[Keloid scars (part I): Clinical presentation, epidemiology, histology and pathogenesis]. / Les cicatrices chéloïdes (première partie) : une pathologie de la cicatrisation cutanée.

Keloid scars are a dysregulated response to cutaneous wound healing and are characterized by excessive deposition of collagen. Clinical and histological aspects are typical but they are often confused with hypertrophic scars. Principal pathogenesis is abnormal regulation of the collagen equilibrium because of TGFß. In this first part, clinical characteristics, physiopathology and histology of keloid scars are explained.

Robust dynamic community detection with applications to human brain functional networks.

While current technology permits inference of dynamic brain networks over long time periods at high temporal resolution, the detailed structure of dynamic network communities during human seizures remains poorly understood. We introduce a new methodology that addresses critical aspects unique to the analysis of dynamic functional networks inferred from noisy data. We propose a dynamic plex percolation method (DPPM) that is robust to edge noise, and yields well-defined spatiotemporal communities that span forward and backwards in time. We show in simulation that DPPM outperforms existing methods in accurately capturing certain stereotypical dynamic community behaviors in noisy situations. We then illustrate the ability of this method to track dynamic community organization during human seizures, using invasive brain voltage recordings at seizure onset. We conjecture that application of this method will yield new targets for surgical treatment of epilepsy, and more generally could provide new insights in other network neuroscience applications.

A procedure to increase the power of Granger-causal analysis through temporal smoothing.

BACKGROUND: How the human brain coordinates network activity to support cognition and behavior remains poorly understood. New high-resolution recording modalities facilitate a more detailed understanding of the human brain network. Several approaches have been proposed to infer functional networks, indicating the transient coordination of activity between brain regions, from neural time series. One category of approach is based on statistical modeling of time series recorded from multiple sensors (e.g., multivariate Granger causality). However, fitting such models remains computationally challenging as the history structure may be long in neural activity, requiring many model parameters to fully capture the dynamics. NEW METHOD: We develop a method based on Granger causality that makes the assumption that the history dependence varies smoothly. We fit multivariate autoregressive models such that the coefficients of the lagged history terms are smooth functions. We do so by modelling the history terms with a lower dimensional spline basis, which requires many fewer parameters than the standard approach and increases the statistical power of the model. RESULTS: We show that this procedure allows accurate estimation of brain dynamics and functional networks in simulations and examples of brain voltage activity recorded from a patient with pharmacoresistant epilepsy. COMPARISON WITH EXISTING METHOD: The proposed method has more statistical power than the Granger method for networks of signals that exhibit extended and smooth history dependencies. CONCLUSIONS: The proposed tool permits conditional inference of functional networks from many brain regions with extended history dependence, furthering the applicability of Granger causality to brain network science.

[Effectiveness of Integra in the management of complete forearm degloving injury. A case report]. / Intérêt de l'Intégra dans la prise en charge d'un dégantage complet de l'avant-bras. A propos d'un cas.

A 43-year-old man suffered complete skin degloving of the right forearm in a work accident with a farm machine. Initial treatment using a total skin flap graft after fat removal failed because of nearly complete necrosis after ten days. Artificial dermis (Intégra) was then used to ensure skin cover and reduce adherence phenomena. Postoperative complications were minor, and a split-thickness graft performed after three weeks led to healing five weeks later. At one year of follow-up, scar quality was considered very good, with normal and symmetric mobility. This case suggests that Intégra could be a valid surgical alternative in the management of skin degloving injuries.

Human seizures couple across spatial scales through travelling wave dynamics.

Epilepsy-the propensity toward recurrent, unprovoked seizures-is a devastating disease affecting 65 million people worldwide. Understanding and treating this disease remains a challenge, as seizures manifest through mechanisms and features that span spatial and temporal scales. Here we address this challenge through the analysis and modelling of human brain voltage activity recorded simultaneously across microscopic and macroscopic spatial scales. We show that during seizure large-scale neural populations spanning centimetres of cortex coordinate with small neural groups spanning cortical columns, and provide evidence that rapidly propagating waves of activity underlie this increased inter-scale coupling. We develop a corresponding computational model to propose specific mechanisms-namely, the effects of an increased extracellular potassium concentration diffusing in space-that support the observed spatiotemporal dynamics. Understanding the multi-scale, spatiotemporal dynamics of human seizures-and connecting these dynamics to specific biological mechanisms-promises new insights to treat this devastating disease.

