Searching for celiac disease in pediatric general practice.
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Abdominal Pain↗
Biomedical subjects
F Benedetti
Publications and source records attributed to F Benedetti.
Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction.
The clinical usefulness of total sleep deprivation (TSD) in the treatment of bipolar depression is hampered by a high-rate short-term relapse. Previous literature has suggested that both long-term lithium treatment and light therapy could successfully prevent relapse. We randomized 115 bipolar depressed inpatients to receive three cycles of TSD, alone or in combination with morning light exposure, given at an intensity of 150 or 2500 lux. Forty-nine patients were undergoing long-term treatment with lithium salts (at least 6 months), while 66 patients were taking no psychotropic medication. Mood was self-rated by the Visual Analogue Scale three times a day during treatment. The results showed that both light therapy and ongoing lithium treatment significantly enhanced the effects of TSD on the perceived mood, with no additional benefit when the two treatments were combined. Subjective sleepiness during TSD, as rated by the self-administered Stanford Sleepiness Scale, was significantly reduced by light exposure, and was correlated with the outcome. This study confirms the possibility of obtaining a sustained antidepressant response to TSD in bipolar patients.
Adult↗
Computational design of new cyclic urea inhibitors for improved binding of HIV-1 aspartic protease.
We report in this paper the design, by means of computational techniques, of new cyclic urea inhibitors of the HIV aspartic protease. The relationship between the complexation energies of the enzyme with known inhibitors and the experimentally determined log K(i) have been studied and used to predict inhibition constants for new inhibitors.
Anti-HIV Agents↗
Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery.
Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia. hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5-17 h), lower peak serum concentrations (aerosol 71 +/- 31 ng/ml, IT 68 +/- 50 ng/ml), and lower liver levels (aerosol 111 +/- 28 ng/g, IT 753 +/- 350 ng/g) than the same dose administered IV (2 h, 838 +/- 56 ng/ml, 4,258 +/- 1,006 ng/g, respectively; P < 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing.
Administration, Inhalation↗
Detection of an anti-RhD antibody 2 years after sensitization in a patient who had undergone an allogeneic BMT.
We describe an HLA matched bone marrow transplantation with minor ABO incompatibility and RhD mismatch (donor RhD negative and recipient RhD positive). GVHD appeared on day +96 and therapy with steroid and cyclosporin was started. When GVHD disappeared and immunosuppressive therapy was stopped (2 years after BMT), an anti-RhD antibody was detected in the patient's serum. The delayed appearance of this antibody may have been associated with the prolonged immunosuppression that was required for treatment of the patient's GVHD.
Adult↗
Aspartic protease inhibitors. An integrated approach for the design andsynthesis of diaminodiol-based peptidomimetics.
Aspartic proteases play key roles in a variety of pathologies, including acquired immunodeficiency syndrome. Peptidomimetic inhibitors can act as drugs to combat these pathologies. We have developed an integrated methodology for preparing human immunodeficiency virus (HIV)-1 aspartic protease diaminodiol inhibitors, based on a computational method that predicts the potential inhibitory activity of the designed structures in terms of calculated enzyme-inhibitor complexation energies. This is combined with a versatile synthetic strategy that couples a high degree of stereochemical control in the central diaminodiol module with complete flexibility in the choice of side chains in the core and in flanking residues. A series of 23 tetrameric, pentameric and hexameric inhibitors, with a wide range of calculated relative complexation energies (-47.2 to +117 kJ.mol-1) and predicted hydrophobicities (logPo/w = 1.8-8.4) was thus assembled from readily available amino acids and carboxylic acids. The IC50 values for these compounds ranged from 3.2 nM to 90 microM, allowing study of correlations between structure and activity, and individuation of factors other than calculated complexation energies that determine the inhibition potency. Multivariable regression analysis revealed the importance of side-chain bulkiness and rigidity at the P2, P2' positions, suggesting possible improvements for the prediction process used to select candidate structures.
Computational Biology↗
Autonomic responses and pain perception in Alzheimer's disease.
