Late neurological dysfunction in adult lumbosacral lipoma with tethered cord

The case of a 59-year-old man with adult-onset neurological dysfunction secondary to a tethered cord and a lumbosacral lipoma is presented. This condition not only affects children, but is known to produce neurological dysfunction in adults and should be kept in mind in the differential diagnosis of patients with sacral root deficits.     

A preprandial intake pattern in weanling rats ingesting a high fat diet

Six male albino rats were weaned at 16 days and their intake of a high fat liquid diet was subsequently monitored with drinkometers for a 25-day period. Intake increased during growth via an increase in meal size and duration; meal frequency declined and intake rate remained stable. Light-dark differences were found only on the meal frequency measure. Immediately after weaning, there was a significant positive correlation between the duration of the preceding interval and the size of the meal; preprandial correlation. This relationship subsequently declined while the magnitude of the correlation between the meal size and the following interval (postprandial correlation) increased. These results indicate that there is a changeover in the mode of food intake regulation during the early postweaning period.     

Moving beyond sodium valproate: choosing the right anti-epileptic drug in children

ABSTRACT

Introduction: Sodium valproate is a widely used anti-epileptic drug with a broad spectrum of activity and mechanism of action. It has consequently been the first-line drug for most seizure types in children for the past fifty years. A wide range of side effects come along with these exceptional properties, including teratogenicity and neuro-cognitive impairments in offspring. Therefore, epilepsy treatment in children and adolescents should be reassessed in light of newer antiepileptic drugs as well as a more targeted-approach with older drugs.

Areas covered: The authors review the main concerns of valproate use in terms of adverse effects on different systems and drug interactions. The current alternatives to valproate in absence, myoclonic, tonic-clonic and focal onset seizures in children/adolescents are also reviewed.

Expert opinion: There are several issues that research should address in antiepileptic therapy and in clinical studies with children, given the peculiarity of this population. Future perspectives in epilepsy therapy should now lead towards an individualized treatment.     

Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing

Background  

Despite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated.     

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain‐containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76‐CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.     

Molecular mechanisms of basic fibroblast growth factor effect on healing of ulcerative colitis in rats

We demonstrated previously that basic fibroblast growth factor (bFGF) accelerated the healing of experimental duodenal ulcers, and we now hypothesize that bFGF might also accelerate the healing of experimental ulcerative colitis (UC). We also explored the potential molecular mechanisms involved in the accelerated healing of UC in rats treated with bFGF. The results demonstrated that colonic lesions were significantly reduced by bFGF treatment, whereas neutralization of bFGF aggravated iodoacetamide-induced UC. Protein expression of bFGF was increased during the healing stage of UC. Tumor necrosis factor-α levels and myeloperoxidase activity were significantly decreased in UC rats treated with bFGF, whereas they increased in rats treated with anti-bFGF antibody. Real-time polymerase chain reaction and immunohistochemistry showed decreased levels of p27 in the UC rats compared with the healthy controls, which was reversed by bFGF treatment in a dose-dependent manner. By immunohistochemistry and double labeling of Ki-67 and CD34, prominent positive staining of Ki-67 and CD34 was seen after bFGF treatment, indicating the enhanced proliferation of fibroblasts and epithelial and endothelial cells, i.e., angiogenesis. We conclude that bFGF plays a beneficial role in the healing of UC in rats. The molecular mechanisms of bFGF in UC healing not only involve the expected increased cell proliferation, especially angiogenesis, but also encompass the reduction of inflammatory cytokines and infiltration of inflammatory cells. Thus, bFGF enema may be a new therapeutic option for UC.     

The presence and origin of autoantibodies against α4 and α7 nicotinic acetylcholine receptors in the human blood: possible relevance to Alzheimer's pathology

Alzheimer's disease (AD) is characterized by a loss of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) in the brain and severe memory impairments. Previously, we found that antibodies elicited against extracellular domain of α7 nAChR subunit decreased the number of α7 nAChRs in the brains of mice and impaired episodic memory. Here we show that antibodies capable to bind α7(1-208) are present in the blood of both healthy humans and AD patients. In healthy individuals, their capacity to compete with [(125)-I]-α-bungarotoxin for the binding to α7(1-208) increased with age. The level of such antibodies was significantly elevated in children with severe form of obstructive bronchitis and in mice injected with Lewis lung carcinoma cells expressing both α4β2 and α7 nAChRs. Elevated antibody levels were accompanied with decreased surface nAChRs on the blood lymphocytes of children and of mice immunized with α7(1-208). Among AD patients, the level of α7 nAChR-specific antibodies was significantly larger in people 62.5 ± 1.5 years old with moderate or severe AD stages (15.2 ± 1.3 MMSE scores) compared to those of 76 ± 1.5 years old with the mild (22.7 ± 0.1 MMSE scores) AD stage. We concluded that α7(1-208) nAChR-specific antibodies found in the human blood are formed as a result of common infections accompanied with the destruction of respiratory epithelium. Elevated blood plasma levels of α7(1-208) nAChR-specific antibodies are characteristic for the early-onset AD and, therefore, are suggested as one of the risk factors for the development of this form of the disease.     

Additive regulation of GluR1 by stargazin and serum- and glucocorticoid-inducible kinase isoform SGK3

The serum- and glucocorticoid-inducible kinase isoform 3 (SGK3) and stargazin have both been shown to enhance the synaptic expression level of GluR1. The present study was performed to elucidate whether SGK3 and stargazin interact or are effective through different pathways in the regulation of GluR1. Proteins were expressed in Xenopus oocytes by injection of complementary RNA (cRNA) encoding GluR1, SGK isoforms, and/or stargazin. In oocytes expressing GluR1 6 days after cRNA injection, glutamate induced an inward current (I_Glu), which was increased approximately fourfold following coexpression of SGK3. Coexpression of stargazin similarly enhanced I_Glu. Coexpression of both SGK3 and stargazin stimulated the current by a factor of 15.5. Replacement of the serine by alanine at the only SGK consensus sequence (RXRXXS/T) in stargazin enhanced the efficacy of stargazin but did not prevent further stimulation of I_Glu by additional coexpression of SGK3. Western blotting showed that stargazin accelerated membrane insertion of GluR1 protein leading to enhanced GluR1 plasma membrane protein abundance 2 days, but not 6 days, after cRNA injection, while SGK3 increased plasma membrane protein abundance 6 days after cRNA injection. In conclusion, SGK3 and stargazin regulate GluR1 independently, and thus, their effects on glutamate-induced currents are additive.     

Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage

Recent breakthroughs in the generation of induced pluripotent stem cells (iPSCs) have provided a novel renewable source of cells with embryonic stem cell-like properties, which may potentially be used for gene therapy and tissue engineering. Although iPSCs have been differentiated into various cell types, iPSC-derived keratinocytes have not yet been obtained. In this study, we report the in vitro differentiation of mouse iPSCs into a keratinocyte lineage through sequential applications of retinoic acid and bone-morphogenetic protein-4 and growth on collagen IV-coated plates. We show that iPSCs can be differentiated into functional keratinocytes capable of regenerating a fully differentiated epidermis, hair follicles, and sebaceous glands in an in vivo environment. Keratinocytes derived from iPSCs displayed characteristics similar to those of primary keratinocytes with respect to gene and protein expression, as well as their ability to differentiate in vitro and to reconstitute normal skin and its appendages in an in vivo assay. At present, no effective therapeutic treatments are available for many genetic skin diseases. The development of methods for the efficient differentiation of iPSCs into a keratinocyte lineage will enable us to determine whether genetically corrected autologous iPSCs can be used to generate a permanent corrective therapy for these diseases.