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Biomedical subjects

F Benedetti

Publications and source records attributed to F Benedetti.

At least 73 records · Page 4Linked to original sources
PubMed1997

The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.

Placebo is a widespread phenomenon in medicine and biology and its mechanisms are understood only partially. Most of our understanding of placebo comes from studies on pain. In particular, placebo analgesia represents a situation where the administration of a substance known to be non-analgesic produces an analgesic response when the subject is told that it is a pain killer. Several theories try to explain this effect by means of anxiety mechanisms, cognitive processes and classical conditioning. However, the placebo response is bidirectional, i.e. analgesic and algesic. In fact, if a subject is told that the ineffective substance is a hyperalgesic drug, a pain increase may occur. The negative effects of placebo are called nocebo and, in extreme cases, they lead to severe pathological conditions. The neurobiology of placebo was born when some authors discovered that placebo analgesia is mediated by endogenous opioids. This claim comes from the observation that the opioid antagonist naloxone can reverse placebo analgesia. On the basis of the discovery of the anti-opioid action of the neuropeptide cholecystokinin, recent studies demonstrate that the blockade of cholecystokinin receptors potentiates the placebo analgesic response, thus suggesting an inhibitory role of cholecystokinin in placebo analgesia. Thus, by antagonizing the anti-opioid action of cholecystokinin during a placebo procedure, a potentiation of the endogenous opioid systems can be obtained.

Analgesia↗
PubMed1997

Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide.

In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

Analgesics, Non-Narcotic↗
PubMed1997

Response to clozapine in acute mania is more rapid than that of chlorpromazine.

The purpose of the present study was to compare the efficacy of clozapine with that of chlorpromazine in an open label manner (both given in association with lithium salts) in the treatment of acute mania. Thirty hospitalized manic patients were entered into the study. All patients met DSM-IV criteria for bipolar disorder, Manic Episode; 27 patients completed the study and three patients dropped for noncompliance. The duration of the study was 3 weeks. Patients were randomly assigned to two treatment groups; group 1 (n = 15) was treated with clozapine at a mean dose of 166 mg/day and group 2 (n = 12) was treated with chlorpromazine at a mean dose of 310 mg/day. Manic symptomatology was rated on Young Rating Scale for Mania (YRSM) each week; side effects were recorded on dosage records and treatment emergent symptoms; extrapyramidal acute side effects were rated on the Simpson-Angus Rating Scale performed at the beginning of the study and after 3 weeks of treatment. A two-way repeated measures analysis of variance on YRMS scores showed a significant time effect (p < 0.0001) and a significant time-group interaction (p < 0.0001). Post-hoc comparison between the two groups showed a significant difference after 2 weeks of treatment (p = 0.0001), with clozapine treated patients showing lower YRSM scores than chlorpromazine treated patients. YRSM scores at the end of the study were not significantly different. Patients treated with clozapine showed a more rapid trend toward amelioration. No clinically relevant side effect was observed during the study.

Acute Disease↗
PubMed1997

Adjuvant therapy for soft tissue sarcomas.

Primary therapy for soft tissue sarcoma is predicated on surgical resection with an adequate margin of normal tissue. For high-risk patients, local control is improved with postoperative adjuvant radiation or intraoperative brachytherapy. Despite the most recent meta-analysis or encouraging phase II data for neoadjuvant chemotherapy, there is no clearly proven role for adjuvant or neoadjuvant chemotherapy in the treatment of sarcoma. Nevertheless, distinct subpopulations of sarcoma patients are appropriate for consideration of investigational neoadjuvant/adjuvant chemotherapy due to their high risk of distant metastasis and potential for chemoresponsiveness.

Adult↗
PubMed1996

Dopamine agonist amineptine prevents the antidepressant effect of sleep deprivation.

In a double-blind study, the effects of the interaction between the administration of amineptine versus placebo and repeated cycles of total sleep deprivation (TSD), which is thought to act through an enhancement in dopaminergic transmission, were analyzed. Twenty-two consecutively admitted patients with bipolar depression formed the study group. Repeated administrations of TSD significantly enhanced perceived mood levels in placebo-treated patients, while amineptine administration blocked the antidepressant action of TSD. Hypothesized changes in brain dopaminergic transmission attributable to amineptine pretreatment are discussed.

Adult↗
PubMed1996

Infradian mood fluctuations during a Major Depressive episode.

