Biomedical subjects

V Piguet

Publications and source records attributed to V Piguet.

At least 37 records · Page 2Linked to original sources

PubMed1999

The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors.

The human and simian immunodeficiency viruses (HIV and SIV) downregulate the cell surface expression of CD4, their primary receptor, and of class I histocompatibility complex (MHC-I), a critical mediator of immune recognition. While the first of these effects seems important to preserve viral infectivity, the second likely promotes immune evasion. Three HIV-1 proteins, Nef, Env and Vpu, contribute to downregulate CD4, Env forms a complex with CD4 in the endoplasmic reticulum, thereby retaining the receptor in this compartment. Nef and Vpu, on the other hand, act as connectors between CD4 and specific intracellular trafficking pathways, targeting the receptor for degradation in the lysosome and the proteasome, respectively. Some of the downstream partners of the viral proteins in these events have been identified, and include the adaptor complex of clathrin-coated pits, the beta subunit of COP-I coatomer, and the ubiquitin pathway-related h-beta TrCP protein. HIV-induced MHC-I downregulation, mostly the effect of Nef, also reflects a redistribution of this receptor, with its accumulation in the Golgi. The modalities of this process, however, are as yet imperfectly understood. New evidence indicates that the mechanisms employed by primate lentiviruses to downmodulate CD4 and MHC-I are also exploited by a number of cellular regulatory processes.

Adaptor Protein Complex alpha Subunits↗

PubMed1999

Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking.

The Nef protein of primate lentiviruses triggers the accelerated endocytosis of CD4 and of class I major histocompatibility complex (MHC-I), thereby down-modulating the cell surface expression of these receptors. Nef acts as a connector between the CD4 cytoplasmic tail and intracellular sorting pathways both in the Golgi and at the plasma membrane, triggering the de novo formation of CD4-specific clathrin-coated pits (CCP). The downstream partners of Nef in this event are the adapter protein complex (AP) of CCP and possibly a subunit of the vacuolar ATPase. Whether Nef-induced MHC-I down-regulation stems from a similar mechanism is unknown. By comparing human immunodeficiency virus type 1 (HIV-1) Nef mutants for their ability to affect either CD4 or MHC-I expression, both in transient-transfection assays and in the context of HIV-1 infection, it was determined that Nef-induced CD4 and MHC-I down-regulation constitute genetically and functionally separate properties. Mutations affecting only CD4 regulation mapped to residues previously shown to mediate the binding of Nef to this receptor, such as W57 and L58, as well as to an AP-recruiting dileucine motif and to an acidic dipeptide in the C-terminal region of the protein. In contrast, mutation of residues in an alpha-helical region in the proximal portion of Nef and amino acid substitutions in a proline-based SH3 domain-binding motif selectively affected MHC-I down-modulation. Although both the N-terminal alpha-helix and the proline-rich region of Nef have been implicated in recruiting Src family protein kinases, the inhibitor herbimycin A did not block MHC-I down-regulation, suggesting that the latter process is not mediated through an activation of this family of tyrosine kinases.

CD4 Antigens↗

PubMed1999

Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan.

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.

Adult↗

PubMed1998

[Influence of sex on reporting pain].

In many epidemiological pain studies, women more frequently report more intense, frequent and long-lasting or chronic transient pain than men. In our retrospective study including hospitalised patients referred to a pain centre, prevalence of headaches, musculoskeletal pain and somatoform pain was observed in women, as described in the literature. Generally pain intensity was higher in women and pain was more frequently controlled in men, but when intensity and pain control were compared according to the pain aetiologies, no gender difference was found. Drug treatments were adapted to pain aetiologies, which accounted for the observed differences. In hospitalised patients the significant differences observed in intensity, pain control and treatment reflect the heterogeneity of pain aetiologies rather than gender differences.

Adult↗

PubMed1998

Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes.

The Nef protein of primate lentiviruses down-regulates the cell surface expression of CD4 and probably MHC I by connecting these receptors with the endocytic machinery. Here, we reveal that Nef interacts with the mu chains of adaptor complexes, key components of clathrin-coated pits. For human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) Nef, this interaction occurs via tyrosine-based motifs reminiscent of endocytosis signals. Mutating these motifs prevents the binding of SIV Nef to the mu chain of plasma membrane adaptor complexes, abrogates its ability to induce CD4 internalization, suppresses the accelerated endocytosis of a chimeric integral membrane protein harboring Nef as its cytoplasmic domain and confers a dominant-negative phenotype to the viral protein. Taken together, these data identify mu adaptins as downstream mediators of the down-modulation of CD4, and possibly MHC I, by Nef.

Amino Acid Sequence↗

PubMed1998

[Factors associated with refractory cancer pain].

