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1.
Philos Trans R Soc Lond B Biol Sci ; 375(1810): 20190513, 2020 10 26.
Article in English | MEDLINE | ID: mdl-32892733

ABSTRACT

During the summer of 2018, a widespread drought developed over Northern and Central Europe. The increase in temperature and the reduction of soil moisture have influenced carbon dioxide (CO2) exchange between the atmosphere and terrestrial ecosystems in various ways, such as a reduction of photosynthesis, changes in ecosystem respiration, or allowing more frequent fires. In this study, we characterize the resulting perturbation of the atmospheric CO2 seasonal cycles. 2018 has a good coverage of European regions affected by drought, allowing the investigation of how ecosystem flux anomalies impacted spatial CO2 gradients between stations. This density of stations is unprecedented compared to previous drought events in 2003 and 2015, particularly thanks to the deployment of the Integrated Carbon Observation System (ICOS) network of atmospheric greenhouse gas monitoring stations in recent years. Seasonal CO2 cycles from 48 European stations were available for 2017 and 2018. Earlier data were retrieved for comparison from international databases or national networks. Here, we show that the usual summer minimum in CO2 due to the surface carbon uptake was reduced by 1.4 ppm in 2018 for the 10 stations located in the area most affected by the temperature anomaly, mostly in Northern Europe. Notwithstanding, the CO2 transition phases before and after July were slower in 2018 compared to 2017, suggesting an extension of the growing season, with either continued CO2 uptake by photosynthesis and/or a reduction in respiration driven by the depletion of substrate for respiration inherited from the previous months due to the drought. For stations with sufficiently long time series, the CO2 anomaly observed in 2018 was compared to previous European droughts in 2003 and 2015. Considering the areas most affected by the temperature anomalies, we found a higher CO2 anomaly in 2003 (+3 ppm averaged over 4 sites), and a smaller anomaly in 2015 (+1 ppm averaged over 11 sites) compared to 2018. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.


Subject(s)
Atmosphere/analysis , Carbon Cycle , Carbon Dioxide/analysis , Droughts , Ecosystem , Europe
2.
Rev. neurol. (Paris) ; 176(5): [1-28], May 2020.
Article in English | BIGG - GRADE guidelines | ID: biblio-1117239

ABSTRACT

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.


Subject(s)
Psychotherapy/organization & administration , Drug Therapy/methods , Pain Management/methods , Neuralgia/prevention & control , Neuralgia/therapy , France
3.
Rev Neurol (Paris) ; 176(5): 325-352, 2020 May.
Article in English | MEDLINE | ID: mdl-32276788

ABSTRACT

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.


Subject(s)
Neuralgia/drug therapy , Neuralgia/therapy , Pain Management/methods , Pain Management/standards , Practice Guidelines as Topic , Analgesics/therapeutic use , Analgesics, Opioid/therapeutic use , Antidepressive Agents/therapeutic use , Cognitive Behavioral Therapy , Complementary Therapies/methods , Complementary Therapies/standards , Complementary Therapies/statistics & numerical data , France/epidemiology , Humans , Mindfulness/methods , Mindfulness/standards , Neuralgia/epidemiology , Pain Management/statistics & numerical data , Practice Guidelines as Topic/standards , Transcranial Magnetic Stimulation
4.
J Nutrigenet Nutrigenomics ; 4(3): 154-64, 2011.
Article in English | MEDLINE | ID: mdl-21757924

ABSTRACT

BACKGROUND: Aging and obesity induce complex transcriptomic changes in the liver, promoting the development of insulin resistance and type 2 diabetes. In spite of an increasing amount of studies on the role of aging and nutrient excess in metabolic disorders, the specific molecular events leading to insulin resistance are still poorly understood. METHODS: This study presents a comparative analysis of hepatic gene expression profiles between young adult C57BL/6J mice fed with a low- or a high-fat diet for 1 and 12 months. We evaluated the expression of a defined set of genes implicated in glucose and lipid metabolism as well as key nuclear receptors and their target genes, IGF1 signaling and clock genes. RESULTS: Aging and short-term high-fat consumption induced insulin resistance, albeit through two distinct processes. Hepatic gene expression changes were more pronounced in the context of aging. We further analyzed expression profiles together with plasma parameters by principal component analysis with regard to diet condition. CONCLUSIONS: Our results suggest that in the liver of C57BL/6J mice, the molecular mechanisms underlying high-fat feeding or aging which mediated insulin resistance were not identical.