Role of prolactin in the photoperiodic control of moulting in the mink (Mustela vison).

Beginning at the summer solstice adult female mink were maintained in long- or short-day photoperiods and treated with bromocriptine or prolactin. In control females kept under natural lighting conditions the moult coincided with the seasonal decrease in prolactin and resulted in the growth of a dense winter coat which was completed by the end of November. Long days, which slowed the decrease in plasma prolactin relative to animals in the natural photoperiod, induced a more or less complete moult followed by growth of a thin summer coat. On the contrary we observed an accelerated decrease in plasma prolactin concentrations followed by an early and brief moult in females kept under long days but treated with bromocriptine and in females under short days. The growth of a dense winter coat was completed by the end of September in all the females of the short-day group and in six of eleven females treated with bromocriptine. In the other five females, moult was followed by the growth of a summer coat. These results may suggest that the decline of prolactin after the summer solstice is responsible for the onset of the autumn moult, but the early, abbreviated moult and the growth of a winter coat observed in females kept under short days and treated with prolactin do not seem to support this hypothesis. However, the huge non-physiological levels of prolactin measured in the plasma of these females and the appearance of abnormal white under-hairs might suggest that the hormonal balance in this group was completely disturbed by the treatment. The physiological role of prolactin in the seasonal moulting cycle in mink is discussed.

Pineal denervation by cervical sympathetic ganglionectomy suppresses the role of photoperiod on pregnancy or pseudopregnancy, body weight and moulting periods in the mink (Mustela vison).

In mink, termination of the delayed implantation period, following reactivation of the corpora lutea, and onset of the spring moult are associated with a rise in prolactin secretion triggered by increasing daylength, while decreasing daylength induces the autumn moult. To establish whether suppression of the function of the pineal rendered the mink unresponsive to daylength changes, the superior cervical ganglion was removed bilaterally 2-4 weeks before mating. Intact and operated females were then left outdoors or were put under a lighting regime of either 15 h light:9 h darkness (15L:9D) or 8L:16D. In July, at the end of the spring moult, the 15L:9D lighting regime was changed to one of 8L:16D. Under artificial photoperiods ganglionectomy suppressed the stimulatory role of long days and the inhibitory role of short days on prolactin secretion, and consequently on progesterone secretion and spring moult. Neither was the autumn moult, induced early in intact females by the change to a short photoperiod, advanced in ganglionectomized females, showing that the latter were unresponsive to the artificial modification of the photoperiod. However, in animals kept outdoors, prolactin and progesterone secretion and spring moult were not changed by ganglionectomy. Increase in body weight and autumn moult were only slightly delayed by the operation suggesting that other environmental factors had replaced the synchronizing effect of the daylength changes. Alternatively the desynchronization between intact females responsive to photoperiodism and those rendered unresponsive may be too slow to be observed soon after ganglionectomy.

In-vitro secretion of prolactin and growth hormone in the presence of melatonin by pituitary gland from mink kept under long or short days.

Mink anterior pituitaries were incubated in Medium 199 for up to 9 or 13 days. Biological activity of prolactin and GH was determined. Daily concentrations of prolactin and GH in the incubation medium were also measured by radioimmunoassay and radioreceptor assay. When females were kept under short days for several weeks before the experiment, a significant decrease in prolactin secretion by the anterior pituitary was observed as compared with that in females maintained under long days. In contrast, secretion of GH was not modified by the photoperiodic history of the animals. Pineal gland denervation by ablation of the superior cervical ganglia a few months before the experiment, or addition of melatonin to the incubation medium of anterior pituitaries from intact or ganglionectomized females, did not modify the secretion of prolactin and GH. The pituitary gland does not therefore seem to be a direct target site for melatonin in transducing the duration of daylength on the hypothalamo-pituitary axis.

Blockade of the final phase of ovulation has no effect on the post-ovulatory surge of serum FSH in the rabbit.