Cancer pain can be effectively controlled in most patients by classical pharmacological treatment. We retrospectively studied the characteristics and factors associated with non responsive pain. Between 1989 and 1996, 1767 patients were referred to our pain center; 831 (47%) had cancer pain and from 787 evaluable cases 118 (15%) experienced non-controlled pain whereas good pain control was achieved within a few days in 669 (85%) patients. Gender, age, cancer type, metastasis, initial pain intensity, nociceptive or neuropathic components and administration of adjuvant therapies were similar in both groups. On the other hand, diffuse pain, abdominal pain, terminal care, near death and doses of strong opioids were significantly different. Factors associated with therapeutic failure were conflicts, life and complications and breakthrough pain. In the presence of refractory cancer pain the factors predictive of therapeutic failure should be identified in order to optimize individual pain treatment.

Adult↗

PubMed1998

[Genetic and environmental effects on neuromodulation and the antinociceptive effect of dextromethorphan].

Administration of NMDA antagonists leads to attenuation or disappearance of some symptoms of central sensitization, such as secondary hyperalgesia. However, the side effects of NMDA antagonists to a large extent counterbalance the expected benefits, thus preventing wide or prolonged use. Dextromethorphan and its metabolite dextrophan, on the other hand, are established and safe drugs. Experimentally they both antagonize the NMDA receptor. This study evaluates the effects of dextromethorphan and its metabolite in pain models using electrical stimulation for testing the antinociceptive effect and capsaicin-induced hyperalgesia. Dextromethorphan shows clear antinociceptive as well as neuromodulary effects, both depending heavily on the cytochrome P450 2D6 phenotype (CYP2D6).

Adult↗

PubMed1998

Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex.

OBJECTIVE: The analgesic efficacy of intravenous doses of acetaminophen (paracetamol) 0.5 g, 1 g and 2 g (administered as propacetamol) was assessed in 11 healthy subjects in a randomised, double-blind, placebo-controlled crossover study. The antinociceptive effect was assessed over 8 h by measurement of the nociceptive flexion reflex threshold (R-III) in response to selective transcutaneous electrical stimulations. RESULTS: After acetaminophen 0.5 g, R-III increased to a mean maximum of 23% over baseline values; after 1 g to 28%, and after 2 g to 40%. The AUC(0-8 h) of the analgesic effects and the AUC(0-8 h) of plasma concentrations closely correlated and were dose-dependent: rs = 0.37, for R-III and rs = 0.94, for the plasma concentrations. Intravenous acetaminophen exerted a dose-dependent central antinociceptive effect.

Acetaminophen↗

PubMed1998

Use of the label "litigation neurosis" in patients with somatoform pain disorder.

The use of the term "litigation neurosis"--a condition with controversial clinical significance--might correspond to the expression for a difficult physician-patient relationship. The characteristics of patients with a DSM-III-R diagnosis of somatoform pain disorder who had been labeled "litigation neurosis" by their physicians were explored. Among 74 patients referred to a pain clinic, 30% had been labeled litigation neurosis, and among 81 patients referred while claiming disability benefits, 19% had been thus categorized. The attribution of this label was neither correlated to actually being involved in a claim for disability benefits nor to involvement in legal action. Patients who had been designated with litigation neurosis were characterized by a lower educational level, a higher rate of DSM-III-R major depression, and a much higher frequency of personality disorders than patients who were not thus labeled. We postulate that the communication style of patients with this constellation of characteristics, in particular the presence of psychiatric comorbidity, may have engendered a difficult doctor-patient relationship, leading physicians to use the label in the absence of objective evidence of litigation or involvement in legal action. We agree that the inappropriate use of labels such as "litigation neurosis" should be questioned.

Adult↗

PubMed1997

Nef-mediated clathrin-coated pit formation.

The sequence of events leading to clathrin-coated pit (CCP) nucleation on the cell surface and to the incorporation of receptors into these endocytic structures is still imperfectly understood. In particular, the question remains as to whether receptor tails initiate the assembly of the coat proteins or whether receptors migrate into preformed CCP. This question was approached through a dissection of the mechanisms implemented by Nef, an early protein of human and simian immunodeficiency virus (HIV and SIV, respectively), to accelerate the endocytosis of cluster of differentiation antigen type 4 (CD4), the major receptor for these viruses. Results collected showed that: (a) Nef promotes CD4 internalization via an increased association of CD4 with CCP; (b) the Nef-mediated increase of CD4 association with CCP is related to a doubling of the plasma membrane area occupied by clathrin-coated structures; (c) this increased CCP number at the plasma membrane has functional consequences preferentially on CD4 uptake and does not significantly affect transferrin receptor internalization or fluid-phase endocytosis; (d) the presence of a CD4 cytoplasmic tail including a critical dileucine motif is required to induce CCP formation via Nef; and (e) when directly anchored to the cytoplasmic side of the plasma membrane, Nef itself can promote CCP formation. Taken together, these observations lead us to propose that CD4 can promote CCP generation via the connector molecule Nef. In this model, Nef interacts on one side with CD4 through a dileucine-based motif present on CD4 cytoplasmic tail and on the other side with components of clathrin-coated surface domain (i.e., adaptins). These Nef-generated complexes would then initiate the nucleation of CCP.