Subject(s)
Adaptation, Physiological , Aging/genetics , Gene Expression Profiling , Liver/metabolism , Obesity/genetics , Animals , Diet , Liver/physiopathology , Male , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain Reaction
5.
J Biol Chem ; 276(12): 9452-9, 2001 Mar 23.
Article in English | MEDLINE | ID: mdl-11254657

ABSTRACT

Heterodimerization of retinoic acid receptors (RARs) with 9-cis-retinoic receptors (RXRs) is a prerequisite for binding of RXR.RAR dimers to DNA and for retinoic acid-induced gene regulation. Whether retinoids control RXR/RAR solution interaction remains a debated question, and we have used in vitro and in vivo protein interaction assays to investigate the role of ligand in modulating RXR/RAR interaction in the absence of DNA. Two-hybrid assay in mammalian cells demonstrated that only RAR agonists were able to increase significantly RAR interaction with RXR, whereas RAR antagonists inhibited RXR binding to RAR. Quantitative glutathione S-transferase pull-down assays established that there was a strict correlation between agonist binding affinity for the RAR monomer and the affinity of RXR for liganded RAR, but RAR antagonists were inactive in inducing RXR recruitment to RAR in vitro. Alteration of coactivator- or corepressor-binding interfaces of RXR or RAR did not alter ligand-enhanced dimerization. In contrast, preventing the formation of a stable holoreceptor structure upon agonist binding strongly altered RXR.RAR dimerization. Finally, we observed that RAR interaction with RXR silenced RXR ligand-dependent activation function. We propose that ligand-controlled dimerization of RAR with RXR is an important step in the RXR.RAR activation process. This interaction is dependent upon adequate remodeling of the AF-2 structure and amenable to pharmacological inhibition by structurally modified retinoids.


Subject(s)
Receptors, Retinoic Acid/antagonists & inhibitors , Dimerization , HeLa Cells , Humans , Ligands , Protein Binding , Protein Conformation , Receptors, Retinoic Acid/chemistry , Receptors, Retinoic Acid/metabolism , Reverse Transcriptase Polymerase Chain Reaction
6.
J Biol Chem ; 274(53): 38225-31, 1999 Dec 31.
Article in English | MEDLINE | ID: mdl-10608897

ABSTRACT

Retinoic acid (RA) regulation of cellular proliferation and differentiation is mediated, at least in part, through two related nuclear receptors, RAR and RXR. RA-induced modulation of gene expression leads generally to cellular differentiation, whereas stimulation of the protein kinase C (PKC) signaling pathway is associated with cellular proliferation. Pursuant to our discovery that prolonged activation of PKCs induced a strong decrease in RA responsiveness of a retinoid-inducible reporter gene, we have further investigated the connections between these two signaling pathways. We demonstrate that PKC isoforms alpha and gamma are able to phosphorylate human RARalpha (hRARalpha) in vitro on a single serine residue located in the extended DNA binding domain (T box). The introduction of a negative charge at this position (serine 157) strongly decreased hRARalpha transcriptional activity, whereas a similar mutation at other PKC consensus phosphorylation sites had no effect. The effect on transcriptional activation was correlated with a decrease in the capacity of hRARalpha to heterodimerize with hRXRalpha. Thus hRARalpha is a direct target for PKCalpha and gamma, which may control retinoid receptor transcriptional activities during cellular proliferation and differentiation.


Subject(s)
Protein Kinase C/metabolism , Receptors, Retinoic Acid/metabolism , Serine/metabolism , Transcription Factors/metabolism , Transcription, Genetic , Amino Acid Sequence , Animals , Base Sequence , DNA Primers , Dimerization , HeLa Cells , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed , Phosphorylation , Rats , Receptors, Retinoic Acid/chemistry , Receptors, Retinoic Acid/genetics , Retinoic Acid Receptor alpha , Retinoid X Receptors , Sequence Homology, Amino Acid , Serine/chemistry , Transcription Factors/chemistry , Transcription Factors/genetics
7.
Mol Cell Biol ; 19(4): 3073-85, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10082574

ABSTRACT

Transcriptional activation by retinoids is mediated through two families of nuclear receptors, all-trans-retinoic acid (RARs) and 9-cis retinoic acid receptors (RXRs). Conformationally restricted retinoids are used to achieve selective activation of RAR isotype alpha, beta or gamma, which reduces side effects in therapeutical applications. Synthetic retinoids mimic some of all-trans retinoic acid biological effects in vivo but interact differently with the ligand binding domain of RARalpha and induce distinct structural transitions of the receptor. In this report, we demonstrate that RAR-selective ligands have distinct quantitative activation properties which are reflected by their abilities to promote interaction of DNA-bound human RXRalpha (hRXRalpha)-hRARalpha heterodimers with the nuclear receptor coactivator (NCoA) SRC-1 in vitro. The hormone response element core motifs spacing defined the relative affinity of liganded heterodimers for two NCoAs, SRC-1 and RIP140. hRXRalpha activating function 2 was critical to confer hRARalpha full responsiveness but not differential sensitivity of hRARalpha to natural or synthetic retinoids. We also provide evidence showing that lysines located in helices 3 and 4, which define part of hRARalpha NCoA binding surface, contribute differently to (i) the transcriptional activity and (ii) the interaction of RXR-RAR heterodimers with SRC-1, when challenged by either natural or RAR-selective retinoids. Thus, ligand structure, DNA, and RXR exert allosteric regulations on hRARalpha conformation organized as a DNA-bound heterodimer. We suggest that the use of physically distinct NCoA binding interfaces may be important in controlling specific genes by conformationally restricted ligands.


