Pierre Arsenault

widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition

&NA; A deficit of endogenous pain inhibitory systems has been suggested to contribute to some chronic pain conditions, one of them being fibromyalgia. The aim of the investigation was to test whether endogenous pain inhibitory systems were activated by a spatial summation procedure in 30 fibromyalgia, 30 chronic low back pain, and 30 healthy volunteers who participated in a cross‐over trial (two sessions). Each session consisted of visual analog scale ratings of pain during the immersion of different surfaces of the arm in circulating noxious cold (12 °C) water. The arm was arbitrarily divided into eight segments from the fingertips to the shoulder. One session was ascending (from the fingertips to the shoulder) and the other was descending (from the shoulder to the fingertips); they included eight consecutive 2‐min immersions separated by 5‐min resting periods. For healthy and low back pain subjects, pain was perceived differently during the ascending and descending sessions (P=0.0001). The descending session resulted in lower pain intensity and unpleasantness. This lowering of the perception curve seems to be due to a full recruitment of inhibitory systems at the beginning of the descending session as opposed to a gradual recruitment during the ascending session. For fibromyalgia subjects, no significant differences were found between the increasing and decreasing sessions (P>0.05). These data support a deficit of endogenous pain inhibitory systems in fibromyalgia but not in chronic low back pain. The treatments proposed to fibromyalgia patients should aim at stimulating the activity of those endogenous systems.

The role of sex hormones on formalin-induced nociceptive responses.

Many chronic pain conditions are more frequent in women than in men. This observation suggests that there is a potential role of sex hormones on pain perception. In the present study, we measured nociceptive responses to the formalin test in normal and gonadectomized male and female rats. The nociceptive responses to formalin injection were divided in four phases: acute (phase I), interphase and late phases (phases II and III). Four groups of rats were tested: (a) males (n = 15), (b) females (n = 16), (c) ovariectomized females (OVX) (n = 15) and (d) castrated males (CAST) (n = 15). Females presented significantly more nociceptive responses than males during phase I, interphase and phase II (P < 0.01). They also presented significantly more nociceptive responses than OVX females during the interphase (P < 0.05). CAST males presented significantly more nociceptive responses during the phases I (P < 0.01), II (P < 0.01) and III (P < 0.05) than the male rats. Finally, the responses of CAST males and OVX females were virtually identical, suggesting that the differences recorded between males and females in the formalin test were related to an activational effect of the sex hormones rather than an organizational effect. In conclusion, these results permit the support of the role of sex hormones on the modulation of pain perception. Interestingly, male and female sex hormones seem to act specifically on the different phases of the formalin test, suggesting some specific roles for sex hormones in different pain conditions.

Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses.

Several factors have been proposed to account for the differences observed between men and women in pain perception. One of these is female and male gonadal hormones. In order to verify this assumption, a hormone replacement (pellets inserted subcutaneously) of (1) 17beta-estradiol, (2) progesterone, (3) 17beta-estradiol + progesterone or (4) testosterone have been performed in gonadectomized female and male Sprague-Dawley rats. Twenty-one days after the hormonal replacement, a formalin test was performed. The nociceptive responses were divided in three distinct phases: acute (phase I), inhibitory (interphase) and tonic (phase II). After analysis, we observed that testosterone has a hypoalgesic effect on phases I and II of the formalin test. At the opposite, female hormones act only on the interphase: the combination of 17beta-estradiol and progesterone in gonadectomized rats reestablishes the weaker nociceptive pain reduction during the interphase as it is observed in the intact female. These effects were not gender specific since they had the same action in female and male. Our results permit to believe that testosterone plays a protective role in pain perception. Moreover, the female hormones act mainly on pain inhibition mechanisms (interphase), suggesting that the prevalence of certain chronic pain conditions in women could be related to a deficit of these pain inhibitory mechanisms rather than an increased nociceptive activity.

Biologic effects of epidermal growth factor in human fetal jejunum

The influence of epidermal growth factor (EGF) on the differentiation and proliferation of human fetal jejunum was studied in organ cultures. Fetal intestine (11-14-wk gestation) was cultured for 5 days at 37 degrees C in serum-free Leibovitz L-15 medium alone or supplemented with 25, 50, and 100 ng EGF/ml culture medium. The addition of hormone did not modify the morphology of the intestinal explants. Biochemical studies revealed that lactase activity was significantly increased with the addition of 50 and 100 ng EGF/ml culture medium. On the other hand, the increase in sucrase, trehalase, and glucoamylase activities that normally occurs during the culture was repressed in the presence of increasing concentrations of EGF. Deoxyribonucleic acid synthesis was significantly decreased after 5 days of culture even in the presence of the lowest EGF concentration used. Concomitantly, the labeling index of the epithelial cells dropped drastically in the presence of EGF. The EGF-induced variation in DNA synthesis was already evident within 24 h of culture, whereas enzymic modifications occurred only between the third and fifth day of culture. The simultaneous addition of EGF and hydrocortisone (50 ng/ml) did not reveal any synergistic action between the two hormones on the hydrolytic activities of the brush border. However, EGF did inhibit hydrocortisone-stimulated DNA synthesis. The present work provides for the first time some basic data on the influence of EGF on brush border hydrolytic activities and on epithelial cell proliferation of human fetal jejunum. These observations strongly suggest that EGF plays an important role in the fetal development of the human gastrointestinal tract.