We investigated the predictability of infradian mood fluctuations during acute depressive episodes in patients affected by mood disorders. Previous findings showed that in a subgroup of patients the depressive symptomathology fluctuates with day-to-day changes which follow cyclical patterns (termed "minicycles'). We applied time series analysis, by means of autocorrelation techniques, to time lagged serial recordings of perceived mood levels of 22 inpatients (13 Major Depressive Recurrent and 9 Bipolar Depressive Disorders). Five patients (22.7%) were shown to exhibit predictable cyclical patterns in their perceived symptomathology, ranging in length from 6 to 14 days. Our study confirms the existence and the predictability, in a subgroup of patients, of cyclical mood patterns. Preliminary evidence suggests that patients with minicycles receive more medication changes than patients without, and thus that cyclical mood fluctuations strongly interacts with both the clinical decision making process and the outcome of acute depressive episodes.

Acute Disease↗
PubMed1996

Decrease in plasma phenylalanine and tyrosine after phenylalanine-tyrosine free amino acid solutions in man.

After an overnight fast, 5 male healthy subjects ingested increasing amounts of a solution containing a fixed proportion of seven essential amino acids (L-isoleucine, 13.3%; L-leucine, 21.0%; L-lysine, 15.2%; L-methionine, 21.0%; L-threonine, 9.5%; L-tryptophan, 4.8% and L-valine, 15.2%) and lacking phenylalanine and tyrosine. The solutions caused a rapid fall in plasma phenylalanine and tyrosine which was proportional to the total amount of amino acids ingested. Following the highest dose administered (31.5 g) plasma phenylalanine and tyrosine fell to a minimum of, respectively, 12.7% and 29.8% the initial levels and remained markedly reduced at 6 hours after treatment. The decrease of tyrosine and phenylalanine levels was associated with a decrease of systolic and diastolic arterial pressure.

Adult↗
PubMed1995

Differential formation of topographic maps on the cerebral cortex and superior colliculus of the mouse by temporally correlated tactile- tactile and tactile-visual inputs.

Coincident electrical activity of nerve fibres seems to play a fundamental role in the development of ordered connections in the CNS. To test this hypothesis on the formation of topographic maps we connected two cutaneous regions of the body of newborn mice by implanting an artificial bridge of pig hair. Through this procedure we produced the mechanical fusion of the ear with either the shoulder or the nose. In these conditions the ear not only was connected with shoulder or nose, but was also in relation with the nasal or the inferior portion of visual space. Therefore the probability of temporally correlated tactile-tactile inputs (ear-shoulder or ear-nose) as well as tactile-visual inputs (ear-inferior or ear-nasal visual space) increased. By recording from the primary somatosensory cortex and superior colliculus, we found that the formation of topographic maps was based on different principles. The somatosensory cortex developed in terms of tactile-tactile correlated inputs, showing somatosensory neurons with receptive fields extending through the fused parts of the body. Conversely, the superior colliculus processed tactile-visual correlated inputs; we found somatosensory-visual bimodal neurons with visual receptive fields extending into the portion of visual space where the artificial bridge was directed. These results suggest that the fusion of two body parts is represented in terms of cutaneous coordinates in the cortex and external world (visual) coordinates in the superior colliculus. Therefore the differential tactile-tactile and tactile-visual coincident activity seems to be correlated to the different meaning of information processing of these two brain regions.

Acoustic Stimulation↗
PubMed1995

Orienting behaviour and superior colliculus sensory representations in mice with the vibrissae bent into the contralateral hemispace.

When a tactile stimulus touches the body on one side, animals show an orienting response toward that side with the eyes, the head or the entire body. This movement requires the transformation of sensory information into motor commands. The superior colliculus is supposed to be a fundamental part of the brain where this sensorimotor transformation occurs and where one of the possible mechanisms could be the alignment among sensory and motor topographies. We changed the body shape of mice in order to analyse the development of new orienting responses following tactile stimulation. To do this, we bent the left vibrissae from left to right such that they were located in the right portion of the visual hemifield. If left-right inversion was performed in adults, tactile stimulation of the left vibrissae performed from the right produced wrong orienting movements to the left. Conversely, if left-right inversion was performed in newborns, mice learned to respond correctly to the right. By recording from superior colliculus multisensory neurons of mice whose vibrissae were displaced at birth, we found a shift of visual and auditory receptive fields from left to right in those multisensory neurons receiving tactile input from the displaced vibrissae. These results show the strict relation existing between the neuronal modifications in the superior colliculus and the changes in orienting behaviour. These findings also suggest two important conclusions. First, sensory mapping in the superior colliculus depends on sensory inputs coming from the same portion of space.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia.

