Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

[Procedure for daylight methyl aminolevulinate photodynamic therapy to treat actinic keratoses]. / Modalités pratiques de traitement des kératoses actiniques par photothérapie dynamique topique en lumière du jour avec l'aminolévulinate de méthyle.

Actinic keratosis (AK), also known as solar keratosis or pre-cancerous keratosis, is frequently observed in areas of skin exposed to sunlight, particularly in light-skinned patients. In France, photodynamic therapy using red light (conventional PDT) and methylamino 5-levulinate (MAL) is indicated in the treatment of thin or non-hyperkeratotic and non-pigmented multiple AK lesions or large zones covered with AK lesions. It is well-known for its efficacy but also for its side effects, especially pain during illumination, which can limit its use. An alternative to PDT using natural daylight has recently been proposed to treat actinic keratosis lesions, and results in greater flexibility as well as significant reduction in pain. The lesions are prepared as for conventional PDT, with MAL cream being applied by the physician or the patient, after which they are exposed to natural daylight for 2hours. The lesions are then gently cleansed and protected from natural light for 24hours. This paper seeks to provide a precise description of the daylight PDT procedure for the treatment of AK.

Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized, controlled trial.

BACKGROUND: The mechanism of action of acetaminophen remains unclear. One hypothesis involves an interaction with the serotoninergic system. Antagonists to serotonin (5-HT)3 receptors (setrons) have antiemetic properties. Therefore, co-administration of acetaminophen and a setron could lead to a decrease or a loss of acetaminophen analgesic effects. The aim of this study was to demonstrate such an interaction. METHODS: Paratron is a prospective, randomized, controlled, double-blind, parallel group trial. All children aged 2-7 years (n = 69) scheduled for a tonsillectomy ± adenoidectomy received intraoperative acetaminophen with ondansetron or droperidol. Pain scores [Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)], morphine consumption and the incidence of post-operative nausea and vomiting (PONV) were measured for 24 h following surgery. RESULTS: Pain scores were not different at all times between the groups but median morphine consumption (µg) in recovery was 322.5 [interquartile range (IQR) 0.0-500.0] and 0 (IQR 0-0) in the ondansetron (n = 35) and droperidol (n = 34) groups, respectively (p = 0.004). The percentages of patients who received morphine titration were 57.1% and 20.6% in the ondansetron and droperidol groups, respectively (p = 0.008). No significant difference was found for PONV. CONCLUSIONS: An interaction between acetaminophen and ondansetron is suggested, with children receiving three times more morphine during pain titration in the recovery room. More studies are necessary to evaluate whether this finding is clinically relevant enough to preclude the simultaneous perioperative administration of both drugs in the future.

Development and psychometric validation of the REFlective evaLuation of psoriasis Efficacy of Treatment and Severity (REFLETS) questionnaire: a common measure of plaque-type psoriasis severity and treatment efficacy for patients and clinicians.

BACKGROUND: To date, there is no global consensus on the definition of the severity of psoriasis. The REFlective evaLuation of psoriasis Efficacy of Treatment and Severity (REFLETS) questionnaire has recently been developed to provide a better understanding of plaque-type psoriasis severity and treatment efficacy from both patient and clinician perspectives. OBJECTIVE: This study aimed to develop and psychometrically validate the new REFLETS questionnaire to evaluate patient and clinician perceptions of plaque-type psoriasis severity and treatment efficacy. METHODS: Two similar versions of the REFLETS questionnaire were developed following a rigorous methodology for clinicians and patients, referring to 'the psoriasis of your patient' or to 'your psoriasis', respectively. An observational, longitudinal, multicentre study was conducted in France with 34 dermatologists and 430 mild to severe plaque-type psoriasis patients to finalize the questionnaire and evaluate its psychometric properties. RESULTS: Two dimensions were defined--severity and treatment efficacy--with three subdimensions within severity (impact of psoriasis, symptoms and disease course), and two individual items on joint pain. The questionnaire was well accepted by clinicians and patients. Excellent internal consistency (Cronbach's alpha = 0.66-0.98) and test-retest reliability (intraclass correlation coefficients = 0.83-0.94) were demonstrated. REFLETS scores were moderately to highly correlated to Psoriasis Area and Severity Index (r = 0.35-0.70), Skindex-29 (r = 0.46-0.82) and DLQI scores (r = 0.36-0.82). Patients with decreased psoriasis severity and those with increased treatment efficacy, according to patient global evaluations, had lower severity and higher treatment efficacy REFLETS scores, respectively. CONCLUSION: REFlective evaLuation of psoriasis Efficacy of Treatment and Severity is a promising tool for assessing plaque-type psoriasis severity and treatment efficacy from patient and clinician perspectives. It may help to improve patient and clinician communication in treatment decision making.

Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia.

The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphine-induced analgesia. In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wild-type (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1µg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail-flick tests. Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB1 or the CB2 receptors, at least at the level of the spinal cord.

French teenagers and artificial tanning.

BACKGROUND: Exposure to solar and artificial ultraviolet (UV) radiations is a major risk factor for skin cancers. France has enacted one of the strictest laws that, notably, restrict tanning-bed access to adults ≥18 years old. OBJECTIVE: We evaluated artificial tanning behaviours of French teenagers (11-17 years old): sunless-tanning products, sunlamps and artificial tanning beds. METHODS: An anonymous questionnaire evaluating sunburn history, skin phototype, behaviours with sunless-tanning products and indoor tanning, and parents' behaviours was distributed to students enrolled in two middle and high schools in Antony, a typical city of the middle class French population, located in the Paris suburbs. RESULTS Among 713 teenagers (mean age: 13.5 years: male/female: 1.1) responding, more than half declared that it was important to be tanned during the summer, 1% reported having already used tanning pills, 9.9% tanning creams and 1.4% indoor tanning. Female teenagers significantly more frequently resorted to indoor tanning (P = 0.02), cited the importance of being tanned all year long (P < 0.0001), used tanning pills (P < 0.0001) or tanning creams (P < 0.006), and their parents relied on indoor tanning (P < 0.0001). Profiles of tanning-pill and -cream users were similar. Mean ages for the two groups were comparable. CONCLUSION: French regulations for indoor tanning seem quite effective. Our analyses revealed a typical teenager profile with sun-exposure risk behaviours, for example, indoor tanning, and use of tanning pills or creams. They could be a selective target for sun-protection information campaigns.

[Socio-demographic study of privately practicing dermatologists in metropolitan France in 2011]. / Étude sociodémographique des dermatologues libéraux en France métropolitaine en 2011.

BACKGROUND: There is currently an alarming decrease in the number of dermatologists in private practice because of the limited number of new graduates, who are unable to compensate for departures into retirement among the "baby boom" generation. Our aim was thus to determine the socio-demographic characteristics of private dermatologists in France in 2011 to forecast the impact over the next 20 years. MATERIALS AND METHODS: Analysis was performed of socio-demographic data (age, sex, place of practice, thesis year and mode of exercise) for all private dermatologists living in France in 2011 and identified in the Rosenwald Directory of Doctors. These data were combined with those of the National Council of the Order to determine the number of GPs and those of INSEE, giving the size and number of inhabitants of each department. RESULTS: There are 3,197 privately practicing dermatologists in France, with a majority of women (65%). The average age is 52 years. Fifty-three per cent of dermatologists are aged over 55 years while 21% are aged between 50 and 54 years, 19% are aged between 40 and 49 and 5% are aged under 39 years. The density of dermatologists in France is 5.1/100,000 inhabitants. There are three types of density zone for dermatologists: high-density zones (over five dermatologists per 10(5) persons), comprising 24 departments (22% of the national territory) in which 61% of dermatologists are practicing; moderate-density zones (three to five dermatologists per 10(5) persons), comprising 41 departments (47% of the French territory in which 30% of dermatologists are practicing; low-density zones (less than three dermatologists per 10(5) persons), considered as "dermatological deserts", comprising 30 departments (31% the national territory) in which 10% of the country's dermatologists are practicing. The population projection shows a decrease in the number of dermatologists in private practice of 45% in 2020, 72% in 2025 and 84% in 2030. DISCUSSION: Our study highlights the disparity in distribution of the density of liberal dermatologists in France. The departments in which the density of dermatologists is low are those where the number of general practitioners is small. In 2021, 54% of dermatologists currently in private practice will be aged over 65 and are therefore likely to end their professional practice. How can we anticipate the fall in the number of dermatologists in private practice over the coming two decades? This question must be addressed urgently.

Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model.

BACKGROUND AND PURPOSE: There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2-AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2-AG biosynthesis and metabolism. It has been clearly demonstrated that 2-AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti-nociceptive effects of the combination of peripherally injected 2-AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. EXPERIMENTAL APPROACH: Mechanical allodynia and thermal hyperalgesia were evaluated in 213 male Wistar rats allocated to 32 different groups. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 muL) 15 min before pain tests. KEY RESULTS: 2-AG, URB602 and URB597 significantly decreased mechanical allodynia and thermal hyperalgesia with ED50 of 1.6+/-1.5 and 127+/-83 mug for 2-AG and URB602, respectively. These effects were mediated locally and were mostly inhibited by the two cannabinoid antagonists. CONCLUSIONS AND IMPLICATIONS: The combination of the three compounds did not produce any greater anti-allodynic or anti-hyperalgesic effects, suggesting that FAAH inhibition could reduce or limit the anti-nociceptive effects of 2-AG. Peripheral administration of endocannabinoids or MGL/FAAH inhibitors is a promising analgesic approach requiring further investigation.