We analysed the effects of electrical noxious stimulation on the autonomic nervous system of Alzheimer's disease (AD) patients who were assessed by means of the Mini Mental State Examination test (MMSE). To do this, we used electrical stimuli at two different intensities: just above pain threshold and twice pain threshold. We recorded heart rate and systolic blood pressure by using conventional electrocardiography and finger photo-plethysmography. When a pain stimulus just above threshold was delivered, AD patients were found to have blunted autonomic responses compared to controls of the same age. Similarly, prestimulus expectation produced a less pronounced increase of the responses in AD patients compared to the controls. However, when the painful stimulus was increased to twice the pain threshold, the systolic blood pressure increase of AD patients did not differ from the controls, whereas heart rate increase was still slightly diminished. By contrast, pain perception was similar in the two groups when the stimulus was at pain threshold, whereas it was blunted in AD patients when the stimulus was twice the pain threshold. These findings show that in AD mild noxious stimulation produces blunted autonomic responses and normal pain perception, whereas strong noxious stimulation produces quasi-normal autonomic responses and blunted pain perception. These results indicate that AD patients have an increased threshold for both autonomic activation and pain tolerance.
Aged↗
Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene.
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Adult↗
Intracellular cytokine profile of cord blood T-, and NK- cells and monocytes.
BACKGROUND AND OBJECTIVES: Many functional peculiarities of cord blood (CB) lymphocytes and antigen presenting cells, including cytokine production, are associated with low intensity of innate and acquired (cellular and humoral) responses. These peculiarities may have implications both for immunologic maturation in post-natal life and for immune functions after CB transplantation [e.g. the lower incidence of graft-versus-host disease (GvHD) in comparison with after bone marrow transplantation (BMT)]. The aim of our study was to compare the intracellular production of cytokines involved both in phagocyte-dependent immunity/inflammation and in humoral immune responses in CB and adult peripheral blood (PB). DESIGN AND METHODS: Intracellular single cell analysis by flow cytometry was used to detect, following aspecific in vitro stimulation, the production of interferon (IFN)-gamma, Interleukin (IL)-2, IL-1alpha, IL-1beta, IL-8, tumor necrosis factor (TNF)-alpha and -beta, IL-4, IL-5, IL-6, IL-10 and IL-13 by T-cell subsets, NK-cells and monocytes obtained from 10 CB and 10 PB samples. The cytokine production was expressed as the percentage of positive cells. RESULTS: Significantly lower number of CD4+ T-cells producing IFN-g (p<0.001), TNF-alpha (p=0.012) and TNF-beta (p=0.03) and of CD8+ T-cells producing IFN-gamma (p<0.001), IL-2 (p=0.005) and TNF-alpha (p<0.001) were found in CB as compared to PB. In CB we have also found a lower number of NK cells and monocytes producing TNF-alpha (p<0.001 and p=0.001, respectively). In contrast, the number of IL-1alpha+ monocytes was higher in CB than in PB (p=0.03). INTERPRETATION AND CONCLUSIONS: Our data confirm that the cytokines which normally sustain the phagocytic-dependent T helper/cytotoxic 1-type immune responses (IFN-gamma, IL-2 and TNF-alpha) and the NK cell/monocyte-dependent aspecific responses (TNF-alpha) are reduced in CB. Since these cytokines are also involved in acute GvHD pathogenesis, these results are in keeping with the evidence of a low incidence of acute GvHD after CB transplantation.
Adult↗
Dopamine receptor D4 is not associated with antidepressant activity of sleep deprivation.
Total sleep deprivation (TSD) is an effective treatment for mood disorders which is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. However, not all patients respond to TSD and genetic factors are likely to play a major role in determining TSD response. The aim of this study is to investigate the influence of dopamine receptor D4 exon 3 (DRD4) variants on TSD antidepressant efficacy in bipolar disorder. One hundred and twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with repeated cycles of TSD and were typed for DRD4 variants at the third exon using polymerase chain reaction (PCR) techniques. DRD4 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. DRD4 exon 3 variants are not a main factor influencing TSD outcome in bipolar disorder.
Alleles↗
Stereoselective synthesis of non symmetric dihydroxyethylene dipeptide isosteres via epoxy alcohols derived from alpha-amino acids.