9-cis retinoic acid (RA) is a high-affinity ligand for both retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). Although all-trans RA does not bind to RXRs, RAR/RXR heterodimers or RXR/RXR homodimers bind to specific DNA response elements and modulate proliferation and differentiation of normal and malignant cells. Because the development of clinical resistance to all-trans RA has been associated with a progressive decrease in plasma drug concentrations, we evaluated the ability of 9-cis RA to induce in vitro cytodifferentiation in subclones of a retinoid-sensitive and resistant APL cell line (NB4) and in short-term cultures of fresh leukemic cells aspirated from patients. We also evaluated the clinical activity and pharmacokinetics of 9-cis RA (LGD 1057) in patients with APL who were previously treated with all-trans RA. In vitro tests of both retinoid-sensitive NB4 cells, as well as samples of fresh cells from 11 patients with APL, showed relatively equivalent degrees of sensitivity to both 9-cis RA and all-trans RA at concentrations ranging from 10(-6) to 10(-8) mol/L; however, no substantial cytodifferentiation was observed using either drug alone or in combination (10(-6) mol/L of each) in retinoid-resistant NB4 cells. Seven patients with APL who had previously relapsed from a remission induced by all-trans RA were treated with 9-cis RA at daily oral doses ranging from 30 to 230 mg/m2. Pharmacokinetic studies showed that the mean terminal plasma half-life of 9-cis RA (1.3 hours) changed very little after several weeks of dosing, although the mean change per dose level in area under the plasma concentration x time curves and peak plasma concentrations showed a decrease by 49% and 45%, respectively. Peak plasma concentrations equaled or exceeded concentrations that were effective against retinoid-sensitive cells in vitro. Despite these favorable pharmacokinetic results, only one of the seven patients achieved complete remission, corroborating in vitro studies of blasts from three of the nonresponders that showed a relatively equivalent degree of resistance to both retinoids. Our results suggest that while 9-cis RA may not induce its own catabolism to the same degree as all-trans RA, this feature does not appear to overcome clinically acquired resistance to all-trans RA in APL. Nonetheless, the drug can induce complete remissions in patients with APL and may be useful for extended therapy in other diseases. Future studies should address the use of lower doses in patients who have not previously received retinoid therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1995

The effects of early postnatal modification of body shape on the somatosensory-visual organization in mouse superior colliculus.

Different regions of the body of an animal have their own shape and location within visual space. Accordingly, in the superior colliculus there are somatosensory-visual bimodal neurons receiving tactile and visual input from the same region of space. In newborn mice, we changed the position of some body parts within visual space in order to see what happened to the alignment of the somatosensory and visual receptive fields of superior colliculus bimodal neurons. To do this, we modified the shape of the head by displacing the superior vibrissae and the ears, normally in the superior portion of visual space, into the inferior visual space. Analogously, we bent the inferior vibrissae into the superior visual space. At the sixth postnatal week we recorded from somatosensory-visual bimodal neurons of the deep layers of the superior colliculus and found that the tactile and visual receptive fields were aligned. Neurons receiving tactile input from the downward-displaced superior vibrissae and ears showed visual receptive fields in the inferior portion of visual space, whereas neurons receiving input from the upward-displaced inferior vibrissae showed visual receptive fields in the superior visual space. These results show that an experience-dependent interaction between visual and somatosensory inputs occurs during development, and that early exposure to abnormal visual-somatosensory experience modifies the organization of multisensory neurons in the superior colliculus.

Animals↗
PubMed1995

Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality.

To determine whether pulmonary function test (PFT) results after marrow transplantation were predictive of nonrelapse mortality, a review was made of prospective, nonrandomized PFT results for association with nonrelapse mortality by log-rank test and Cox proportional hazards modeling. The setting was a tertiary referral center. The patients were all marrow recipients who performed PFT between Days 60 and 120 after marrow transplantation between July 1, 1983 and December 31, 1990 (n = 906). At 3 mo after transplantation, the mean values for total lung capacity (TLC) and diffusing capacity decreased, and restrictive ventilatory defects (TLC < 80% of predicted) were noted in 34% of the cohort. Airflow rates (FEV1/FVC) were unchanged. A restrictive lung defect at 3 mo after transplant or a significant decline (> or = 15%) in TLC from baseline despite remaining within the normal range was associated with a twofold increased risk of nonrelapse mortality. Neither airflow obstruction nor impairment in diffusing capacity was associated with an increased risk. Abnormalities of the TLC at 3 mo after transplant were associated with death with respiratory failure, but not with an increased risk of chronic graft-versus-host disease (GVHD). There is an increase in the nonrelapse mortality rate associated with either the presence of a restrictive defect 3 mo after marrow transplantation or a significant decline in lung volume compared with baseline. This effect is most pronounced more than 1 yr after marrow transplant and appears to be a result of an increase in the rate of death with respiratory failure, not chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Implantation of artificial whiskers on the ears of newborn mice induces visual re-mapping in the superior colliculus.

