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.

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.

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).

Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.

1. We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A-81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2. Pairs of SHR were mated while drinking tap water or A-81988 in tap water, and the progeny was maintained on the parental regimen until 14 weeks of age. At this stage, A-81988-treated rats showed lower systolic blood pressure and body weight values (136 +/- 5 versus 185 +/- 4 mmHg and 247 +/- 4 versus 283 +/- 4 g in controls, P < 0.01); while heart rate was similar. In addition, mean blood pressure was reduced (101 +/- 7 versus 170 +/- 7 mmHg in controls, P < 0.01), and the pressor responses to intravenous or intracerebroventricular angiotensin II were inhibited by 27 and 59%, respectively. Heart/body weight ratio was smaller in A-81988-treated rats (3.2 +/- 0.1 versus 3.8 +/- 0.1 in controls, P < 0.01). 3. The antihypertensive and antihypertrophic effect of A-81988 persisted in rats removed from therapy for 7 weeks (systolic blood pressure: 173 +/- 4 versus 220 +/- 4 mmHg, heart/body weight ratio: 3.4 +/- 0.1 versus 4.1 +/- 0.1 in controls at 21 weeks of age, P < 0.01 for both comparisons), whereas the cardiovascular hypertensive phenotype was fully expressed in the subsequent generation that was maintained without treatment. 4. These results indicate that chronic blockade of angiotensin AT1-receptors attenuates the development of hypertension in SHR but it does not prevent the transmission of hypertension to the following generation. Thus, heritability of the SHR's hypertensive trait is not affected by pharmacological manipulation of the cardiovascular phenotype.

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.

Biofeedback-assisted heart rate modification after myocardial infarction.

Four patients who had suffered a myocardial infarction were given biofeedback training in order to assess (1) the possibility of increasing heart rate variability with the help of a feedback; (2) the possible cardiac consequences, from the clinical viewpoint, of biofeedback treatment. A biofeedback procedure alternately increasing and decreasing heart rate under instruction and feedback-plus-instruction conditions, was used. Evaluation of clinical parameters was effected by Holter dynamic ECG and by means of a graded submaximal effort test on the cycloergometer. The results show: (1) poor capacity to increase heart rate variability, but a tendency towards small unidirectional modifications; (2) no significant clinical modification except in isolated parameters. Further study is necessary to assess the usefulness of biofeedback training in the rehabilitation treatment of post-infarction patients. The datum, confirmed elsewhere, concerning apparent cardiovascular "rigidity' in such patients, is interesting but requires clarification.

Immunosuppressive treatment of the glomerulonephritis of systemic lupus.

To evaluate the results, the long-term prognosis and the rates of complication of an immunosuppressive regimen with corticosteroids and cyclophosphamide in the treatment of the nephritis of systemic lupus erythematosus, 21 patients with lupus glomerulonephritis were studied. Renal biopsies were performed in 17/21 of them and indicated diffuse proliferative (6 patients), diffuse mesangial (4) and membranous (7) glomerulonephritis. Treatment was structured in 4 phases: 1) induction with methylprednisolone 250 mg i.v. for 7-14 days, and cyclophosphamide 100-200 mg p.o., q.d., or 20 mg/kg i.v. every 28 days; 2) maintenance with prednisone p.o., 2 mg/kg q.o.d. for 45 days, and cyclophosphamide as before; 3) tapering, with reduction of prednisone by 15% each month for 4 months; 4) indefinite maintenance with prednisone slowly tapered to the least effective q.o.d. dose and cyclophosphamide discontinued after six months of treatment. This cycle was repeated in the event of a relapse. After a first immunosuppressive cycle, 20/21 patients achieved remission of glomerulonephritis. Plasma creatinine fell from 97 +/- 6 to 80 +/- 3 microMol/l (p < 0.01). Proteinuria fell from 2.1 +/- 0.4 to 0.2 +/- 0.4 g/d (p < 0.0001) and the nephrotic syndrome, present in 8 patients, disappeared. After an average of 20 +/- 7 months, 8 patients relapsed: all remitted again after a repeat cycle, but 1 later progressed to end-stage renal failure during pregnancy. After an average of 56 months 4 out of these 8 patients relapsed again: 1 progressed to end-stage renal disease following an abortion and 3 remitted completely after a third cycle. Thus, 18 out of 21 patients are presently in remission with an average dose of prednisone of 13.7 mg/day after an average follow-up of 52 +/- 38 months (range 2 to 156). Three patients are presently off treatment. In 16 patients with extended follow-up of 2 to 13 years, anti-nuclear antibodies, anti-DNA antibodies, albuminuria and cylindruria fell below post-cycle levels (p < 0.001 for all). We conclude that intensive immunosuppression with steroids and cyclophosphamide can achieve excellent long-term results in the treatment of systemic lupus with glomerulonephritis.

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).

Baroreceptor cortical effects, emotions and pain.