Mating induces a surge of both LH and FSH in the blood of female rabbits, followed 10-12 h later by a surge of FSH only, which begins at the time of ovulation. We have studied the effect of suppression of ovulation on the post-ovulatory surge of FSH. In the first experiment, follicular fluid and oocytes were withdrawn from the largest follicles 8 h after coitus. In the second experiment, ovulation was inhibited by injecting the rabbits with 25 mg indomethacin/kg body weight 7.5 h after mating. Levels of serum FSH and LH were measured for 24-48 h after mating. Control rabbits ovulated normally in both experiments. The treatments did not significantly affect the levels of serum FSH in either experiment, although the second surge of FSH was slightly higher after fluid had been aspirated from the preovulatory follicles. These observations show that the post-ovulatory surge of serum FSH is not dependent upon the completion of ovulation and that it is programmed before 7.5-8 h post coitum.

Effect of short photoperiods on the in vitro GnRH release by hypothalamic explants in intact and castrated male Syrian hamsters: relation to testicular regression and recrudescence.

Prolonged exposure of adult Syrian hamsters to short days decreases LH and FSH circulating levels within 2-4 weeks, then induces testicular regression. After 18 weeks of short days, the testis size and gonadotropin levels increase spontaneously. This study investigated whether these phases of photosensitivity and photorefractoriness corresponded to variations of in vitro GnRH release. Male hamsters were either kept under long days (LD 16:8) or transferred to short days (SD 6:18) and sacrificed from 2-26 weeks after transfer. To separate the effects of testis feedback from a possible direct photoperiodic drive on the hypothalamus, males were bilaterally castrated, kept under LD or transferred to SD, and sacrificed from 2-14 weeks after transfer. Hypothalamic explants were incubated in a saline buffer for three periods of 15 min and exposed to KCl (60 mM) for 15 min. The return to basal values was followed for six periods of 15 min, then the explants were stimulated with copper complexed equimolarly with histidine (Cu/His, 200 microM) and prostaglandin E2 (PGE2, 10 microM). At the end of the incubation period, the concentration of GnRH remaining in the explants was measured. In intact males, GnRH release in vitro increased significantly between 2 and 4 weeks after transfer to short days; it returned to values similar to LD ones between 6 and 12 weeks, during the phase of testis involution. At the beginning of photorefractoriness (SD 14-18), it increased transiently and returned to values similar to LD ones from SD 20, during the testis spontaneous recrudescence. After castration, the in vitro GnRH release decreased significantly under LD and SD. The transfer of castrated hamsters to SD resulted in transient increases of GnRH release (SD 4, 8 and 14), and in a progressive loss of the explant's ability to release GnRH in vitro. These results showed a photoperiodic regulation of in vitro GnRH release and a testis feedback effect on this release. They demonstrated an inverse relationship between the readily releasable pool of GnRH and the circulating levels of gonadotrophins at the beginning of photosensitive and photorefractory phases and after castration.

Effects of Timed Melatonin Infusions and Lesions of the Suprachiasmatic Nuclei on Prolactin and Progesterone Secretions in Pregnant or Pseudopregnant Mink (Mustela vison).

Abstract To test the hypothesis that the duration of melatonin secretion may be a critical parameter in the transduction of photoperiodic signals on prolactin and progesterone secretions, timed intravenous melatonin infusions were carried out in intact and ganglionectomized pregnant and pseudopregnant mink. To localize the target sites of melatonin, electrolytic lesions of hypothalamic nuclei were performed in females receiving melatonin infusions. As a control, the first experiment was designed to confirm that pineal denervation by bilateral ablation of the superior cervical ganglion rendered the pregnant mink totally unresponsive to the inhibitory effects of short days on progesterone secretion. In the following experiments, timed intravenous melatonin infusions were carried out in intact and ganglionectomized females from Day 12 to 32 of pregnancy or pseudopregnancy. Daily infusions of melatonin for 16 h in intact females or for 11 or 13 h in ganglionectomized females suppressed the rise in plasma prolactin and progesterone levels. In intact as in ganglionectomized females, daily infusions of melatonin for 9 h delayed the rise in plasma prolactin concentrations without affecting the secretion of progesterone. In ganglionectomized females, saline infusions for 13 h or melatonin infusions for 7h did not modify the secretions of prolactin and progesterone. In ganglionectomized females bearing lesions of the Suprachiasmatic nuclei or the retrochiasmatic area, melatonin infusions for 13 h were still able to inhibit prolactin and progesterone secretions. These results are consistent with the hypothesis postulating that the peak duration of melatonin secretion is a critical parameter for transducing photoperiodic responses in pregnant or pseudopregnant mink. Secondly, they suggest that the Suprachiasmatic nuclei and the retrochiasmatic area are not essential for the action of melatonin in the photoperiodic control of prolactin and progesterone secretions during pregnancy or pseudopregnancy in the mink.