In newborn mice, we modified the body scheme by implanting artificial whiskers (pig hair) on the ears, which are located in the superior and temporal portions of the visual field. In normal mice, multisensory neurons in the deep layers of the superior colliculus receiving somatosensory input from the ears showed visual receptive fields in the superior and temporal portions of visual space. By contrast, in the implanted mice, there was a modification of the visual receptive fields strictly related to the direction of the artificial whiskers. If these were directed toward the nose, visual receptive fields expanded in the nasal direction. If the whiskers were directed downward, visual receptive fields expanded downward. These results show that an interaction between visual and somatosensory inputs occurs in the superior colliculus during development, and that the collicular visual topography undergoes a re-mapping on the basis of the altered tactile experience.

Animals↗
PubMed1994

T suppressor activated lymphocytes (CD8+/DR+) inhibit megakaryocyte progenitor cell differentiation in a case of acquired amegakaryocytic thrombocytopenic purpura.

Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare disease, characterized by isolated thrombocytopenia and the absence of megakaryocytes in bone marrow. Recent studies suggest that this syndrome is due to diverse etiologies. Humoral or cellular mediated suppression has been alternately demonstrated using an in vitro colony assay for megakaryocytic progenitor cells (colony forming units megakaryocyte, [CFU-meg]). We studied a patient affected by AATP, who was not responsive to conventional therapy, but did respond to antilymphocyte globulin. The immunological characterization of marrow lymphocytes showed a marked increase of T activated suppressor cells (CD8+/DR+). Low density bone marrow mononuclear nonadherent cells (MNAC) from the patient, either in aplastic phase or in remission phase, were plated in plasma clot either directly or after T cell depletion (T-dep MNACs). Co-cultures with normal marrow cells were performed using either T lymphocytes from a normal volunteer donor or patient T lymphocytes. In some experiments we added autologous serum instead of fetal calf serum (FCS). In standard conditions, we observed increased colony formation, which was more evident in remission phase and especially significant after T cell depletion. The T lymphocytes from patient marrow did not modify the number of CFU-meg when co-cultured with allogeneic cells. These results indicate that an immune-mediated mechanism could be responsible for this case of AATP, and that the T cell subset CD8+/DR+ is capable of exerting suppression on megakaryocyte differentiation. This suppressive effect seems restricted to patient cells, suggesting a specific auto-sensitization.

Adult↗
PubMed1994

Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin's disease and correlate with clinical features and prognosis.

PURPOSE: To evaluate the serum levels of the soluble form of the CD30 molecule (sCD30) in patients with Hodgkin's disease (HD) to establish whether there is a correlation with clinical features at presentation and prognosis. PATIENTS AND METHODS: The sCD30 serum levels of 117 patients were measured at diagnosis with a commercial sandwich enzyme-linked immunoadsorbent assay (ELISA) test kit, and in 78 of these patients the sCD30 levels were also recorded during the follow-up period. RESULTS: sCD30 levels at diagnosis were increased (> 20 U/mL) in a high proportion of patients (87.2%; mean +/- SD, 108 +/- 134 v 5.3 +/- 5.7 U/mL in controls, P < .0001) and correlated with stage (stages I + II, 73 +/- 97 U/mL; III + IV, 162 +/- 165 U/mL; P < .0001), with presence of B symptoms (stage A, 69 +/- 82 U/mL; stage B, 162 +/- 171 U/mL; P < .0001), and, to some extent, with tumor burden (bulky presentation, 141 +/- 129 U/mL; nonbulky, 91 +/- 133 U/mL; P = .058). Patients with sCD30 levels greater than 100 U/mL at diagnosis had a significantly higher rate of poor outcome in terms of failure to achieve a complete remission (CR) or disease relapse after CR achievement. In fact, the event-free survival (EFS) duration of patients with sCD30 levels greater than 100 U/mL was significantly worse (P = .0016). Using multivariate analysis, an sCD30 level greater than 100 U/mL retained its significance after adjustment for other prognostic parameters. CONCLUSION: sCD30 in HD at presentation strictly correlates with clinical features. Serum levels greater than 100 U/mL at diagnosis entail a significantly higher risk of treatment failure, a factor that is independent of other prognostic parameters.

Adolescent↗