The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors.

BACKGROUND AND PURPOSE: 2-arachidonoyl glycerol (2-AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase (MGL) whose activity is inhibited by URB602, a new synthetic compound. The peripheral antinociceptive effects of 2-AG and URB602 in an inflammatory model of pain are not yet determined. We have evaluated these effects with and without the cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. EXPERIMENTAL APPROACH: Inflammation was induced in rat hind paws by intraplantar injection of formalin. Nociception was assessed behaviourally over the next 60 min, in 19 experimental groups: (1) control; (2-6) 2-AG (0.01-100 microg); (7) AM251 (80 microg); (8) AM251+2-AG (10 microg); (9) AM630 (25 microg); (10) AM630+2-AG (10 microg); (11-16) URB602 (0.1-500 microg); (17) 2-AG+URB602 (ED(50)); (18) AM251+URB602 (ED(50)); (19) AM630+URB602 (ED(50)). Drugs were injected s.c. in the dorsal surface of the hind paw (50 microl), 15 min before formalin injection into the same paw. KEY RESULTS: 2-AG and URB602 produced dose-dependent antinociceptive effects for the late phases of the formalin test with ED(50) of 0.65+/-0.455 mug and 68+/-14.3 microg, respectively. Their combination at ED(50) doses produced an additive antinociceptive effect. These effects were inhibited by AM630 but not by AM251 for 2-AG and by the two cannabinoid antagonists for URB602. CONCLUSIONS AND IMPLICATIONS: Locally injected 2-AG and URB602 decreased pain behaviour in a dose-dependent manner in an inflammatory model of pain. The antinociceptive effect of 2-AG was mediated by the CB(2) receptor.

Antinociceptive effects of tetrodotoxin (TTX) in rodents.

BACKGROUND: Tetrodotoxin (TTX) is a powerful sodium channel blocker extracted from the puffer fish. The analgesic effects of TTX were investigated in different animal pain models. METHODS: Wistar rats were submitted to the formalin test and to partial ligation of the sciatic nerve (Seltzer's model). Swiss Webster mice were used in the writhing test. Rodents were divided into six groups receiving a s.c. injection of either 0.9% NaCl, TTX 0.3, 1, 3, or 6 microg kg(-1), or morphine (5 mg kg(-1)). Substances were injected 30 min before 2.5% formalin injection into the hind paw, acetic acid administration intraperitoneally or neuropathic pain testing consisting of mechanical allodynia (von Frey filament) and thermal hyperalgesia (Plantar test). RESULTS: TTX decreased pain behaviour in the formalin test at the highest dose and in the writhing test at 3 and 6 microg kg(-1). It also diminished mechanical allodynia and thermal hyperalgesia with an ED(50) of 1.08 (0.89) and 0.62 (0.33) microg kg(-1), respectively. Observation of the rats after TTX injection did not show any motor deficit, respiratory distress or sedation. Morphine was also effective in relieving pain in all three tests but with signs of considerable sedation. CONCLUSION: Systemic injections of TTX diminished pain behaviour in a dose-dependent manner in models of inflammatory, visceral and neuropathic pain without causing adverse events, whereas morphine analgesia was associated with heavy sedation. TTX is a very promising substance for the treatment of various types of pain but needs further evaluation.

Guidelines for the use of cannabinoid compounds in chronic pain.

OBJECTIVE: To provide clinicians with guidelines for the use of cannabinoid compounds in the treatment of chronic pain. METHODS: Publications indexed from 1990 to 2005 in the National Library of Medicine Index Medicus were searched through PubMed. A consensus concerning these guidelines was achieved by the authors through review and discussion. RESULTS: There are few clinical trials, case reports or case series concerning the use of cannabinoid compounds in the treatment of chronic pain. There are no randomized clinical trials examining the use of herbal cannabis in the treatment of chronic pain. CONCLUSIONS: A practical approach to the treatment of chronic pain with cannabinoid compounds is presented. Specific suggestions about the off-label dosing of nabilone (Cesamet, Valeant Canada limitee/Limited) and dronabinol (Marinol, Solvay Pharma Inc, Canada) in the treatment of chronic pain are provided.

Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain.

