[Association between vascularization and its impact for recurrence of juvenile nasoangiofibroma]. / Asociación entre vascularización y su impacto en la recurrencia de nasoangiofibroma juvenil.

Background: Juvenile nasoangiofibroma (JNA) is a rare, highly vascular, locally aggressive benign tumor which affects male adolescents. It accounts for 0.05-0.5% of head and neck tumors with recurrence rates of 6-50%. The internal maxillary artery is the main source of JNA. Objective: To evaluate the relationship between vascular supply as a factor associated with JNA recurrence. Material and methods: An cohort study was performed in patients diagnosed with NAJ. We collected demographic data, vascular contribution by angiography and tomography results to classify them according to their stage (Radkowski classification), and if they received adjuvant radiotherapy. Post-surgical CT scans were requested to evaluate recurrence and if any of the variables were related to this. Results: A sample of 14 male patients who met the inclusion criteria was collected. The mean age was 14.71 ± 4.08 years. According to Radkowski classification, stage IA, IIA and IIC were reported in 14.3%, IIB and IIB in 7.1% and IIIA in 42.9%. 42.9% had recurrence and out of these, 66.7% had irrigation of the right carotid system and the same percentage of patients received radiotherapy as adjuvant treatment. Conclusions: There is a tendency in tumor recurrence associated with vascular contribution from the right carotid system, as well as with patients who received radiotherapy.

Introducción: el nasoangiofibroma juvenil (NAJ) es un tumor benigno, raro, altamente vascular y localmente agresivo que afecta a adolescentes del sexo masculino. Representa de 0.05 a 0.5% de los tumores de cabeza y cuello con tasas de recurencia del 6-50%. La arteria maxilar interna se considera el principal aporte de los NAJ. Objetivo: evaluar la relación entre el aporte vascular como factor asociado con la recurrencia de NAJ. Material y métodos: se realizó un estudio de cohorte en pacientes con diagnóstico de NAJ. Se recabaron datos demográficos, el aporte vascular por resultados de angiografía y de tomografía para clasificarlos según su estadio (clasificación de Radkowski), y si recibieron radioterapia adyuvante. Se solicitaron tomografías postquirúrgicas para evaluar la recurrencia y si alguna de las variables tiene relación con esta. Resultados: se recolectó una muestra de 14 pacientes del sexo masculino que cumplieron con los criterios de inclusión. La edad promedio fue de 14.71 ± 4.08 años. Según la clasificación de Radkowski, se reportó un estadio IA, IIA y IIC en 14.3%, IIB y IIB en un 7.1% y IIIA en 42.9%. El 42.9% tuvo recurrencia y de estos, el 66.7% tenía irrigación del sistema carotídeo derecho y recibieron radioterapia como tratamiento adyuvante el mismo porcentaje de pacientes. Conclusiones: existe una tendencia en la recurrencia del tumor asociada al aporte vascular proveniente del sistema carotídeo derecho y también a los pacientes que recibieron radioterapia.

[Factors related with microbiological contamination of surgical site in patients undergoing tracheotomy]. / Factores relacionados con la contaminación microbiológica de sitio quirúrgico en pacientes traqueotomizados.

Background: Tracheotomy is a common technique; however, microbiological contamination of the surgical site can increase morbimortality. Up to 90% of patients present a positive culture of the airway. Among the most important related factors is the lack of tracheal cannula replacement and lower airway infections. It is convenient to identify microbiological contamination of surgical site in tracheal secretions samples and the specific microorganism associated. Objective: To determine the factors related to microbiological contamination of surgical site. Material and methods: A prospective cohort study which included patients undergoing tracheotomy was carried out. Tracheal secretion was sampled by direct swabbing for culture during surgery and from the surgical site 5 days after. Results: The initial report showed contamination of samples in 58.3%, and 5 days after in 80.6%, with an incidence of contamination of 22.3%. Initially the main agents identified were Pseudomonas aeruginosa in 13.9% of the cultures, Klebsiella pneumoniae in 11.1% and Enterobacter spp. in 11%. On day 5, the most common agents were Klebsiella pneumoniae in 25% of the cases, Acinetobacter baumannii in 11.1% and Pseudomonas aeruginosa in 11.1. Conclusions: The frequency of microbiological contamination is high. The main agents were Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa. No risk factors for the presence of post-tracheotomy contamination were identified.

