pNa+, pK+, MAP and HR were observed. Plasma osmolality was significantly lower in Group 2 before and during the experimental procedure, since we deliberately expanded the volume in animals of Group 2 to partially suppress ADH, in order to evaluate its modifications. Plasma ADH fell in the first experimental group (-37.4%+/-6.3 sem) after the ventricular pressure had been increased, and rose in the second (+47.3%+/-14.7 sem) after ventricular decompression. These changes were statistically significant in comparison with those occurring in control subjects (-0.9+/-18.9 sem;P =0.07 and P =0.03, respectively). These results suggest the presence of additional volume receptors probably located in the cerebral ventricles, capable of controlling ADH. The importance of these receptors in physiological situations of plasma volume contraction or expansion remains to be established.

Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene.

BACKGROUND: To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B2-receptor gene (Bk 2r-/-). METHODS AND RESULTS: Under basal conditions, tail-cuff blood pressure was higher in Bk2r-/- than in wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (124+/-1 versus 109+/-1 and 111+/-2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice. Heart weight was greater in Bk2r-/- than in Bk2r+/+ and Bk2r+/- mice (505+/-10 versus 449+/-12 and 477+/-10 mg/100 g body wt, P<.05). Chronic blockade of B2-receptors by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice. Compared with the wild-type strain, both Bk2r-/- and Bk2r+/- mice showed exaggerated vasopressor responses to angiotensin II. In addition, chronic administration of an angiotensin AT1-receptor antagonist reduced the basal blood pressure of Bk2r-/- by 21+/-3 mmHg (P<.05) to the levels of Bk2r+/+. No difference was detected between strains as far as plasma renin activity and the expression of renin and AT1-receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15 days) increased the blood pressure of Bk2r-/- and Bk2r+/- by 34+/-3 and 14+/-6 mm Hg, respectively, whereas it was ineffective in Bk2r+/+. CONCLUSIONS: Our results suggest that a normally functioning B2-receptor is essential for the maintenance of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system could contribute to increase blood pressure levels by leaving the activity of vasoconstrictor agents unbalanced.

Visual evoked potentials, heart rate responses and memory to emotional pictorial stimuli.

Although the effects of emotional stimuli on event-related cortical potentials, heart rate, and memory have been extensively studied, the association of these variables in a single study has been neglected. The influence of pleasant, unpleasant, and neutral photographic slides on visual evoked potentials (VEPs), heart rate responses, and free recall, was investigated in 20 normal subjects. VEPs were recorded from Cz and Pz locations, and analyses were performed on both amplitudes and latencies of identifiable endogenous peaks (P2, N2 and P3), and mean amplitude in the 100-200-ms, 400-600-ms, and 600-900-ms latency ranges. An emotional effect was present on VEPs starting from about 282 ms on, as revealed by the N2, P3, and late components. Both pleasant and unpleasant slides yielded larger cortical positivity as compared to neutral ones. Peak latencies did not show any emotional effect. Heart rate data showed a deceleratory response that was larger to unpleasant slides. Free recall of the projected slides showed a better performance for emotional slides compared to neutral ones. VEPs and memory data showed the same pattern: both pleasant and unpleasant slides induced larger positivity in the event-related potentials and were better remembered than neutral slides. Positive correlations were found between the late negative VEPs component (600-900 ms), recorded from Cz, and heart rate deceleration (r = 0.62), and between P3 (at Pz location) and the number of remembered slides (r = 0.53).

Respiratory sinus arrhythmia in blood phobic subjects.

12 blood-phobic subjects, selected according to the Fear Survey Schedule and the Mutilation Questionnaire, and 50 control subjects performed a paced respiration task during which heart rate and respiration were recorded. Respiratory Sinus Arrhythmia (RSA) was analyzed as an autonomic index of vagal influence on the heart. Analysis showed a larger RSA in the blood-phobic group than the controls and points to a difference in vagal activity at rest between the groups.

Startle reflex and emotion modulation impairment after a right amygdala lesion.

In the present study, startle responses during resting states as well as during the presentation of a set of emotive slides were recorded from a 32-year-old male patient with a rare localized lesion of the right amygdala. The startle reflex is a response modulated by affective states: it has been reliably used in the literature to measure the aversiveness of emotive stimuli. The animal literature has shown that the circuit of this reflex is directly influenced by amygdala projections. The startle responses of the patient were compared with those of eight age-matched normal subjects. The patient's startle amplitudes showed an overall impaired response and an inhibited reflex contralateral to the lesion. In addition, he failed to show the typical startle potentiation induced by an aversive emotive background. The data confirm, in the human, previous results from the literature in other species on amygdala involvement in startle and emotional responses. Furthermore, the observation of the importance of the right amygdala in the modulation of emotion is consistent with the hypothesis of right hemisphere specialization for aversive emotions. The results are discussed in the context of the literature on human amygdala lesions.

Metabolic and renal effects of Laevo-carnitine and propionyl-carnitine in rats with subtotal nephrectomy.

The renal and metabolic effects of chronic carnitine administration were evaluated in the early stages of experimentally-induced renal failure. Laevo-carnitine (n = 5), Propionyl-carnitine (n = 5) both at 200 mg kg-1 of body weight, or vehicle (physiological saline solution, 0.4 ml kg-1 body weight, n = 5) were administered daily for 3 days prior to 2/3 nephrectomy and for 25 days thereafter, by intraperitoneal route. At the end of the experiment, no significant differences were found in systolic blood pressure and heart rate among groups. During the 25 days after nephrectomy, body weight increased by 71 +/- 13 g in the control group and by 50 +/- 26 g and 42 +/- 9 g in Laevo-carnitine and Propionyl-carnitine groups, respectively (P < 0.05 vs control for both comparisons). Urinary sodium excretion was increased in carnitine-treated rats (Laevo-carnitine: from 1.03 +/- 0.3 to 1.36 +/- 0.3 mEq day-1, Propionyl-carnitine: from 1.2 +/- 0.2 to 1.66 +/- 0.2 mEq day-1, P < 0.05 for both comparisons), but not in those given vehicle. Twenty-five days after nephrectomy, plasma creatinine was lower in carnitine-treated rats (Laevo-carnitine: 0.98 +/- 0.12 mg dl-1, Propionyl-carnitine: 1.06 +/- 0.15, vehicle: 1.52 +/- 0.09, P < 0.05 vs control for both comparisons). Plasma triglycerides and VLDL were decreased by nephrectomy and this effect was prevented by carnitine treatment. The data indicate that the carnitine blunts the increase in plasma creatinine that occurs early after partial nephrectomy and normalizes the plasma lipoprotein pattern. Thus, carnitine might protect against the development of renal failure in this experimental model.