Seasonal variation of melatonin binding sites in the pars tuberalis of the male mink (Mustela vison).

The seasonal changes of 2-[125I]iodomelatonin binding were studied using quantitative autoradiography in the pars tuberalis (PT) of the mink, a short-day breeder, kept out of doors. Studies were performed at 7 times of the year (July, September, October, January, February, and May), corresponding to different states of responsiveness of the gonadal system to the photoperiod. Melatonin binding was observed in the PT and on the ventral border of the pars distalis. Histological staining revealed that the binding on the border of the pars distalis corresponded to the zona tuberalis, a ventral extension of the PT. The binding was specific and saturable. The density of melatonin binding varied significantly with the time of year. The lowest density of binding was found in July, when animals experienced a long daylength and sexual rest, increased from July to reach a maximum in October, when animals experienced decreasing daylength and the hypothalamo-pituitary activity resumed, then slightly decreased and remained constant from November to May. The saturation study demonstrated that the decrease in melatonin binding density between October and February resulted from a change in the number (Bmax: October 70.6 +/- 4.0 vs February 49.6 +/- 2.8 fmol/mg protein; P < 0.01) but not in the affinity (Kd: October 33.6 +/- 7.1 vs February 20.8 +/- 5.1 pM; P > 0.05) of the binding sites. These results are discussed according to the different phases of mink reproductive cycle and to reported data on the sites of action of melatonin on seasonal reproduction and prolactin secretion.

Effect of melatonin on the release of gonadotropin-releasing hormone and cyclic AMP from the rat hypothalamus: an in vitro study.

Using an in vitro static incubation system of adult male rat hypothalami, we have studied the effect of melatonin on the release of gonadotropin-releasing hormone (GnRH) and cyclic adenosine monophosphate (cAMP). Mediobasal hypothalamus (MBH) and preoptic area (POA) were incubated separately in Minimum Essential Medium (MEM) for 6 h. The release of GnRH was measured by radioimmuno-assay in the incubation medium sampled every 7.5 min. In the MBH and POA incubation medium, the mean amount of GnRH released was 8.9 +/- 1.1 and 3.4 +/- 0.6 pg GnRH/7.5 min, respectively (P < 0.01). The mean number of GnRH pulses under basal conditions was 2 +/- 0.3 per 2 h in the MBH and 1.6 +/- 0.3 per 2 h in the POA (P > 0.05). Melatonin (10(-8) M) did not alter the release of GnRH in the presence or absence of forskolin (10(-4) M). Melatonin, which was without effect on basal cAMP, inhibited forskolin-stimulated cAMP accumulation in the medium by 50% in the MBH and 40% in the POA. These results suggest that in our incubation system, melatonin does not modify GnRH release, but probably acts through the melatonin binding sites located in the hypothalamus to inhibit forskolin-stimulated cAMP.

Vasoactive intestinal polypeptide in the suprachiasmatic nucleus of the mink (Mustela vison) could play a key role in photic induction.