Introducción: la traqueotomía es un procedimiento común; sin embargo, la contaminación microbiológica del sitio quirúrgico puede aumentar la morbimortalidad. Hasta el 90% de los pacientes presentan un cultivo positivo de la vía respiratoria. Como factores relacionados, resaltan la falta de recambio de cánulas traqueales y las infecciones de vías aéreas bajas. Es conveniente identificar la contaminación microbiológica de secreción traqueal del sitio quirúrgico y el microorganismo asociado. Objetivo: determinar los factores relacionados con la contaminación microbiológica del sitio quirúrgico. Material y métodos: se hizo un estudio de cohorte prospectiva que incluyó a pacientes sometidos a traqueotomía. Se tomó cultivo por hisopado directo de secreción traqueal durante la cirugía y del sitio quirúrgico 5 días después. Resultados: la muestra inicial mostró contaminación en 58.3% de los pacientes y a los 5 días postquirúrgicos en 80.6%, con incidencia de contaminación de 22.3%. Inicialmente se aisló Pseudomonas aeruginosa en 13.9% de los casos, Klebsiella pneumoniae en 11.1% y Enterobacter spp. en 11%. Al quinto día se aisló Klebsiella pneumoniae en 25% de los casos, Acinetobacter baumannii en 11.1% y Pseudomonas aeruginosa en 11.1%. Conclusiones: la frecuencia de contaminación microbiológica es alta y se encontraron principalmente Staphylococcus aureus, Klebsiella pneumoniae y Pseudomonas aeruginosa. No se identificaron factores de riesgo para la contaminación postquirúrgica.

Tracking tsunami propagation and Island's collapse after the Hunga Tonga Hunga Ha'apai 2022 volcanic eruption from multi-space observations.

The quantity and accuracy of satellite-geodetic measurements have increased over time, revolutionizing the monitoring of tectonic processes. Global Navigation Satellite System (GNSS) and satellite radar signals provide observations beyond ground deformation, including how earthquake and tsunami processes affect variations in the ionosphere. Here, we study the Hunga Tonga Hunga Ha'apai (HTHH) volcanic eruption 2022 and its associated tsunami propagation with the analysis GNSS derived Total Electron Content (TEC), Synthetic Aperture Radar (SAR) Sentinel-1 data, complemented with tide gauge observations. We utilize GNSS sites data within a ~ 5000 km radius from the volcanic eruption for estimating the ionospheric perturbation as Vertical TEC. We give evidence on the detection of acoustic gravity, internal gravity, and atmospheric Lamb waves signatures in the TEC perturbation. In particular, the internal gravity waves that concentrated in the southwest of Tonga, directly correlates with the observed tsunami propagation direction as accounted by the tide gauge measurements. However, the acoustic gravity wave signature in the TEC is dominant in the north direction suggesting a surface deformation, which could be verified using Sentinel-1A SAR amplitude data. The analysis presented herein shows that within 5 h of the volcanic eruption, the central part of the HTHH island landscape disappeared with the biggest explosion. The unprecedented detail resolved by integrating satellite data yields previously unknown details of the deformation of the 2022 HTHH volcano eruption.

Fast relocking and afterslip-seismicity evolution following the 2015 Mw 8.3 Illapel earthquake in Chile.

Large subduction earthquakes induce complex postseismic deformation, primarily driven by afterslip and viscoelastic relaxation, in addition to interplate relocking processes. However, these signals are intricately intertwined, posing challenges in determining the timing and nature of relocking. Here, we use six years of continuous GNSS measurements (2015-2021) to study the spatiotemporal evolution of afterslip, seismicity and locking after the 2015 Illapel earthquake ([Formula: see text] 8.3). Afterslip is inverted from postseismic displacements corrected for nonlinear viscoelastic relaxation modeled using a power-law rheology, and the distribution of locking is obtained from the linear trend of GNSS stations. Our results show that afterslip is mainly concentrated in two zones surrounding the region of largest coseismic slip. The accumulated afterslip (corresponding to [Formula: see text] 7.8) exceeds 1.5 m, with aftershocks mainly occurring at the boundaries of the afterslip patches. Our results reveal that the region experiencing the largest coseismic slip undergoes rapid relocking, exhibiting the behavior of a persistent velocity weakening asperity, with no observed aftershocks or afterslip within this region during the observed period. The rapid relocking of this asperity may explain the almost regular recurrence time of earthquakes in this region, as similar events occurred in 1880 and 1943.

B-value variations in the Central Chile seismic gap assessed by a Bayesian transdimensional approach.

