“White dot syndromes”, an inappropriate and outdated misnomer

International Ophthalmology -     

Alleviation of Abeta-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

A new therapeutic approach to treat Alzheimer's disease (AD) is needed, and the use of growth factors is considered to be a candidate. Hepatocyte growth factor (HGF) is a unique multifunctional growth factor, which has the potential effect to exert neurotrophic action and induce angiogenesis. In this study, we examined the effects of overexpression of human HGF plasmid DNA using ultrasound-mediated gene transfer into the brain in an Abeta-infused cognitive dysfunction mouse model. We demonstrated that HGF gene transfer significantly alleviated Abeta-induced cognitive impairment in mice in behavioral tests. These beneficial effects of HGF might be due to (1) significant recovery of the vessel density in the dentate gyrus of the hippocampus, (2) upregulation of BDNF, (3) a significant decrease in oxidative stress and (4) synaptic enhancement. A pharmacological approach including gene therapy to increase the HGF level in combination with anti-Abeta therapy might be a new therapeutic option for the treatment of AD.     

Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome

A role for gamma-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11-q13, resulting mainly from a 4-Mb deletion that includes GABA(A) receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11-q13 deletion (AS Del), two AS patients without a 15q11-q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6+/-4.8 ms) than in non-AS patients (19.5+/-1.2 ms, P<0.001) or normal control subjects (18.4+/-1.8 ms, P<0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA(A) receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.     

A new training method to improve deep microsurgical skills using a mannequin head

Neurosurgeons need fine and special microsurgical techniques, such as the ability to suture deep microvasculature. Intensive training is required to perform microsurgery, especially in deep microvascular anastomosis. There have been many previous reports of training methods for typical microsurgical techniques, including suturing of surgical gloves, Silastic tubes, living animals, and chicken wing arteries. However, there have been no reports of training methods to improve deep microsurgical skills under the various hand positions specific to neurosurgical operation. Here, we report a new training method using a mannequin head, water balloons, and clay to mimic actual deep microsurgery in the brain. This method allows trainees to experience microsurgery under various hand positions to approach the affected areas located at various depths in the brain from various angles.     

Prospective randomized efficacy of ultrasound-guided foam sclerotherapy compared with ultrasound-guided liquid sclerotherapy in the treatment of symptomatic venous malformations

OBJECTIVE: To compare the clinical outcome between ultrasound-guided foam sclerotherapy (UGFS) and ultrasound-guided liquid form sclerotherapy (UGLS) in patients with venous malformations (VM). METHODS: Eighty-nine patients with symptomatic VM were treated with ultrasound-guided sclerotherapy. There were 22 males and 67 females with mean age of 14.5 years. The sclerosing agents used were 1% polidocanol (POL) or 10% ethanolamine oleate (EO). POL was injected predominantly into smaller, superficial lesions, whereas EO was used for large, deeper lesions. Foam sclerosing solution was provided using Tessari's method. Patients were randomized to receive either UGFS or UGLS. Post-sclerotherapy surveillance was done at 6 months after last session using duplex ultrasound. Findings obtained by duplex scanning were divided into four groups: (1) disappeared group: the venous space was occluded and was totally shrunk; (2) partially recanalized group: the venous space was partially recanalized and was partially shrunk; (3) totally recanalized group: the venous space was totally recanalized and returned at the same size; and (4) worsened group: the venous space was totally recanalized and became worse. RESULTS: Forty-nine patients were treated with UGFS and the remaining 40 were treated with UGLS. There were no significant differences in age and men:women ratio. There was no significant difference in the anatomic distribution of VMs between the two groups. The amount of POL was significantly smaller in patients who were treated with UGFS (P = .022). Similarly, there was a significant reduction in the use of EO in patients treated with UGFS (P = .005). The proportion of VM with total disappearance and partial recanalization was significantly higher in patients treated with UGFS (P = .002). No major complications related to sclerotherapy were encountered in both groups. CONCLUSIONS: These findings suggest that UGFS could have greater promise compared with UGLS in the treatment of VMs.     

Evidence of different pharmacokinetics between cyclosporine and tacrolimus in renal transplant recipients: why cyclosporine is monitored by C2 level and tacrolimus by trough level

The clinical efficacy of calcineurin inhibitors administered to renal transplant recipients is considered to be a strong function of the area under the concentration time curve (AUC). Monitoring of blood concentrations for two similar calcineurin inhibitors, cyclosporine (CyA) and tacrolimus (TAC) are different. Namely, CyA blood concentration is usually monitored at two hours after administration (C₂), a surrogate for peak concentration (C_p), and TAC at trough concentration (C_t). We examined the behavior of blood concentration curves simultaneously for both CyA and TAC in renal transplant recipients with similar clinical backgrounds. Furthermore, we analyzed the correlation of C_p and C_t vs AUC implementing an area under the trough level, or area above the trough level as new pharmacokinetic parameters, so that C₂ for CyA and C_t for TAC has validated using controlled clinical data. We observed differences in the pharmacokinetics between,     

Biotransformation of phenolic 1-benzyl-N-methyltetrahydroisoquinolines in plant cell cultures followed by LC/NMR, LC/MS, and LC/CD

(+/-)-1-Benzyl- N-methyltetrahydroisoquinolines 7-10 and 11-14 with one and two hydroxy groups on the aromatic rings, respectively, were fed individually to cultured cells of Corydalis and Macleaya species, respectively. The structures of the metabolites were determined by using combinatorial techniques, including LC/NMR, LC/MS-MS, and LC/CD. The enantiomeric excesses of the metabolites were derived from LC/CD and LC/MS-MS analyses. In cell cultures of Corydalis and Macleaya species, laudanine (7), with a hydroxy group at C-3', can form the berberine bridge at C-2' and C-6' to produce S- and R-enantiomers of 2,3,9,10- and 2,3,10,11-oxygenated protoberberines (20 and 21), respectively, whereas reticuline (11) and protosinomenine (12), incoporating a hydroxy group at C-3', form the berberine bridge at C-2' to furnish the S-enantiomer of 2,3,9,10-oxygenated protoberberines (23 and 21), respectively.     

Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells

This study found that phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling was activated in human T-cell lymphotropic virus type I (HTLV-1)-infected leukemia cells. Rapamycin (1-100 nM, 48h), the inhibitor of mTOR and its analog RAD001 (1-100 nM, 48 h)-induced growth inhibition and G0/G1 cell cycle arrest of these cells in association with de-phosphorylation of p70S6K and 4E-BP-1, although IC50 was not achieved. Paradoxically, rapamycin-stimulated phosphorylation of Akt at Ser473. Blockade of Akt signaling by the PI3K inhibitor LY294002 (1-20 microM, 48 h) also resulted in the growth inhibition and G0/G1 cell cycle arrest of HTLV-1-infected cells, with IC50 ranging from 5 to 20muM, and it caused de-phosphorylation of p70S6K and 4E-BP-1. Of note, when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Moreover, both LY294002 and rapamycin down-regulated the levels of c-Myc and cyclin D1 proteins in these cells, and their combination further decreased levels of these cell cycle-regulating proteins. Taken together, longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with adult T-cell leukemia.     

Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor

We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly, a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.