Effect of PTK/ZK on the Angiogenic Switch in Head and Neck Tumors

Transformation of small avascular masses of tumor cells into rapidly progressive cancers is triggered by the angiogenic switch, a process that involves vascular endothelial growth factor (VEGF) signaling. We have shown that VEGF enhances the survival and angiogenic potential of endothelial cells by activating the Bcl-2-CXCL8 signaling axis. The purpose of this study was to evaluate the effect of a small-molecule inhibitor of VEGF receptors (PTK/ZK) on the initial stages of head and neck tumor angiogenesis. In vitro, PTK/ZK blocked head and neck tumor cell (OSCC3 or UM-SCC-17B)-induced Bcl-2 and CXCL8 expression in endothelial cells. Oral administration of PTK/ZK decreased xenograft head and neck tumor microvessel density, and inhibited Bcl-2 and CXCL8 expression in tumor-associated endothelial cells. Analysis of these data demonstrates that PTK/ZK blocks downstream targets of VEGF signaling in endothelial cells, and suggests that PTK/ZK may inhibit the angiogenic switch in head and neck tumors. Abbreviations: HDMEC, human dermal microvascular endothelial cells; VEGF, vascular endothelial growth factor; CXCL8, CXC ligand-8; PTK/ZK, PTK787/ZK222584.

The requirement of zinc and calcium ions for functional MMP activity in demineralized dentin matrices

The progressive degradation of resin-dentin bonds is due, in part, to the slow degradation of collagen fibrils in the hybrid layer by endogenous matrix metalloproteinases (MMPs) of the dentin matrix. In in vitro durability studies, the storage medium composition might be important because the optimum activity of MMPs requires both zinc and calcium. Objective. This study evaluated the effect of different storage media on changes in matrix stiffness, loss of dry weight or solubilization of collagen from demineralized dentin beams incubated in vitro for up to 60 days. Methods. Dentin beams (1 mm x 2 mm x 6 mm) were completely demineralized in 10% phosphoric acid. After baseline measurements of dry mass and elastic modulus (E) (3-point bending, 15% strain) the beams were divided into 5 groups (n = 11/group) and incubated at 37 degrees C in either media containing both zinc and calcium designated as complete medium (CM), calcium-free medium, zinc-free medium, a doubled-zinc medium or water. Beams were retested at 3, 7, 14, 30, and 60 days of incubation. The incubation media was hydrolyzed with HCl for the quantitation of hydroxyproline (HOP) as an index of solubilization of collagen by MMPs. Data were analyzed using repeated measures of ANOVA. Results. Both the storage medium and the storage time showed significant effects on E, mass loss and HOP release (p < 0.05). The incubation in CM resulted in relatively rapid and significant (p < 0.05) decreases in stiffness, and increasing amounts of mass loss. The HOP content of the experimental media also increased with incubation time but was significantly lower (p < 0.05) than in the control CM medium, the recommended storage medium. Conclusions. The storage solutions used to age resin-dentin bonds should be buffered solutions that contain both calcium and zinc. The common use of water as an aging medium may underestimate the hydrolytic activity of endogenous dentin MMPs. (c) 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Evaluation of distances between the mandibular teeth and the alveolar process in Brazilians with normal occlusion

Introduction: The aims of this study were to evaluate the distances between the mandibular permanent teeth and the alveolar process in Brazilians with normal occlusion and to compare them with normal American values. Methods: We used 59 mandibular casts from untreated subjects who had permanent dentition and the 6 keys to normal occlusion. A computer program was used to calculate the distances between the dental reference points and the alveolar process for each tooth. The mean values were then compared to the normal values by applying the Student t test at a significance level of 0.05. Results: The results showed a progressive increase of these distances from the anterior region (incisors) to the posterior region (molars), from 0.00 to 2.49 mm. All measurements had statistically significant differences from the American sample, except for the values for canines and first premolars. Conclusions: Brazilians with normal occlusion have more lingual crown positions for the incisors, second premolars, and molars compared with Americans with normal occlusion. Although these findings were statistically significant, they are unlikely to be clinically significant. (Am J Orthod Dentofacial Orthop 2010; 137: 308.e1-308.e4)

Osteointegration of Autogenous Bone Graft Associated With Osteoblastic Cells Under Treatment With Caffeine