The b-value can be used to characterize the seismic activity for a given earthquake catalog and provide information on the stress level accumulated at active faults. Here we develop an algorithm to objectively estimate variations of b-value along one arbitrary dimension. To this end, we employ a Bayesian transdimensional approach where the seismic domains will be self-defined according to information in the seismic catalog. This makes it unnecessary to prescribe the location and extent of domains, as it is commonly done. We first show the algorithm's robustness by performing regressions from synthetic catalogs, recovering the target models with great accuracy. We also apply the algorithm to a microseismicity catalog for the Central Chile region. This segment is considered a seismic gap where the last major earthquake with shallow slip was in 1730. Our results illuminate the downdip limit of the seismogenic zone and the transition to intraslab seismicity. In the along-strike direction, low b-value coincides with the extent of locked asperities, suggesting a high-stress loading at the Central Chile seismic gap. Our results indicate the reliability of the Bayesian transdimensional method for capturing robust b-value variations, allowing us to characterize the mechanical behavior on the plate interface of subduction zones.

Histidine decarboxylase inhibitors: a novel therapeutic option for the treatment of leydigioma.

Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.

Heme oxygenase-1 arrests Leydig cells functions and impairs their regulation by histamine.

Testicular Leydig cells (LC) are modulated by several pathways, one of them being the histaminergic system. Heme oxygenase-1 (HO-1), whose upregulation comprises the primary response to oxidative noxae, has a central homeostatic role and might dysregulate LC functions when induced. In this report, we aimed to determine how hemin, an HO-1 inducer, affects LC proliferative capacity and whether HO-1 effects on LC functions are reversible. It was also evaluated if HO-1 interacts in any way with histamine, affecting its regulatory action over LC. MA-10 and R2C cell lines and immature rat LC were used as models. Firstly, we show that after a 24-h incubation with 25 µmol/L hemin, LC proliferation is reversibly impaired by cell cycle arrest in G2/M phase, with no evidence of apoptosis induction. Even though steroid production is abrogated after a 48-h exposure to 25 µmol/L hemin, steroidogenesis can be restored to control levels in a time-dependent manner if the inducer is removed from the medium. Regarding HO-1 and histamine interaction, it is shown that hemin abrogates histamine biphasic effect on steroidogenesis and proliferation. Working with histamine receptors agonists, we elucidated that HO-1 induction affects the regulation mediated by receptor types 1, 2 and 4. In summary, HO-1 induction arrests LC functions, inhibiting steroid production and cell cycle progression. Despite their reversibility, HO-1 actions might negatively influence critical phases of LC development and differentiation affecting their function as well as other androgen-dependent organs. What's more, we have described a hitherto unknown interaction between HO-1 induction and histamine effects.

Earthquake segmentation in northern Chile correlates with curved plate geometry.

We performed an integrated analysis of the coseismic slip, afterslip and aftershock activity of the 2014 Mw 8.1 Pisagua earthquake. This earthquake seems to be spatially located between two major historical earthquakes, the 1868 Mw 8.8 earthquake in southern Peru and the 1877 Mw 8.5 earthquake in northern Chile. Continuous GPS data were used to model the coseismic slip of the mainshock and the largest aftershock (Mw 7.6). The afterslip was modeled for 273 days (end of year 2014) after the largest aftershock, revealing two patches of afterslip: a southern patch between the mainshock and the largest aftershock and a patch to the north of the mainshock. Observations from the seismic network indicate that aftershocks were concentrated near the southern patch. Conversely, the northern patch contained hardly any aftershocks, indicating a dominant aseismic slip. The Pisagua earthquake occurred within a prominent, curved section of the Andean subduction zone. This section may have acted as a barrier for the largest historical earthquakes and as an isolated segment during the Pisagua earthquake.

Back to full interseismic plate locking decades after the giant 1960 Chile earthquake.

Great megathrust earthquakes arise from the sudden release of energy accumulated during centuries of interseismic plate convergence. The moment deficit (energy available for future earthquakes) is commonly inferred by integrating the rate of interseismic plate locking over the time since the previous great earthquake. But accurate integration requires knowledge of how interseismic plate locking changes decades after earthquakes, measurements not available for most great earthquakes. Here we reconstruct the post-earthquake history of plate locking at Guafo Island, above the seismogenic zone of the giant 1960 (Mw = 9.5) Chile earthquake, through forward modeling of land-level changes inferred from aerial imagery (since 1974) and measured by GPS (since 1994). We find that interseismic locking increased to ~70% in the decade following the 1960 earthquake and then gradually to 100% by 2005. Our findings illustrate the transient evolution of plate locking in Chile, and suggest a similarly complex evolution elsewhere, with implications for the time- and magnitude-dependent probability of future events.

Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys.

