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.

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.

[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.

Molecular mechanisms of natural killer cell activation in response to cellular stress.

Protection against cellular stress from various sources, such as nutritional, physical, pathogenic, or oncogenic, results in the induction of both intrinsic and extrinsic cellular protection mechanisms that collectively limit the damage these insults inflict on the host. The major extrinsic protection mechanism against cellular stress is the immune system. Indeed, it has been well described that cells that are stressed due to association with viral infection or early malignant transformation can be directly sensed by the immune system, particularly natural killer (NK) cells. Although the ability of NK cells to directly recognize and respond to stressed cells is well appreciated, the mechanisms and the breadth of cell-intrinsic responses that are intimately linked with their activation are only beginning to be uncovered. This review will provide a brief introduction to NK cells and the relevant receptors and ligands involved in direct responses to cellular stress. This will be followed by an in-depth discussion surrounding the various intrinsic responses to stress that can naturally engage NK cells, and how therapeutic agents may induce specific activation of NK cells and other innate immune cells by activating cellular responses to stress.

[Perioperative interstitial brachytherapy for recurrent keloid scars]. / La curiethérapie interstitielle périoperatoire dans le traitement des cicatrices chéloïdes récidivantes.

PURPOSE: Evaluation of the results of perioperative interstitial brachytherapy with low dose-rate (LDR) Ir-192 in the treatment of keloid scars. PATIENTS AND METHODS: We performed a retrospective analysis of 73 histologically confirmed keloids (from 58 patients) resistant to medicosurgical treated by surgical excision plus early perioperative brachytherapy. All lesions were initially symptomatic. Local control was evaluated by clinical evaluation. Functional and cosmetic results were assessed in terms of patient responses to a self-administered questionnaire. RESULTS: Median age was 28 years (range 13-71 years). Scars were located as follows: 37% on the face, 32% on the trunk or abdomen, 16% on the neck, and 15% on the arms or legs. The mean delay before loading was four hours (range, 1-6h). The median dose was 20Gy (range, 15-40Gy). Sixty-four scars (from 53 patients) were evaluated. Local control was 86% (follow-up, 44.5 months; range, 14-150 months). All relapses occurred early - within 2 years posttreatment. At 20 months, survival without recurrence was significantly lower when treated lengths were more than 6cm long. The rate was 100% for treated scars below 4.5cm in length, 95% (95% CI: 55-96) for those 4.5-6cm long, and 75% (95% CI: 56-88) beyond 6cm (p=0.038). Of the 35 scars (28 patients) whose results were reassessed, six remained symptomatic and the esthetic results were considered to be good in 51% (18/35) and average in 37% (13/35) (median follow-up, 70 months; range, 16-181 months). CONCLUSION: Early perioperative LDR brachytherapy delivering 20Gy at 5mm reduced the rate of recurrent keloids resistant to other treatments and gave good functional results.

[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.

Long-term exposure of hypothalamic explants to melatonin alters the release of gonadotrophin releasing hormone and the density of melatonin binding sites in the pars tuberalis of the male mink (Mustela vison).

To investigate the action of melatonin on the reproductive system, the effect of prolonged versus short-term exposure to melatonin on the release of gonadotrophin releasing hormone (GnRH) was examined in hypothalamic explants of male mink sacrificed in July, September or November. Mediobasal hypothalamic (MBH) explants including the pars tuberalis (PT) were incubated for 1 night with or without melatonin (10(-8) M) for 8 hr or 16 hr and the release of GnRH was then measured. The next day, the explants were incubated further but in a melatonin free buffer, and the release of GnRH was measured with increasing time. Half of the July and September explants had melatonin binding sites quantified by autoradiography. In November, a 16-hr exposure to melatonin induced a significant increase in the release of GnRH during the night, compared with control or 8-hr melatonin exposure. This increase persisted for at least 45 min after the withdrawal of melatonin, suggesting a stimulatory effect of melatonin on the synthesis of GnRH; this effect was apparent in July, September and November. In September, the density of melatonin binding in the PT was significantly lower in the explants incubated for 16 hr with melatonin, compared with those incubated for 8 hr. Thus, in vitro, a long exposure to melatonin, mimicking a single long night, stimulates the release and synthesis of GnRH in parallel with a decrease in the density of melatonin binding in the PT. These effects seem to depend heavily on the duration of exposure to melatonin.

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.

Neurons containing gastrin-releasing peptide and vasoactive intestinal polypeptide are involved in the reception of the photic signal in the suprachiasmatic nucleus of the Syrian hamster: an immunocytochemical ultrastructural study.