The present study was conducted to visualize neuropeptides in the SCN of a mustelid, the American mink in which seasonal cycles of reproduction rely totally on the annual changes in day length. At this time, data in mustelids are lacking. Results were obtained with in situ hybridization (ISH) using synthetic oligonucleotide vasopressin (AVP) and somatostatin (SOM) and with single and dual immunohistochemistry (IHC) performed with antisera against AVP, SOM, vasoactive intestinal polypeptide (VIP), gastrin releasing peptide (GRP) and met-enkephalin (Met-ENK) in untreated (AVP and VIP) or colchicine (SOM, Met-ENK and GRP) treated adult male and female mink. The most striking result, evidenced by ISH as well as IHC was the lack of AVP, SOM and Met-ENK immunoreactive (ir)-neurons in the SCN. In contrast, strongly VIP ir-perikarya were widely distributed within the SCN and gave rise to a dense network of fibres extending within the periventricular (peVA) and subparaventricular (subPVA) areas. Weakly GRP ir-perikarya were also observed in the median part of the SCN. Dual IHC revealed that the magnocellular neurons located just dorsal to the SCN, in the peVA and subPVA co-stored AVP with VIP, SOM or Met-ENK. The lack of SCN AVP and SOM ir-neurons, reported for the first time in a mammalian species, raises the question of their implication in the functions of the circadian pacemaker and its entrainment by the light/dark cycle in other species. The significance of the large neurons co-storing peptides in the terminal field of VIPergic fibres originating in the SCN has also to be determined. These results suggest that VIP could be of major importance in processing photic information mediating circadian entrainment and consequently annual rhythms.

Melatonin and the circadian clock in mink: effects of daily injections of melatonin on circadian rhythm of locomotor activity and autoradiographic localization of melatonin binding sites.

The present study examines a putative effect of exogenous melatonin on the circadian organization of the mink. Two approaches were used to determine first whether entrainment of free-running rhythms of locomotor activity in constant darkness can be obtained by daily melatonin injections, thus demonstrating a control of melatonin on the clock generating circadian rhythms, the suprachiasmatic nucleus of the hypothalamus. Entrainment was never obtained in the 8 vehicle-injected females and 7 out of the 8 melatonin injected-ones. In 3 females free-running in constant darkness, a phase advance followed by a few days of transient effect was observed when melatonin injections coincided with the onset of activity. However, the comparison of the regression of the daily activity onset related to successive days by covariance analysis revealed that true entrainment was effective in only 1 female. Second, we examined the distribution of melatonin binding sites within the brain of juvenile and adult mink using an in vitro autoradiographic procedure with [125I]2-iodomelatonin. No binding sites were observed in the suprachiasmatic nucleus of any of the animals. However, all animals displayed a high density of melatonin binding sites in the pars tuberalis of the pituitary. The relation between a modulatory control of melatonin on the circadian clock and the presence and density of melatonin binding sites in the clock is discussed. In mink, melatonin does not seem to act as an internal Zeitgeber.

Annual variations of in vitro GNRH release by hypothalamic explants in intact and castrated male mink: relations with LH, FSH and testosterone circulating serum levels.

In mink, a short-day breeder, testis growth begins in autumn (November), reaches a maximum in February, before matings occur, and decreases from March to very low volumes during spring and summer. To study the effects of season and testosterone feedback on gonadotrophin and GnRH secretion, the annual variations of LH, FSH, testosterone and GnRH were studied in intact and castrated mink. As portal blood sampling raised serious difficulties, an in vitro static incubation system was used for studying GnRH variations. In intact mink, serum LH concentrations did not vary significantly throughout the year, whereas FSH concentrations increased significantly between September and November then decreased to a minimum in January. Testosterone values rose significantly from November to a maximum from January to March, decreased very rapidly thereafter. Castration in November resulted in a significant increase in LH and FSH concentrations which remained higher than the values measured in intact males throughout the year. In long-term castrated mink, FSH concentrations did not fluctuate during the year, whereas LH concentrations showed an annual variation, with high values in April and August. For the study of in vitro GnRH liberation, medio-basal hypothalamic explants were incubated in Krebs-Ringer phosphate buffer for 3 periods of 15 min, and stimulated with copper complexed equimolarly with histidine (Cu/His, 200 microM) and prostaglandin E2 (PGE2, 10 microM). After Cu/His, the release of GnRH was 1 to 4 fold the basal release; after PGE2, the increase was 4-7 fold the basal release. The basal release of GnRH increased significantly between September and October to reach a maximum in November, decreased significantly in December to a minimum in February then increased progressively from May. The release of GnRH stimulated by Cu/His and PGE2 showed the same seasonal variation as the basal release. Castration 8 days before the sacrifice did not alter the release of GnRH, except in December: the release stimulated by PGE2 was then higher in intact than in castrated mink. Taken together, these results indicate that, with an in vitro static incubation system, it is possible to study the annual variations of GnRH release and to correlate these variations with those of serum gonadotrophin and testosterone concentrations. The synthesis and release of GnRH increased slightly from May, under long days, then more rapidly from September, resulting in an increased secretion of FSH in October, responsible for testis recrudescence. The annual pattern of basal and stimulated GnRH release was similar in intact and castrated mink, suggesting a direct effect of the season on the hypothalamus, rather than a negative feedback effect of the testis; however, testosterone seemed to feedback mainly at the pituitary level.