The saphenous partial ligation (SPL) model is a new, easily performed, rodent model of neuropathic pain that consists of a unilateral partial injury to the saphenous nerve. The present study describes behavioral, pharmacological and molecular properties of this model. Starting between 3 and 5 days after surgery, depending on the modality tested, animals developed clear behaviors indicative of neuropathic pain such as cold and mechanical allodynia, and thermal and mechanical hyperalgesia compared with naive and sham animals. These pain behaviors were still present at 1 month. Signs of allodynia also extended to the sciatic nerve territory. No evidence of autotomy or bodyweight loss was observed. Cold and mechanical allodynia but not thermal and mechanical hyperalgesia was reversed by morphine (4 mg/kg i.p.). The cannabinoid receptor agonist WIN 55,212-2 (5 mg/kg i.p.) improved signs of allodynia and hyperalgesia tested except for mechanical hyperalgesia. Gabapentin (50 mg/kg i.p.) was effective against cold and mechanical allodynia but not hyperalgesia. Finally, amitriptyline (10 mg/kg i.p.) failed to reverse allodynia and hyperalgesia and its administration even led to hyperesthesia. Neurobiological studies looking at the expression of mu opioid receptor (MOR), cannabinoid CB(1) and CB(2) receptors showed a significant increase for all three receptors in ipsilateral paw skin, L3-L4 dorsal root ganglia and spinal cord of neuropathic rats compared with naive and sham animals. These changes in MOR, CB(1) and CB(2) receptor expression are compatible with what is observed in other neuropathic pain models and may explain the analgesia produced by morphine and WIN 55,212-2 administrations. In conclusion, we have shown that the SPL is an adequate model that will provide a new tool for clarifying peripheral mechanisms of neuropathic pain in an exclusive sensory nerve.

[The pharmacology of cannabinoid derivatives: are there applications to treatment of pain?]. / Pharmacologie des dérivés cannabinoïdes: applications au traitement de la douleur?

OBJECTIVE: To present the cannabinoid system together with recent findings on the pharmacology of these compounds in the treatment of pain. DATA SOURCES: Search through Medline database of articles published in French and English since 1966. Also use of other publications such as books on cannabis. STUDY SELECTION: All the relevant documents within the theme of this review were used. DATA EXTRACTION: All the data linked to the present topic were searched. DATA SYNTHESIS: Recent advances have dramatically increased our understanding of cannabinoid pharmacology. The psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors and ligands. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio. CONCLUSION: The cannabinoid system is a major target in the treatment of pain and its therapeutic potential should be assessed in the near future by the performance of new clinical trials.

Phonomyography of the corrugator supercilii muscle: signal characteristics, best recording site and comparison with acceleromyography.

BACKGROUND: This study investigated the acoustic signal characteristics and best recording site of phonomyography at the corrugator supercilii muscle and compared phonomyography with acceleromyography. METHODS: In 12 patients (group I), after induction of anaesthesia and insertion of a laryngeal mask, a microphone (frequency range 2.5 Hz to 10 kHz) was placed on six different areas on the forehead and the peak-to-peak response after single-twitch stimulation of the facial nerve was measured. The microphone was placed where the response was largest and mivacurium 0.2 mg kg(-1) was administered. Fast Fourier transformation was applied to all signals to determine peak frequencies and the power-frequency relationship at different stages of neuromuscular block. In an additional 15 patients (group II), the same microphone and an acceleromyographic probe were placed above the middle portion of the left and right eyebrows respectively. Onset and offset of neuromuscular block were determined after mivacurium 0.2 mg kg(-1). RESULTS: In all seven women and all five men in group I, the best response was obtained just above the middle portion of the eyebrow. Peak frequency was 4.1 (SD 0.9) Hz without neuromuscular block and did not change significantly during onset and offset of neuromuscular block. Ninety per cent of the total signal power was below 40 Hz. In group II, mean onset time and maximum effect measured were 104 (20) s and 76 (10)% respectively using acceleromyography and 134 (30) s and 92 (4)% using phonomyography (P<0.04). Mean time to reach 25, 75 and 90% of control was 9.5 (2.8), 14 (5.1) and 15.1 (5.3) min respectively using acceleromyography and 6.9 (2.8), 12.5 (5.9) and 13.6 (4.9) min using phonomyography (P<0.04). Bland-Altman testing revealed significant bias (precision) for onset time, maximum effect and time to reach 25% of control (acceleromyography minus phonomyography) at -30 (38) s, -16 (11)% and 2.6 (2.8) min respectively. CONCLUSIONS: Phonomyography can be used to determine neuromuscular block at the corrugator supercilii muscle. In comparison with acceleromyography, phonomyography tends to measure a longer onset with more pronounced maximum effect and shorter recovery of neuromuscular block.

Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.

p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.