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Summary Purpose:  Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α‐subunit type‐1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs. Methods:  Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high‐performance liquid chromatography (dHPLC) and sequencing. Whole‐cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Nav1.1 in tsA201 cells. Results:  Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Nav1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED‐induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues. Conclusions:  Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Nav1.1, which may be the basis of seizure aggravation by sodium channel–blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.

This article is available online at http://www.jlr.org linked ␣ -and ␤ -subunit, with each subunit having a large extracellular domain, a single membrane-spanning domain, and a short, noncatalytic cytoplasmic tail. Integrins seem to be the major receptors by which cells attach to components of the extracellular matrix (ECM), such as vitronectin, etc. ( 4 ), and are involved in the metastasis signaling of hepatocellular carcinoma (HCC) ( 5 ).The integrin ␣ V subunit associates with one of fi ve integrin ␤ subunits, ␤ 1, ␤ 3, ␤ 5, ␤ 6, or ␤ 8, to form fi ve distinct ␣ V ␤ heterodimers ( 6 ). The integrin ␣ V ␤ heterodimers on the cell surface interact with cell adhesive proteins, such as collagen, fi brinogen, fi bronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. Integrins increase in invasive tumors and distant metastases, characterize the metastatic phenotype, and play a key role in tumor metastasis ( 7,8 ). Many studies have documented marked differences in the surface expression and distribution of integrins between malignant tumors and preneoplastic tissues. For example, the integrin ␣ V ␤ 3 complex is strongly expressed in the invasive front cells of malignant melanoma and angiogenic blood vessels, but it is weakly expressed on preneoplastic melanomas and quiescent blood vessels ( 9 ). Also, it has been demonstrated that ␣ V ␤ 3 integrin is specifi cally required to sustain neovascularization induced in vivo by fibroblast growth factor-2 ( 10 ). Integrin ␣ V ␤ 3 physically associates with phosphorylated and activated insulin-like growth factor receptor, and it may be involved in the HCC cell migration and progression ( 11 ). Furthermore, inducing the expression of the integrin ␣ V ( 7 ) or ␤ 3 ( 12 ) subunit in melanoma cells increases their metastatic potential. Integrins have been implicated as very important adhesion molecules that are involved in multiple physiological processes, such as cell adhesion, proliferation, and survival ( 1-3 ). Each integrin generally consists of a noncovalently Abstract Integrin is important in migration and

The present study explored a key miRNA that plays a vital role in sciatic nerve conditioning injury promoting repair of injured dorsal column, and validated its function. Microarray analysis revealed miR-17-5p expression decreased sharply at 3, 7 and 14 days in the sciatic nerve conditioning injury group compared with the simple dorsal column lesion group. After miR-17-5p inhibition in DRG neurons, GAP-43 expression was upregulated and neurite growth was increased. STAT3 together with p-STAT3 showed opposite trends with miR-17-5p. MiR-17-5p inhibition extended neurite and upregulated STAT3, p-STAT3 and GAP-43. To further determine a substitution therapy for sciatic nerve conditioning injury, beta-phenethyl isothiocyanate (PEITC), which downregulates miR-17-5p, was assessed. The results showed that treatment with 10 µM PEITC resulted in longest neurite length. Further experiments demonstrated PEITC induced neurite growth by inhibiting miR-17-5p and further upregulating STAT3, p-STAT3 and GAP-43. The somatosensory evoked potential test confirmed similar treatment effects for PEITC, Ad-miRNA-17-5p inhibitor, and sciatic nerve conditioning injury on the dorsal column lesion. In conclusion, the miR-17-5p/STAT3/GAP-43 axis is an indispensable component of sciatic nerve conditioning injury promoting repair of injured dorsal column. PEITC could promote repair of injured dorsal column via the miR-17-5p/STAT3/GAP-43 axis, and could mimic the treatment effect of sciatic nerve conditioning injury.

FEWP showed good efficacy, safety, and tolerability in PSD patients. We conclude that FEWP is well tolerated and may be a useful therapeutic option in patients with PSD.

Background: Human mesenchymal stem cells (MSCs) have been studied and applied extensively because of their ability to self-renew and differentiate into various cell types. Since most human diseases models are murine, mouse MSCs should have been studied in detail. The mdx mouse -a Duchenne muscular dystrophy model -was produced by introducing a point mutation in the dystrophin gene. To understand the role of dystrophin in MSCs, we compared MSCs from mdx and C57BL/10 mice, focusing particularly on the aspects of light and electron microscopic morphology, immunophenotyping, and differentiation potential.

SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screened SCN1A mutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high-performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missense SCN1A mutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ∼25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ∼12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice-site mutations identified in the majority of previous studies. This is the first report of mosaic SCN1A mutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.

To investigate the potential of myristic acid (MC) to mediate brain delivery of polyethylenimine (PEI) as a gene delivery system, a covalent conjugate (MC-PEI) of MC, and PEI was synthesized. A near-infrared fluorescence probe, IR820 was conjugated to MC-PEI to explore its in vivo distribution after intravenous (i.v.) administration in mice. The brain targeting ability of MC-PEI was evaluated by near-infrared fluorescence imaging and analyzed semiquantitatively by fluorescence intensity, respectively. Significant NIR fluorescent signal was detected in the brain 12 h after i.v. administration and further confirmed by imaging the whole brain and brain slices. Semiquantitative results from fluorescence intensity further supported the successful brain delivery of MC-PEI which led to a very significant increase ( approximately 200%) in the brain uptake after i.v. injection in comparison with unmodified PEI. The capability of MC-PEI to condense DNA was further confirmed using agarose gel retardation assay, indicating its potential for gene delivery. The significant in vivo and ex vivo results suggest that MC-PEI is a promising brain-targeting drug delivery system, especially for gene delivery.