CD4 Antigens↗

PubMed1997

DuP 532, an angiotensin II receptor antagonist: first administration and comparison with losartan.

We investigated the tolerability and angiotensin II antagonist activity of oral DuP 532 in healthy male subjects. DuP 532 (1 to 200 mg) was well tolerated, with no effect on blood pressure or heart rate. Compared with losartan (100 mg), DuP 532 (200 mg) was a weak antagonist of pressor responses to intravenous angiotensin II. Maximum inhibition of diastolic pressor response was 86% (95% confidence interval [CI], 84%, 88%) approximately 4.6 hours after losartan and 48% (95% CI, 38%, 56%) 8.7 hours after DuP 532. Twenty-four hours after dosing, inhibition by losartan and DuP 532 was similar (40% to 45%). DUP 532 is extensively bound in human plasma, with an in vitro free fraction of 0.06. Although DuP 532 and EXP3174 (losartan's active metabolite) have similar AT1-receptor potency, and plasma concentrations of DuP 532 were much greater than losartan/EXP3174, the level of antagonism was much less for DuP 532. These results indicate that multiple factors determine the in vivo potency of angiotensin II antagonists, including affinity for and distribution to the receptor as modulated by plasma binding.

Adult↗

PubMed1996

Contribution of monoaminergic modulation to the analgesic effect of tramadol.

1. In humans, the central analgesic effect of tramadol 100 mg orally is only partially reversed by the opioid antagonist naloxone (0.8 mg intravenously). As suggested by in vitro and animal data tramadol analgesia may thus result from an action on opioid as well as monoaminergic pathways. We therefore investigated the effect of alpha 2-adrenoceptor antagonism with yohimbine on tramadol analgesia. 2. Healthy volunteers (n = 10) received tramadol (100 mg orally), followed (+3 h) by yohimbine (0.1 mg kg-1 intravenously), and yohimbine + naloxone (0.8 mg intravenously) and their respective placebo according to a randomized, double-blind crossover, placebo (P) controlled design. Analgesia was assessed over 8 h by subjective pain threshold (pain intensity numerical scale--PINS) and objective pain threshold (RIII nociceptive reflex--RIII) monitoring. 3. Tramadol induced a significant increase in both pain thresholds. Peak analgesic effect was observed at 3.7 h (RIII + 39.6 +/- 3.9% and PINS 50.1 +/- s.e.mean 5%) and the analgesia lasted about 6 h. 4. Yohimbine significantly reversed the analgesic effects of tramadol for 2.8 h with a maximum decrease of 97 +/- 4% (RIII) and 67 +/- 12% (PINS), whereas the addition of naloxone abolished tramadol effects throughout the study period with a decrease of 90 +/- 6% (RIII) and 79 +/- 9% (PINS), P < 0.05). 5. Yohimbine alone did not significantly reduce pain thresholds. 6. alpha 2-Adrenoceptor antagonism reverses tramadol effects, thus pointing to the significant role of monoaminergic modulation and the synergy with opioid agonism in tramadol antinociception after a single oral dose.

Adrenergic alpha-Antagonists↗

PubMed1995

[Rural communes and small towns in the urban hierarchy].

"A determining factor in the demographic and employment dynamics of rural communes and certain small towns [in France] is how far they are from the nearest large town. Demographic dynamics and employment trends are somewhat adverse for those living far from urban influences. The main reasons for this would appear to be the slump in agriculture. This said, demographic and employment trends are much improved nearer the large towns, especially since the towns exerting the influence have more inhabitants." (SUMMARY IN ENG AND GER AND SPA)

Demography↗

PubMed1994

[Which analgesic dosage of paracetamol?].