Subject(s)
DNA/metabolism , Receptors, Retinoic Acid/metabolism , Retinoids/metabolism , Transcription Factors/metabolism , Transcriptional Activation , Adaptor Proteins, Signal Transducing , DNA-Binding Proteins/metabolism , Dimerization , Gene Expression Regulation , Histone Acetyltransferases , Humans , Ligands , Models, Molecular , Nuclear Proteins/metabolism , Nuclear Receptor Co-Repressor 2 , Nuclear Receptor Coactivator 1 , Nuclear Receptor Interacting Protein 1 , Protein Binding , Receptors, Retinoic Acid/agonists , Repressor Proteins/metabolism , Retinoid X Receptors , Sequence Deletion
8.
Sleep ; 10 Suppl 1: 73-8, 1987.
Article in English | MEDLINE | ID: mdl-3326118

ABSTRACT

A randomized, double-blind, comparative trial of zopiclone versus nitrazepam was conducted in 74 geriatric chronic insomniac patients. Following a 7-day wash-out period, two parallel groups, successively received a placebo for 7 days, then either 7.5 mg zopiclone or 5 mg nitrazepam for another 7-day period. Efficacy on sleep was assessed by a sleep analogue scale and the Spiegel Sleep Questionnaire, residual effects by psychometric tests and tolerance by a standardized question, as well as by clinical and laboratory tests. Zopiclone and nitrazepam were more active than placebo on all tests of efficacy. In contrast with nitrazepam, zopiclone was devoid of effect on neurological function. In addition, the condition on awakening was better with zopiclone.


Subject(s)
Hypnotics and Sedatives/therapeutic use , Nitrazepam/therapeutic use , Piperazines/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Aged , Azabicyclo Compounds , Clinical Trials as Topic , Double-Blind Method , Drug Evaluation , Drug Tolerance , Female , Humans , Hypnotics and Sedatives/administration & dosage , Male , Nitrazepam/administration & dosage , Nitrazepam/adverse effects , Piperazines/administration & dosage , Sleep/drug effects , Wakefulness/drug effects
10.
Pharmacology ; 27 Suppl 2: 242-7, 1983.
Article in English | MEDLINE | ID: mdl-6142467

ABSTRACT

We carried out a randomized double-blind study. This was a crossover design with two periods of 2 days each with one compound (either zopiclone or triazolam). The next 2 days of active trial periods the patients were allowed to choose the preferred coloured capsule of which both neither the patients nor the investigators knew about its real contents. 40 volunteers were chosen from our patients suffering from chronic alcoholism who just finished their detoxification. There were given coloured coded capsules, each of them containing either 0.25 mg triazolam or 3.75 mg zopiclone. The capsules should be swallowed when patients felt a desire for alcohol. The maximal dosage was 8 capsules per day (2.0 mg triazolam and 30 mg zopiclone). There was a significant difference of degrees of freedom and probability at a level of 0.0005 for the items of the Addiction Research Centre Inventory and a level of 0.0005 for the items of the 'profile of mood states'. None of the volunteers developed a special desire for zopiclone after withdrawal of the medication.


Subject(s)
Anti-Anxiety Agents/adverse effects , Hypnotics and Sedatives/adverse effects , Piperazines/adverse effects , Substance-Related Disorders/etiology , Triazolam/adverse effects , Adult , Azabicyclo Compounds , Blood Pressure/drug effects , Body Temperature/drug effects , Double-Blind Method , Emotions/drug effects , Heart Rate/drug effects , Humans , Male , Random Allocation
11.
Int Pharmacopsychiatry ; 17 Suppl 2: 242-7, 1982.
Article in English | MEDLINE | ID: mdl-6145680

ABSTRACT

We carried out a randomized double-blind study. This was a crossover design with two periods of 2 days each with one compound (either zopiclone or triazolam). The next 2 days of active trial periods the patients were allowed to choose the preferred coloured capsule of which both neither the patients nor the investigators knew about its real contents. 40 volunteers were chosen from our patients suffering from chronic alcoholism who just finished their detoxification. There were given coloured coded capsules, each of them containing either 0.25 mg triazolam or 3.75 mg zopiclone. The capsules should be swallowed when patients felt a desire for alcohol. The maximal dosage was 8 capsules per day (2.0 mg triazolam and 30 mg zopiclone). There was a significant difference of degrees of freedom and probability at a level of 0.0005 for the items of the Addiction Research Centre Inventory and a level of 0.0005 for the items of the 'profile of mood states'. None of the volunteers developed a special desire for zopiclone after withdrawal of the medication.


Subject(s)
Anti-Anxiety Agents/adverse effects , Hypnotics and Sedatives/adverse effects , Piperazines/adverse effects , Substance-Related Disorders/etiology , Triazolam/adverse effects , Adult , Alcoholism/psychology , Azabicyclo Compounds , Double-Blind Method , Humans , Male , Random Allocation
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