Leydig-cell tumours (LCTs) are rare endocrine tumours of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/or gynaecomastia, in adults. So far, scientific evidence points to aromatase (CYP19) overexpression and excessive oestrogen and insulin-like growth factor (IGF) -1 production as responsible for Leydig-cell tumourigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumour cells, a well-documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, oestrogen receptor (ER) α, ERß, androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF-1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERß were overexpressed compared with NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs.

Proliferative effect of histamine on MA-10 Leydig tumor cells mediated through HRH2 activation, transient elevation in cAMP production, and increased extracellular signal-regulated kinase phosphorylation levels.

Mast cells (MC) occur normally in the testis with a species-specific distribution, yet their precise role remains unclear. Testicular MC express histidine decarboxylase (HDC), the unique enzyme responsible for histamine (HA) generation. Evidence to date supports a role for HA as a local regulator of steroidogenesis via functional H1 and H2 receptor subtypes (HRH1 and HRH2, respectively) present in Leydig cells. Given that HA is a well-known modulator of physiological and pathological proliferation in many different cell types, we aimed in the present study to evaluate whether HA might contribute to the regulation of Leydig cell number as well as to the control of androgen production. Herein, we demonstrate, to our knowledge for the first time, that MA-10 Leydig tumor cells, but not normal immature Leydig cells (ILC), exhibit a proliferative response upon stimulation with HA that involves HRH2 activation, transient elevation of cAMP levels, and increased extracellular signal-regulated kinase (ERK) phosphorylation. Our results also reveal that MA-10 cells show significantly heightened HDC expression compared to normal ILC or whole-testicular lysate and that inhibition of HDC activity decreases MA-10 cell proliferation, suggesting a possible correlation between autocrine overproduction of HA and abnormally increased proliferation in Leydig cells. The facts that germ cells are also both source and target of HA and that multiple testicular cells are susceptible to HA action underline the importance of the present study, which we hope will serve as a first step for further research into regulation of non-MC-related HDC expression within the testis and its significance for testicular function.

Composição corporal de pacientes acamados por fraturas do quadril / Body composition in bed-ridden adult patients by hip fracture

As fraturas do quadril são a maior causa de hospitalização da terceira idade, e constituem um considerável encargo econômico e social. A taxa de mortalidade atual após um ano de fratura é acima de 33 por cento, e o risco de morte é maior do quarto ao sexto mês após a fratura. O objetivo deste estudo foi de avaliar alterações na composição corporal de pacientes idosos, durante sua hospitalização por fraturas fêmur proximal, através de métodos antropométricos e análise dos valores fisiológicos de gasto energético. Foi realizado um estudo prospectivo utilizando-se 45 pacientes consecutivos com diagnóstico de fratura do quadril. Em todos os casos, foram obtidas medidas diretas e avaliações antropométricas indiretas baseadas em estimativas, nas primeiras 24 horas e repetidas após uma semana de admissão hospitalar. Após uma semana de internação houve diminuição da média do perímetro do braço (0,73 cm, p=0.0052) e da espessura da prega tricipital (1.41 mm, p=0.0181), sem haver modificação das outras variáveis estudadas. A avaliação antropométrica como um meio de se fazer um mapa da composição corporal, em conjunto com as estimativas indiretas sugeridas neste estudo, podem ajudar a determinar o estado nutricional e necessidades calóricas de pacientes idosos.

Hip fractures are a major cause of hospitalization among the elderly, and constitute a considerable social and economic burden. The current mortality rate one year after hip fracture is over 33 percent, the risk of death is greatest 4 to 6 months after fracture. The objective of this study was to use anthropometric methods and physiological energy-expenditure values to assess changes in body composition during hospitalization, in elderly patients admitted for fractures of the proximal femur. A prospective study was performed using a consecutive sequence of 45 patients with diagnosed hip fracture. In all cases, direct measurements and indirect estimate-based anthropometric evaluation were performed in the first 24 hours following admission, and again one week after admission. By one week after admission, there was a decrease in mean arm girth (0.73 cm, p=0.0052) and in triceps fold thickness (1.41 mm, p=0.0181), but not in the other variables tested. Anthropometric evaluation as a means of charting body composition, in conjunction with the indirect estimates suggested here, may help to determine nutritional status and calorie requirements in elderly patients.

Galectin-1: biphasic growth regulation of Leydig tumor cells.