An International, Randomized, Double-blind, Placebo-controlled, Phase III Trial of Pregabalin Monotherapy in Treatment of Patients with Fibromyalgia

Objective. To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. Methods. This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. Results. Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (−0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score −5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. Conclusion. Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Explant culture of human fetal small intestine

Human fetal intestine (10-14 wk gestation) has been cultured as explants in a serum-free Leibovitz L-15 medium for periods up to 9 days. As determined by light microscopy, the overall architecture of the intestinal explant was maintained throughout the culture period. At the ultrastructural level the villus absorptive cells remained tall with well-defined brush border, apical tubular system, and supranuclear and infranuclear accumulations of glycogen. All other epithelial cell types were also preserved. The incorporation of [3H]thymidine and [3H]leucine continued during the culture period, reflecting a sustained synthesis of deoxyribonucleic acid and proteins. The hydrolytic activities of the brush border membrane were established based on data obtained throughout the course of the culture of a large number of intestinal specimens. Sucrase, maltase, glucoamylase, trehalase, lactase, alkaline phosphatase, and gamma-glutamyl transpeptidase activities increased during the 9 days of culture even though different patterns were recorded. These observations clearly established that human fetal small intestine can be maintained in organ culture for at least 9 days in a serum-free medium.

Sleep quality in mechanically ventilated patients: comparison between NAVA and PSV modes

BackgroundMechanical ventilation seems to occupy a major source in alteration in the quality and quantity of sleep among patients in intensive care. Quality of sleep is negatively affected with frequent patient-ventilator asynchronies and more specifically with modes of ventilation. The quality of sleep among ventilated patients seems to be related in part to the alteration between the capacities of the ventilator to meet patient demand. The objective of this study was to compare the impact of two modes of ventilation and patient-ventilator interaction on sleep architecture.MethodsProspective, comparative crossover study in 14 conscious, nonsedated, mechanically ventilated adults, during weaning in a university hospital medical intensive care unit. Patients were successively ventilated in a random ordered cross-over sequence with neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV). Sleep polysomnography was performed during four 4-hour periods, two with each mode in random order.ResultsThe tracings of the flow, airway pressure, and electrical activity of the diaphragm were used to diagnose central apneas and ineffective efforts. The main abnormalities were a low percentage of rapid eye movement (REM) sleep, for a median (25th-75th percentiles) of 11.5% (range, 8-20%) of total sleep, and a highly fragmented sleep with 25 arousals and awakenings per hour of sleep. Proportions of REM sleep duration were different in the two ventilatory modes (4.5% (range, 3-11%) in PSV and 16.5% (range, 13-29%) during NAVA (p = 0.001)), as well as the fragmentation index, with 40 ± 20 arousals and awakenings per hour in PSV and 16 ± 9 during NAVA (p = 0.001). There were large differences in ineffective efforts (24 ± 23 per hour of sleep in PSV, and 0 during NAVA) and episodes of central apnea (10.5 ± 11 in PSV vs. 0 during NAVA). Minute ventilation was similar in both modes.ConclusionsNAVA improves the quality of sleep over PSV in terms of REM sleep, fragmentation index, and ineffective efforts in a nonsedated adult population.

Insulin Influences the Maturation and Proliferation of Suckling Mouse Intestinal Mucosa in Serum-Free Organ Culture

Explants of suckling mouse jejunum have been maintained in serum-free organ culture with or without insulin added to the medium in order to determine the possible direct effect of this hormone on the hydrolytic functions of the brush border and on the proliferation of the crypt cells. The addition of insulin induced the precocious appearance of sucrase activity and increased trehalase, glucoamylase and lactase activities. Alkaline phosphatase activity remained unaffected in the tissue as well as in the medium. An increased DNA content and 3H-thymidine incorporation into DNA were already recorded after 24 h of culture. The mitotic index was significantly increased after 24 h and remained elevated when the culture was extended to 48 h. These results show that insulin directly influences the enzymatic maturation and the proliferation of intestinal epithelial cells of suckling mouse.

Influence of hydrocortisone on human fetal small intestine in organ culture

The influence of hydrocortisone on the differentiation and proliferation of human fetal small intestine was studied. Fetal intestine (12− to 14-week gestation) was cultured during 5 days at 37

Differential Effects of Epidermal Growth Factor and Hydrocortisone in Human Fetal Colon

dEC in serum-free Leibovitz L-15 medium alone or supplemented with hydrocortisone (12.5, 25, and 50 ng/ml). The addition of different concentrations of hormonc did not affect the morphology of the intestinal explants. Brush border membrane hydrolytic activities, namely, sucrase, lactase, glucoamylase, trehalase, and alkaline phosphatase activities, were assayed in the intestinal tissue. A specific increase of lactase and alkaline phosphatase activities was induced by the addition of 25 and 50 ng hydrocortisone/ml culture medium. The DNA synthesis evaluated by the incorporation of [3H]thymidinc was increased by the addition of 50 ng hydrocortisone/ml. The sites of incorporation into the different layers of the intestinal wall were studied by radioautography. The incorporation of the radioactive precursor occurred mainly in the epithelium and to a lesser degree in the mesenchyme and muscular layers. Labeled epithelial nuclei were located in the intervillous areas and developing crypts but not on the villi. The addition of hydrocortisone induced a significant increase of the labeling index of the epithelial cells. The present work provided for the first time some basic data on the influence of hydrocortisone on brush border hydrolytic activities and on epithelial cell proliferation of human fetal small intestine.