Role of the pineal gland in circadian organization of diurnal ground squirrels.

Golden-mantled ground squirrels, Spermophilus lateralis, pinealectomized (pinx) or sham-pinx at 70 days of age, were maintained in a LD 10:14 photoperiod; phase angles of activity onset were 1.6 +/- 0.3 and 1.9 +/- 0.3 hr in advance of light onset, respectively, and did not differ significantly between the groups. Rates of phase shifting of the activity rhythm after a 6 hr phase advance in the LD cycle also were comparable for the two groups and stable re-entrainment was achieved in 11 days. The period of the free-running activity rhythm in constant light did not differ between the groups. As demonstrated previously in nocturnal rodents, the pineal gland exerts little if any influence on generation or entrainment of the ground squirrel diurnal circadian activity rhythm. The rodent pineal is neither a master circadian oscillator nor a significant component of the transduction process by which light entrains the circadian activity rhythm.

A chronic jugular catheterization for remote blood sampling in freely moving mink.

The cannulation method consists of implanting a silastic catheter in the jugular vein. Passing subcutaneously, the catheter emerges on the back between the scapulae. It is protected by a spiral spring and anchored on a support outside the wire pen. Two swivels, the first one at the point of subcutaneous entry of the catheter on the mink, the second one on the emerging catheter at the top of the cage, allow movements of the mink without twisting up the catheter. Using this chronic cannulation system, the effects of handling and anaesthesia on concentrations of plasma PRL and LH have been studied.

Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent.

The present study determined first the dose-response (0.5 to 10 mg.kg-1) to daily oral administration of S-20098, a melatonin agonist, in entraining circadian rhythms of rats free-running in constant darkness; second, the relation between entrainment and the plasma concentration of S-20098. Finally, responses to 8 mg.kg-1 of S-20098 were compared with those obtained with the same dose of melatonin and ipsapirone. Responses were classified as negative, transient, or true entrainment. The data indicated a clear dose-dependent response from 2.5 to 10 mg.kg-1 of S-20098 with an ED50 of 5.7 mg.kg-1 for true entrainment and a clear relation between entrainment and the plasma concentration of S-20098. S-20098 was as effective as melatonin to entrain free-running rhythms. Ipsapirone was ineffective in our experimental conditions.

Immediate postnatal inoculation of a microbial barrier to prevent neonatal diarrhea induced by Clostridium difficile in young conventional and gnotobiotic hares.

The cecal content of a healthy young hare (a 10-fold dilution prepared in anaerobiosis) was transferred into gnotobiotic recipient mice. The fecal flora of recipient mice was inoculated into 49 conventional young hares (kept in a closed building) immediately after birth. All the inoculated hares survived until weaning whereas 35% of 48 non-treated conventional hares died of diarrhea. Clostridium difficile and C perfringens were present in all the diarrheal noninoculated hares, whereas these species were present only in 50% of healthy inoculated or noninoculated hares at low concentrations (less than 10(6)/g of feces). A microbial barrier effect against challenge-exposure strains of C difficile and C perfringens was evidenced in the intestinal tract of recipient gnotobiotic mice and young hares. Seemingly, the protective effect of the microbial inoculum was due to antagonisms exerted against C difficile and C perfringens in the intestinal tract of inoculated conventional hares.