Children who stutter show reduced action-related activity in the rostral cingulate zone.

Previous studies have indicated that children who stutter show not only speech-related problems, but also wider difficulties in self-control. In this study we test the novel hypothesis that children who stutter may experience difficulties with inhibitory control over voluntary actions. We used functional MRI to compare brain activity between children who stutter and children who do not stutter in a task that captures key cognitive aspects of voluntary action control. Participants performed a rolling marble task, in which they were instructed to press a key to stop a rolling marble from crashing on some of the trials (instructed action condition). They were also asked to choose voluntarily whether to execute or inhibit this prepotent response in other trials (volition condition). Children who stutter reported less motor and cognitive impulsivity and had shorter stop-signal reaction times when controlled for IQ, consistent with greater inhibition, compared to children who do not stutter. At the neural level, children who stutter showed decreased activation in the rostral cingulate zone during voluntary action selection compared to children who do not stutter. This effect was more pronounced for children who were rated as showing more stuttered syllables in the stutter screening, and was furthermore correlated with stop-signal reaction times and impulsivity ratings. These findings suggest that stuttering in childhood could reflect wider difficulties in self-control, also in the non-verbal domain. Understanding these neural mechanisms could potentially lead to more focused treatments of stuttering.

Management of congenital venous malformations of the vulva.

OBJECTIVE: To discuss the differential diagnosis and the management of venous malformations of the vulva. METHODS: Five symptomatic patients were treated. The degree of pain and discomfort was self-assessed by using a horizontal visual analog scale before and after treatment. Preoperative evaluation included Doppler ultrasound scanning in all patients and magnetic resonance imaging (MRI) in one. All patients had direct-injection venography and sclerotherapy during the same session. Ethanol was used in two cases and polidocanol in three. Patients were followed-up by means of Doppler ultrasound scanning and office visits. RESULTS: All patients experienced marked swelling after the injection, and one developed cutaneous necrosis that healed within 2 weeks. Transient hemoglobinuria was observed in two cases. No early or late major complications occurred. At a mean follow-up of 23 months (range 5-43), all patients experienced complete relief from symptoms and currently have normal vulvar sensation. Four patients had complete ablation of the treated lesion. In one patient the procedure resulted in a significant, albeit incomplete, occlusion of the lesion, and no further treatment was deemed necessary. From a cosmetic standpoint, both patients and physicians considered the results successful. CONCLUSION: Vulvar venous malformations should be distinguished from vulvar varicosities, hematomas, soft-tissue neoplasms, and other vascular anomalies. Doppler ultrasound, MRI, and direct-injection venography are the most accurate diagnostic modalities. Sclerotherapy can successfully treat this condition. The procedure should be monitored with an imaging modality, preferably direct-injection venography with digital subtraction serial imaging.

Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis.

BACKGROUND: Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. METHODS AND RESULTS: Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 microgram/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P<0.05) at the highest level tested (187 microgram/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P<0.05) with increasing dose (P<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P<0.05) with escalating dose (P<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. CONCLUSIONS: Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.

Minoxidil inhibits proliferation and migration of cultured vascular smooth muscle cells and neointimal formation after balloon catheter injury.

The goal of the study was to investigate the in vitro and in vivo inhibition of minoxidil on smooth muscle cell (SMC) proliferation and migration as well as neointimal formation. The in vitro effect of minoxidil was investigated by Boyden chamber assay and cell-cycle analysis. To evaluate the in vivo effect, we treated the animals with minoxidil in their drinking water before and after balloon catheter injury to carotid artery. Results showed that minoxidil inhibited SMC migration across type I collagen membrane in a dose-related manner (13.5% by 0.01 mg/ml; p < 0.05; 16.8% by 0.05 mg/ml: p < 0.01; 40.4% by 0.25 mg/ml; p < 0.001; and 65.8% by 1.25 mg/ml; p < 0.001). Minoxidil (0.8 mg/ml) increased the number of SMCs in G1 phase (p < 0.05) and decreased the number of SMCs in S phase (p < 0.001). In vivo minoxidil treatment reduced neointimal mass by 31.7% (120 mg/L) and 42.3% (200 mg/L), respectively. Data demonstrate that minoxidil inhibits vascular SMC proliferation and migration both in vitro and in vivo, and therefore may be useful to inhibit SMC hyperplasia that occurs in restenosis and other vascular diseases.