The specificity of baroreceptor-dependent inhibition of pain reactions to electrical stimuli was investigated during induction of different emotional states in 27 subjects. Baroreceptors were stimulated through the PRES (Phase Related External Suction) technique, while emotions were induced by means of pleasant, neutral and unpleasant slides. The dependent variables were pain ratings, somatic evoked potentials (N150 and P260) recorded from Fz, Cz and Pz, and skin conductance response (SCR), while heart rate was recorded as a PRES requirement. Valence and arousal ratings were obtained in front of each slide. During suction (external baroreceptor activation) reduced pain ratings, cortical disfacilitation (from Pz, as revealed by N150) and lower SCR were found as compared to pressure (baroreceptor deactivation). Moreover, brain evoked potentials (N150 and P260) reflecting cortical inhibition were found under condition of baroreceptor stimulation during unpleasant slides, but not during pleasant or neutral ones: this result was found in the high blood pressure subjects only. Data showed also a valence effect on pain ratings: pain was evaluated to be higher during unpleasant slides, than neutral and pleasant ones. Results are discussed in the light of "baroreceptor reward" hypothesis, which proposes a learning mechanism for the development of essential hypertension.

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 information processing and visual evoked brain potentials.

Visual evoked potentials to emotional slides presented for 2 sec. were investigated in 13 subjects. 73 emotional slides (pleasant, unpleasant, and neutral) were selected from a standardized set of photographic slides, the 1988 International Affective Picture System of Lang, Ohman, and Vaitl Visual evoked potentials were recorded from three head locations, frontal, central and parietal (Fz, Cz, and Pz). Analyses were performed in the two latency ranges: 300-400 msec. and 400-500 msec. Analyses showed an arousal effect, as indicated by a quadratic trend, indicating that emotional slides (both pleasant and unpleasant) gave higher cortical positivity than neutral ones, for all components. In addition, in the two latency epochs, larger positivities were found at Pz, compared to Fz and Cz, whereas Fz and Cz did not differ from each other.

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.

Effects of an emotional negative stimulus on the cardiac, electrogastrographic, and respiratory responses.

The experiment investigated the effects of two film sequences, one neutral and the other emotional, on the cardiac (ECG), electrogastrographic (EGG) and respiratory activities of 24 healthy students during digestion. The physiological activity was recorded before and during the projection of each film sequence. 12 subjects were shown a neutral film sequence and 12 an emotional film sequence. At the end of each viewing period, each subject completed a self-rating questionnaire on the emotional experience. Analysis indicated, with respect to the previewing (baseline) values, an increase in cardiac and respiratory rates and a decrease in electrogastrographic rates during the viewing of the film sequences. Changes in the EGG rate (baseline to viewing) were negatively correlated with the changes in ECG and respiratory rates, whereas the changes in these latter two were positively correlated. In comparing the effects of the neutral and emotional scenes the only significant result was the heart-rate increase in subjects watching the emotional sequence. Also, the self-rating of emotional experience varied with the emotional value of the sequence.

Modifications of electrogastrographic activity during the viewing of brief film sequences.

The experiment assessed the effects of two film sequences, a pleasant documentary and a distressful scene, on electrogastrographic (EGG), electromyographic (EMG), and heart-rate responses during digestion by 30 healthy students. The physiological measures were recorded before and during the projection of each film sequence. At the end of each viewing period, subjects completed a self-rating questionnaire on the emotional experience. Analysis yielded a significant increase in heart-rate and EMG values during the viewing of the film sequences and a significant decrease in amplitude of the 3 cycles per minute (cpm) wave of EGG during the unpleasant film. The type of film sequence had also a statistically significant effect on the self-ratings of emotional states.

Acute effects of furosemide on blood pressure in functionally anephric, volume-expanded rats.

The hypotensive effect of loop diuretics is primarily mediated by a decrease in extracellular fluid volume that follows the intense diuresis. In the present study we investigated whether furosemide (1.25 mg/kg i.v.) can acutely lower blood pressure independently of its diuretic action. The experiments were performed in four groups of male Wistar rats: (a) rats in which furosemide was administered after bilateral ligation of renal vessels and saline (0.9% NaCl at a rate of 0.25 ml/min to a final volume of 1% of body weight) infusion; (b) rats in which furosemide was injected after bilateral ligation of ureters and saline infusion; (c) rats pretreated with indomethacin (3 mg/kg i.p. for 4 days) in which furosemide was injected after bilateral ligation of ureters and saline infusion; (d) sham-operated rats with intact kidneys. All the groups were compared with appropriate time controls. After furosemide injection, heart rate and blood pressure were serially recorded for 30 min by plethysmography. Hematocrit, plasma 6-keto-prostaglandin F1 alpha levels and plasma renin activity were measured at baseline and 20 min after furosemide injection. No change in blood pressure followed furosemide administration in rats with ligation of the renal vessels. Conversely, furosemide induced a rapid and significant fall in blood pressure associated with a significant increase in heart rate in rats with ligation of the ureters and rats with intact kidneys. Indomethacin pretreatment prevented the furosemide-induced decrease in blood pressure in rats with ligation of the ureters. Hematocrit and plasma 6-keto-prostaglandin F1 alpha levels were not affected by furosemide in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

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.