Antineoplastic effects of chemotherapeutic agents are potentiated by NM-3, an inhibitor of angiogenesis

Antiangiogenic therapy, although effective in shrinking tumors, has not yet been established as a standalone treatment for cancer. This therapeutic limitation can be overcome by combining angiogenesis inhibitors with chemotherapeutic agents. NM-3, a small molecule isocoumarin, is a recently discovered angiogenesis inhibitor. Here we demonstrate that NM-3 inhibits the proliferation of human umbilical vein endothelial cells in vitro, at concentrations 10-fold less than those required to inhibit normal fibroblasts or tumor cells (HT29, MKN28, and MCF-7). NM-3 alone inhibits endothelial sprouting and tube formation in vitro. The results also show that synergistic antiproliferative activity is observed when human umbilical vein endothelial cells are treated with NM-3 in combination with 5-fluorouracil. The effects of treatment with NM-3 and various chemotherapeutic agents were also evaluated in tumor xenografts. The results demonstrate that combined treatment with NM-3 and chemotherapeutic agents significantly reduced mean tumor volume compared with either treatment alone, with no effects on body weight changes. Taken together, these findings demonstrate that NM-3 is a well-tolerated angiogenesis inhibitor that significantly increases the efficacy of existing antineoplastic agents.     

White matter changes mimicking a leukodystrophy in a patient with Mucopolysaccharidosis: characterization by MRI

Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.     

Intensity-modulated radiation therapy for the treatment of pediatric cancer patients

Intensity-modulated radiation therapy (IMRT) is a novel form of radiotherapy, which has the potential to reduce the amount of radiation unintentionally delivered to normal tissues while maintaining a high radiation dose to the tumor in comparison with standard radiation techniques. In adults, this technology has been implemented in a number of tumor sites, but in children it has been little used. This article will review the current studies in which IMRT has been used in children. It will also discuss possible future applications for IMRT, and anticipated problems with its use.     

Fibrous dysplasia of the temporal bone

Fibrous dysplasia of the temporal bone is a rare disease which may lead to progressive stenosis of the external auditory canal with conductive hearing loss. Sensorineural hearing loss has usually been attributed to involvement of the otic capsule or inner auditory canal. The case of fibrous dysplasia of the temporal bone in 11 years old girl was described. The conductive hearing loss with sensorineural component improved after surgical treatment.     

Alzheimer's disease related peptides affected cholinergic receptor mediated poly(ADP-ribose) polymerase activity in the hippocampus

Our previous studies indicated that Alzheimer's disease (AD) related amyloid beta peptide (Abeta) significantly altered muscarinic cholinergic receptor (mChR) signaling on the level of G protein regulated phospholipase C (PLC) leading to the lower formation of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Recent studies indicated that poly (ADP-ribose) polymerase-1 (PARP-1) is a new nuclear target in signal transduction pathway in the brain. In this study the effect of Abeta 25-35 (25 microM) and non-Abeta component of Alzheimer's disease amyloid (NAC, 10 microM) on mChR-dependent signaling to PARP-1 was determined. PARP-1 activity was estimated radiochemically using egzogenous substrate adenine[14C]NAD. The results showed that the non hydrolysable agonist of mChR, carbachol (1 mM) together with GTP(g)S (100 microM) stimulated PARP-1 activity in the hippocampus by about 100%. TMB-8, inhibitor of IP3 receptor decreased PARP-1 activation evoked by carbachol/GTP(g)S. Stimulation of mChR did not lead to free radicals generation but activate PARP-1 through IP3/Ca2+ regulated processes. This cholinergic receptor dependent PARP-1 activation was abolished by Abeta and NAC peptide. These toxic peptides themselves significantly stimulated PARP-1 activity by free radicals mediated DNA damage. These data indicated that Abeta and NAC peptide affected mChR-dependent signal transduction to PARP-1 probably through free radicals evoked inhibition of IP3 formation by phospholipase C.     

Atrial fibrillation as a relevant risk factor for stroke

Atrial fibrillation, one of the most frequent heart rhythm disturbances and the most common source of embolic material in cerebral circulation, is associated with a fivefold increased risk of ischemic stroke. Except thromboembolic complications, atrial fibrillation affects hemodynamic activity of the heart, reduces cardiac output and might decrease cerebral blood flow. It is possible that atrial fibrillation disturbs autoregulation mechanisms of cerebral circulation in patients suffering from an acute stroke. This could be the reason of higher early mortality and more severe clinical outcome versus strokes in patients with the sinus rhythm. An ongoing increase of population with atrial fibrillation is observed. Such patients often need intensive antithrombotic prevention with oral anticoagulants. Worldwide prescribing effective anticoagulant therapy is insufficient in relation to the needs. The leading reason underlying the under-utilization of oral anticoagulation in patients with atrial fibrillation is the lack of knowledge about importance of this kind of stroke prevention and fear of bleeding among doctors, particularly among general practitioners.     

Cortical mapping by functional magnetic resonance imaging in patients with brain tumors

The aim of our study was to establish the effectiveness of the functional MRI (fMRI) technique in comparison with intraoperative cortical stimulation (ICS) in planning cortex-saving neurosurgical interventions. The combination of sensory and motor stimulation during fMRI experiments was used to improve the exactness of central sulcus localization. The study subjects were 30 volunteers and 33 patients with brain tumors in the rolandic area. Detailed topographical relations of activated areas in fMRI and intraoperative techniques were compared. The agreement in the location defined by the two methods for motor centers was found to be 84%; for sensory centers it was 83%. When both kinds of activation are taken into account this agreement increases to 98%. A significant relation was found between fMRI and ICS for the agreement of the distance both for motor and sensory centers (p=0.0021–0.0024). Also a strong dependence was found between the agreement of the location and the agreement of the distance for both kinds of stimulation. The spatial correlation between fMRI and ICS methods for the sensorimotor cortex is very high. fMRI combining functional and structural information is very helpful for preoperative neurosurgical planning. The sensitivity of the fMRI technique in brain mapping increases when using both motor and sensory paradigms in the same patient.     

Effect of adrenomedullin on c-Met receptor expression after reserpine-induced gastric damage in the rat

Here, we show an increase in c-Met receptor expression during reserpine-induced gastric damage in the rat, as assessed by immunohistochemistry. Pretreatment of animals with adrenomedullin prevented this increase in c-Met expression. c-Met immunoreactivity was localized in gastric glands. c-Met immunoreactivity was associated with increased phosphorylation of c-Met receptor and extracellular signal-regulated kinase (ERK(1/2)). Our results suggest that both adrenomedullin and c-Met act as parallel defence mechanisms during pharmacologically induced gastric mucosa injury.