(1R,2R,3S,4S)-4-Amino-3-hydroxy-1,2-epoxybutanes, accessible in four steps from L-aminoesters, react regio- and stereoselectively with diethyl aluminum cyanide to give (1R,2S,3S,4S)-4-amino-2,3-dihydroxynitriles. Hydrolysis yields hydroxylactones equivalent to 2,3-dihydroxy-4-aminoacids. The sequence provides a novel approach to dihydroxyethylene isosteres potentially useful for new HIV-protease inhibitors.
Alcohols↗
Olanzapine-induced neutropenia after clozapine-induced neutropenia.
Olanzapine is a new antipsychotic drug, pharmacodynamically similar to clozapine, but putatively devoid of haematological iatrogenicity. We report a case of relapse of previously clozapine-induced neutropenia after olanzapine treatment.
Adult↗
Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression.
Sleep deprivation is a potentially useful non-pharmacological treatment for depression. A relationship between sleep loss and the onset of mania has been reported, so it is possible that a switch from depression into mania after sleep deprivation might be expected in bipolar depressed patients who are treated with sleep deprivation. In a sample of 206 bipolar depressed treated with three cycles of sleep deprivation, alone or in combination with heterogeneous medications, we observed a 4.85% switch rate into mania and a 5.83% switch rate into hypomania. These percentages are comparable to those observed with antidepressant drug treatments.
Adult↗
Somatotopic activation of opioid systems by target-directed expectations of analgesia.
We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediated by endogenous opioid systems. These findings show that a spatially directed expectation of pain reduction is capable of inducing a specific effect only on the part of the body which is the target of the expectation. Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body but only on the part where expectancy is directed. This suggests that a highly organized and somatotopic network of endogenous opioids links expectation, attention, and body schema.
Analgesia↗
Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.
We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.
Adult↗
Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine.
Three patients with pancreatic carcinoma treated with gemcitabine for 1 year developed clinical and laboratory findings compatible with an indolent form of the hemolytic-uremic syndrome. Renal biopsy specimens in two of these patients showed the characteristic features of thrombotic microangiopathy, and a skin biopsy specimen from the third patient, who presented with livedo reticularis, showed intravascular fibrin deposition. Thrombotic microangiopathy may represent a toxic effect of long-term gemcitabine therapy.
Aged↗
Pain threshold and tolerance in Alzheimer's disease.
We tested both pain thresholds and pain tolerance in patients with Alzheimer's disease (AD) by means of phasic and tonic noxious stimuli. In the first case, electrical stimulation was used, whereas in the second case arm ischemia was studied. By comparing AD patients with normal subjects of the same age, we found no differences in stimulus detection and pain thresholds, whereas a clearcut increase in pain tolerance was present in AD patients. The severity of AD was assessed by means of the Mini Mental State Examination test (MMSE) and the spectral analysis of the electroencephalogram (EEG). There was a straightforward correlation between MMSE scores and pain tolerance such that the more severe the cognitive impairment the higher the tolerance to pain. In addition, analysis of the EEG power spectra indicated that patients with low alpha and high delta peaks showed an increase in pain tolerance to both electrical stimulation and ischemia. These findings show that, whereas the sensory-discriminative component of pain is maintained in AD patients, pain tolerance is altered and depends on cognitive and affective factors. Thus, pain tolerance is tightly related to the severity of the disease according to the rule, 'the more severe the MMSE and EEG changes, the higher the tolerance to pain'.
Aged↗
Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial.
Total sleep deprivation (TSD) shows powerful but transient clinical effects in patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT1A autoreceptor, thus improving the antidepressant effect of selective serotonin reuptake inhibitors. We evaluated the interaction of TSD and pindolol in the treatment of acute episodes of bipolar depression. Forty bipolar depressed inpatients were randomized to receive pindolol 7.5 mg/day or placebo for nine days in combination with three consecutive TSD cycles. Pindolol significantly improved the antidepressant effect of TSD, and prevented the short-term relapse after treatment. The response rate (HDRS scores < 8) at the end of treatment was 15/20 for pindolol, and 3/20 for placebo. Coadministration of pindolol and TSD resulted in a complete response, which could be sustained for six months with lithium salts alone, in 65% of cases. This results suggest a major role for serotonergic transmission in the mechanism of action of TSD, and makes TSD treatment more effective in the treatment of bipolar depression.
Acute Disease↗