The purpose of this study was to evaluate the dose-response of paracetamol and to assess its plasma concentration-effect relationship. According to a randomized, double-blind, and placebo controlled design healthy volunteers (n = 11) received 0.5, 1 and 2 g paracetamol (as propacetamol) intravenously (15 min). The extent of analgesic effect was measured over 8 hours by objective pain threshold (R-III) monitoring after selective transcutaneous electrical stimulation of the ipsilateral sural nerve. Maximal R-III threshold increase is at 2 hours after 0.5 g and 2.5 hours after 1 g and 2 g. The delayed peak effects, when compared to peak plasma concentrations, draw counter clockwise hysteresis. Duration of paracetamol antinociceptive effect increased concomitantly to dosage increment. Intravenous paracetamol exerts a dose-dependent central analgesia.

Acetaminophen↗

PubMed1994

[Absence from work and illness behavior in patients with chronic pain].

Factors relating to working status, i.e. whether the subject is still at work or on workmen's compensation, have been studied in chronic pain patients. Sociodemographic and pain variables were not correlated with absence from work, nor was diagnosis. However, beliefs and attitudes concerning pain differed between patients still working and those on workmen's compensation. In chronic pain patients medical attention should focus not only on description of symptoms but also on the "illness behaviour" dimension.

Absenteeism↗

PubMed1994

[Predictive factors of resistance to treatment of neuropathic pain].

The aim of this retrospective study was to examine factors related to symptomatic pain treatment in 992 hospitalized patients referred to the pain clinic. These patients accounted for 1440 different pains (1.5 pains/patient), of nociceptive (59%), or neuropathic (24%) origin, a combination of both (16%) and of unidentified (1%) origin. Patients resistant to therapy did not differ from nonresistant patients (62%) in terms of age, sex, or number of pains. Although recommended pharmacological treatments were pursued, the neuropathic origin of pain was a factor in resistance to treatment. Among the neuropathic pains resistant to treatment (42%) a central nervous origin is more frequently found. Resistance to pain was more frequently encountered after strokes, primitive tumor of the central nervous system or traumatic plexopathy, whereas peripheral lesions of the nervous system were more easily controlled by symptomatic treatment. This study shows that central neuropathic pain is more frequently associated with resistance to recommended pharmacological symptomatic treatments. This observation underlines the limits of conventional medical therapy.

Analgesia↗

PubMed1994

[Evaluation of chronic pain in geriatric patients].

This retrospective study considers the influence of chronological age on the perception and consequential effects of chronic non-cancer pain in 203 patients referred to an ambulatory pain clinic. One patient in four (50) was 65 years or older. Pain had existed for more than a year in 66%. It was referred to an "unbearable" by 54% of elderly adults vs 44% (NS) of the younger adult population, and as "intense" by 61% vs 44% (p < 0.05). A higher proportion of neurogenic pain (54% vs 26%, p < 0.05) could explain this significant difference. Cognitive factors could also have amplified the painful syndrome since 59% (vs 54%) of the elderly considered they had received insufficient information on the potential consequences of their painful condition. However, despite a higher occurrence of other severe illnesses in the elderly (52% vs 35%, p < 0.05), they appear to worry less about their health problems (58% vs 78%, p < 0.01). Finally, in spite of increased severity of pain in the elderly, depression scores and consequential effects are similar in the two populations. In conclusion, the intensity of chronic pain appears to be more severe in the elderly, perhaps due to its more frequent neuropathic origin. Nonetheless, its repercussions on daily life activity seem no worse than for younger adults, and could reflect better coping strategies towards chronic pain.

Activities of Daily Living↗

PubMed1992

[Value of simultaneous determination of cyclosporin blood levels using specific and nonspecific methods in liver transplantation].

Cyclosporine's narrow therapeutic window and the large inter- and intra-individual variation of its pharmacokinetics require therapeutic monitoring. Cyclosporine is metabolized in the liver and excreted with its metabolite into the bile. An accumulation of metabolites occurs in liver dysfunction, leading to a high cyclosporine blood concentration when measured by a non-specific method (polyclonal antibodies). Specific methods (HPCL, monoclonal antibody) are therefore recommended by some authors. We evaluated the potential usefulness of simultaneous cyclosporine determination by a non-specific (fluorescent polarisation TDx, polyclonal antibodies) and a specific method (I125-RIA, monoclonal antibody). 10 patients were followed from 51 days to 32 months after hepatic transplantation. 2 patients who showed no graft rejection presented a polyclonal antibodies/monoclonal antibody ratio below or equal to 4 throughout their evolution. Other patients presented a rise of this ratio during periods of liver dysfunction, particularly in acute graft rejection. When bilirubin concentrations are plotted versus this ratio, an hysteresis is present during periods of acute rejection, but not during an episode of histological hepatitis. The same holds true for alkaline phosphatase and gamma-GT. These data suggest that this ratio could be a sensitive test for early detection of rejection. Simultaneous cyclosporine blood determination with specific and nonspecific methods may be useful in the follow-up of liver-transplanted patients.

Adult↗