Adenovirus-mediated gene transfer of the human tissue inhibitor of metalloproteinase-2 blocks vascular smooth muscle cell invasiveness in vitro and modulates neointimal development in vivo.

BACKGROUND: Endovascular injury induced by balloon withdrawal leads to the increased activation of matrix metalloproteinases (MMPs) in the vascular wall, allowing smooth muscle cells (SMCs) to digest the surrounding extracellular matrix (ECM) and migrate from the media into the intima. The objective of this study was to examine the effects of a replication-deficient adenovirus carrying the cDNA for human tissue inhibitor of metalloproteinase-2 (AdCMV.hTIMP-2) on SMC function in vitro and neointimal development in the injured rat carotid artery. METHODS AND RESULTS: Infection of cultured rat aortic SMCs at a multiplicity of infection of 100 with AdCMV.hTIMP-2 resulted in high-level expression of hTIMP-2 mRNA and protein secretion into the medium. Conditioned media (CM) from AdCMV. hTIMP-2-infected but not control virus (AdCMV.null or AdCMV. betagal)-infected SMCs inhibited MMP-2 activity on gelatin zymograms as well as the chemoattractant-directed migration of SMCs across reconstituted basement membrane proteins in the Boyden chamber assay. In contrast, AdCMV.hTIMP-2 CM had no effect on chemoattractant-directed migration of SMCs occurring in the absence of an ECM barrier or on the proliferation of cultured neointimal SMCs. Delivery of AdCMV.hTIMP-2 (2.5x10(9) pfu) to the carotid artery wall at the time of balloon withdrawal injury inhibited SMC migration into the intima by 36% (P<0.05) at 4 days and neointimal area by 53% (P<0.01) at 8 days and by 12% (P=NS) at 21 days after injury. AdCMV.hTIMP-2 had no effect on medial area. CONCLUSIONS: Adenovirus-mediated hTIMP-2 gene transfer inhibits SMC invasiveness in vitro and in vivo and delays neointimal development after carotid injury.

Increased expression of membrane-type matrix metalloproteinase and preferential localization of matrix metalloproteinase-2 to the neointima of balloon-injured rat carotid arteries.

BACKGROUND: Remodeling of the injured vascular wall is dependent on the action of several extracellular proteases. Previous studies have shown that expression of matrix metalloproteinases (MMP-2 and MMP-9) is upregulated after vascular injury and that MMP-2 is required for the migration of cultured vascular smooth muscle cells across complex extracellular matrix barriers. The present study examined changes in the expression of membrane-type metalloproteinase (MT-MMP-1), a putative regulator of MMP-2, in the tissue localization of MMP-2, and in the expression of activated and latent forms of MMP-2 and the tissue inhibitor of metalloproteinases, TIMP-2, in rat carotid arteries subjected to balloon catheter injury. METHODS AND RESULTS: MT-MMP-1 mRNA levels increased sixfold after 3 days of injury, coinciding with an increase in MMP-2 activation assessed by gelatin zymography. Western blotting and gelatin zymography showed an increase in MMP-2 protein levels beginning 5 to 7 days after injury; immunocytochemistry and Western blotting showed that the increase occurred preferentially in the developing neointima. CONCLUSIONS: These results show that increased expression of MT-MMP-1 and activation of MMP-2 occurs early after injury to the rat carotid artery and that at later times MMP-2 is preferentially localized to the developing neointima.