Galectin-1 (Gal-1) is a widely expressed beta-galactoside-binding protein that exerts pleiotropic biological functions. To gain insight into the potential role of Gal-1 as a novel modulator of Leydig cells, we investigated its effect on the growth and death of MA-10 tumor Leydig cells. In this study, we identified cytoplasmic Gal-1 expression in these tumor cells by cytofluorometry. DNA fragmentation, caspase-3, -8, and -9 activation, loss of mitochondrial membrane potential (DeltaPsim), cytochrome c (Cyt c) release, and FasL expression suggested that relatively high concentrations of exogenously added recombinant Gal-1 (rGal-1) induced apoptosis by the mitochondrial and death receptor pathways. These pathways were independently activated, as the presence of the inhibitor of caspase-8 or -9 only partially prevented Gal-1-effect. On the contrary, low concentrations of Gal-1 significantly promoted cell proliferation, without inducing cell death. Importantly, the presence of the disaccharide lactose prevented Gal-1 effects, suggesting the involvement of the carbohydrate recognition domain (CRD). This study provides strong evidence that Gal-1 is a novel biphasic regulator of Leydig tumor cell number, suggesting a novel role for Gal-1 in the reproductive physiopathology.

Characterization of L-arginine transport in adrenal cells: effect of ACTH.

Nitric oxide synthesis depends on the availability of its precursor L-arginine, which could be regulated by the presence of a specific uptake system. In the present report, the characterization of the L-arginine transport system in mouse adrenal Y1 cells was performed. L-arginine transport was mediated by the cationic/neutral amino acid transport system y+L and the cationic amino acid transporter (CAT) y+ in Y1 cells. These Na+-independent transporters were identified by their selectivity for neutral amino acids in both the presence and absence of Na+ and by the effect of N-ethylmaleimide. Transport data correlated to expression of genes encoding for CAT-1, CAT-2, CD-98, and y+LAT-2. A similar expression profile was detected in rat adrenal zona fasciculata. In addition, cationic amino acid uptake in Y1 cells was upregulated by ACTH and/or cAMP with a concomitant increase in nitric oxide (NO) production.

Inhibition of the proteasome by lactacystin enhances oligodendroglial cell differentiation.

We have used lactacystin, a specific inhibitor of the 26S proteasome, in oligodendroglial cell (OLGc) primary cultures to explore the possible participation of the proteasome-ubiquitin-dependent pathway in the decision of the OLGcs to arrest their proliferation and start differentiation. Addition of lactacystin at various concentrations to cultures containing a majority of OLGc was found to produce their withdrawal from the cell cycle and to induce their biochemical and morphological differentiation, with the appearance of extensive myelin-like sheets. The three classic proteolytic activities of the proteasome were significantly decreased in the lactacystin-treated cultures, and the immunocytochemical analysis showed an increase in the number of O4-, O1-, myelin basic protein-, and myelin proteolipid protein-positive cells and a decrease in A2B5-reacting cells. Quantitative immunochemical evaluation of the expression of certain proteins controlling the cell cycle showed an increase in p27kip1-, cyclin D-, and cdk4-positive cells, with a decrease in cyclin E- and cdk2-positive cells. In the lactacystin-treated OLGcs, there was a dose-dependent decrease in the number of cells incorporating bromodeoxyuridine and in the activity of the complexes cyclin D-cdk4 and cyclin E-cdk2. Furthermore, increased levels of expression of several STAT factors were found, suggesting that proteasome inhibition in OLGcs could stabilize signals of survival and differentiation that might be processed through the JAK/STAT signaling cascade.

Apotransferrin decreases migration and enhances differentiation of oligodendroglial progenitor cells in an in vitro system.

We have previously shown that a single intracranial injection of apotransferrin (aTf) in neonatal rats produces an accelerated mylinogenesis and increases the expression of certain myelin proteins such as myelin basic protein (MBP). In the present work, we studied the effects of aTf upon oligodendrocyte progenitor cell (Opc) cultures. In the presence of aTf, cells developed a multipolar morphology and showed an increased expression of O(4), MBP, O(1) and myelin-associated glycoprotein compared to controls. Migration studies using the agarose drop assay showed that aTf strongly inhibited OPc migration. This effect was not observed when an antibody against the transferrin receptor was added. The expression of two cell adhesion molecules, neural cell adhesion molecule (NCAM), N-cadherin and of polysialylated NCAM (PSA-NCAM) was evaluated by immunocytochemistry and by Western blot. Although NCAM expression did not change, there was a significant increase in N-cadherin expression and a decrease in PSA-NCAM in the aTf-treated cells. Time lapse studies of the expression of PSA-NCAM as an indicator of migration and of MBP as a marker of differentiation showed that in the cultures treated with aTf there is first a decrease in the percentage of cells expressing the former molecule which is followed by an increase in the percentage of cells expressing MBP. These results suggest that aTf added in vitro to cultured OPcs inhibits first their migration and then enhances their differentiation.