In mammals, the suprachiasmatic nuclei are involved in the generation of biological rhythms and are synchronized by light input coming from the retina. The targets of retinal afferents and the involvement of neurons containing gastrin-releasing and vasoactive intestinal peptides in photic reception were investigated in the suprachiasmatic nuclei of the Syrian hamster by using light- and electron-microscopic immunocytochemistry. Cholera toxin was used to trace retinal fibers and Fos immunoreactivity to visualize cellular response to light stimulation. Ultrastructural observations were made in the intermediate third of the nuclei, the area of highest overlap for the immunoreactivities investigated. Gastrin-releasing peptide and vasoactive intestinal peptide cell bodies were localized in the ventral part of the nuclei; their dense immunoreactive fiber network often displayed synaptic contacts. Both neuropeptides were colocalized in elongated cells observed near the optic chiasm. Following a light pulse in the middle of the subjective night, Fos protein was expressed in most gastrin-releasing peptide perikarya and in some vasoactive intestinal peptide cells. Retinal terminals mostly occurred in the midline zone between the suprachiasmatic nuclei. Symmetrical or asymmetrical retinal synapses were observed on gastrin-releasing peptide-immunoreactive dendrites and somata, but never on vasoactive intestinal peptide neurons. These results are discussed in relation to the photic entrainment of the circadian clock.

Estrogen receptor and progesterone receptor-immunoreactive cells are not co-localized with gonadotropin-releasing hormone in the brain of the female mink (Mustela vison).

The distribution of gonadal steroid (estrogen, progesterone) receptors in the brain of the adult female mink was mapped by immunocytochemistry. Using a monoclonal rat antibody raised against human estrogen receptor (ER), the most dense collections of ER-immunoreactive (IR) cells were found in the preoptic/anterior hypothalamic area, the mediobasal hypothalamus (arcuate and ventromedial nuclei), and the limbic nuclei (amygdala, bed nucleus of the stria terminalis, lateral septum). Immunoreactivity was mainly observed in the cell nucleus and a marked heterogeneity of staining appeared from one region to another. A monoclonal mouse antibody raised against rabbit uterine progesterone receptor (PR) was used to identify the PR-IR cells in the preoptic/anterior hypothalamic area and the mediobasal hypothalamus (arcuate and ventromedial nuclei). This study also focused on the relationship between cells containing sex-steroid receptors and gonadotropin-releasing hormone (GnRH) neurons on the same sections of the mink brain using a sequential double-staining immunocytochemistry procedure. Although preoptic and hypothalamic GnRH neurons were frequently in close proximity to perikarya containing ER or PR, they did not themselves possess receptor immunoreactivity. The present study provides neuroanatomical evidence that GnRH cells are not the major direct targets for gonadal steroids and confirms for the first time in mustelids the results previously obtained in other mammalian species.

Ontogenesis of the retinohypothalamic tract, vasoactive intestinal polypeptide- and peptide histidine isoleucine-containing neurons and melatonin binding in the hypothalamus of the mink.

The development of the retinohypothalamic tract (RHT) labeled with cholera toxin and of the vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) systems was studied in the hypothalamus of neonatal mink by using immunohistochemistry. Retinal fibers were observed in the suprachiasmatic nucleus (SCN) from birth and were adult-like by day 14. VIP and PHI immunoreactivity was also present from birth. Melatonin binding was studied by autoradiography using [125I]melatonin as a ligand. A specific binding was detected in near-term fetal and neonate brains in the olfactory epithelium, various thalamic nuclei, the pineal gland, and the pars tuberalis of the pituitary gland, but never in the SCN. These results are discussed in the context of the potential role of daylight cycles and/or melatonin in entraining circadian rhythms in neonate 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.

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.

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.

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.

Effects of melatonin treatment on the gonadotropin-releasing hormone neuronal system and on gonadotropin secretion in male mink, Mustela vison, in the presence or absence of testosterone feedback.

The effects of subcutaneous melatonin capsules on the gonadotropin-releasing hormone (GnRH) immunoreactive (ir) system and the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) have been tested in intact, castrated, and castrated adult male mink supplemented with testosterone. Animals were transferred in July, i.e., during the period of sexual rest, under a daily light:dark cycle of 16-hr light and 8-hr darkness and studied over 13 weeks. GnRH (ir) perikarya, visualized by immunocytochemistry, were counted on serial coronal sections from the diagonal band of Broca to the infundibulum. Serum FSH and LH concentrations were measured by radioimmunoassay. In intact mink, melatonin induced a significant increase in the number of (ir) perikarya and in FSH and LH concentrations 3 and 8 weeks, respectively, after melatonin capsule implantation. In castrated mink, the number of perikarya and the concentrations of FSH, which had increased within 2 weeks after castration, did not change during melatonin treatment. In contrast, the concentration of LH, which were not altered by castration, increased 3-6 weeks after the onset of melatonin administration, suggesting a stimulation of GnRH release. In castrated testosterone-treated mink, the number of perikarya was increased as in castrated males, but the elevation of FSH in response to castration was prevented. Within 2 weeks after melatonin capsule implantation, the concentrations of FSH decreased while those of LH remained low, indicating an inhibition of GnRH release. These results show that testosterone modulates the effect of melatonin on the activity of the GnRH-gonadotropin system.

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.