Purpose: The present study investigated osteointegration of autogenous bone (AB) from calvaria graft associated with osteoblastic cells (OC) in bone defects in rats subjected to daily administration of caffeine. Materials and Methods: Male rats received daily intraperitoneal injection of 1.5% caffeine (0.2 mL/100 g body weight) or saline solution for 30 days. Then they were anesthetized, submitted to the extraction of the upper right incisor, and implanted with AB only and AB + OC. The animals were killed on 7th, 21st, and 42nd days after surgery, and their maxilla were processed for obtaining semiserial sections (5 mu m) stained with hematoxylin and eosin. Through image analysis system, the bone volume and the quality of graft in adjacent areas were estimated. Results: The results showed that in caffeine treatment, the AB + OC graft showed no foreign body and acute inflammatory reactions inside the defect when compared to AB. The histometric results revealed that the association AB + OC produced significant increase (10%-15%) in bone volume in later experimental period (42 days) when compared with saline solution group (P <= 0.01). Conclusions: It was concluded that the association of AB from calvaria + OC demonstrated progressive osteointegration and accelerated the repair of bone defects in animals treated with daily caffeine. (Implant Dent 2011;20:369-373)

Altered expression of neuronal nitric oxide synthase in weaver mutant mice

The weaver mouse represents the only genetic animal model of gradual nigrostriatal dopaminergic neurodegeneration which is proposed as a pathophysiological phenotype of Parkinson`s disease. The aim of the present study was to analyze the nitric oxide and dopaminergic systems in selected brain regions of homozygous weaver mice at different postnatal ages corresponding to specific stages of the dopamine loss. Structural deficits were evaluated by quantification of tyrosine hydroxylase and neuronal nitric oxide synthase-immunostaining in the cortex, striatum, accumbens nuclei, subthalamic nuclei, ventral tegmental area, and substantia nigra compacta of 10-day, 1- and 2-month-old wildtype and weaver mutant mice. The results confirmed the progressive loss of dopamine during the postnatal development in the adult weaver mainly affecting the substantia nigra pars compacta, striatum, and subthalamic nucleus and slightly affecting the accumbens nuclei and ventral tegmental area. A general decrease in neuronal nitric oxide synthase-immunostaining with age was revealed in both the weaver and wild-type mice, with the decrease being most pronounced in the weaver. In contrast, there was an increase in the substantia nigra pars compacta nitric oxide synthase-immunostaining and a decrease mainly in the subthalamic and accumbens nuclei of the 2-month-old weaver mutant. The decrease in the expression of nNOS may bear functional significance related to the process of aging. DA neurons from the substantia nigra directly modulate the activity of subthalamic nucleus neurons, and their loss may contribute to the abnormal activity of subthalamic nucleus neurons. Although the functional significance of these changes is not clear, it may represent plastic compensating adjustments resulting from the loss of dopamine innervation, highlighting a possible role of nitric oxide in this process. (C) 2010 Elsevier B.V. All rights reserved.

Persistent Impairment of Testicular Histology and Sperm Motility in Adult Rats Treated with Cisplatin at Peri-Puberty

Cisplatin is one of the most widely used and effective chemotherapeutic agents for the treatment of several human malignancies. This study evaluated the effects of peri-pubertal cisplatin administration on several reproductive end-points and the reversibility of these effects in adulthood. Peri-pubertal Wistar male rats (45 days old) were divided into two groups: control (saline 0.9%) and cisplatin (1 mg/kg/day, 5 days/week, for 3 weeks, i.p.). The study was conducted in two steps and evaluations were performed at ages of 66 (post-pubertal age) and 140 (adult age) days on: (i) organ weights, serum gonadotropins and testosterone levels, sperm counts, motility and morphology, testicular histomorphometry, spermatogenesis kinetics, Sertoli cell number and in situ detection of apoptotic germ cells and (ii) sexual behaviour, fertility and intratesticular testosterone. At the end of cisplatin therapy, rats showed reductions in sperm production and reserves, sperm with progressive movement, tubular diameter, intratesticular testosterone and fertility potential, but increased numbers of TUNEL-positive seminiferous tubules, immotile sperm and pre-implantation losses compared with control. Moreover, cisplatin-treated post-pubertal rats displayed impaired testicular histopathology and sexual behaviour. Serum gonadotropins and testosterone levels, sperm morphology, spermatogenesis kinetics and Sertoli cell number were comparable between experimental groups at both ages. Alterations found in post-puberty were recovered at adulthood, except for sperm motility and damage to testicular histology. The persistence of these cisplatin effects, despite the unaltered fertility after natural mating in rats, may have implications for reproductive function of young boys undergoing cancer therapy, given the lower reproductive efficiency in human beings compared with rats.

NITRIC OXIDE SYNTHASE INHIBITION ATTENUATES L-DOPA-INDUCED DYSKINESIAS IN A RODENT MODEL OF PARKINSON`S DISEASE

Chronic L-DOPA pharmacotherapy in Parkinson`s disease is often, accompanied by the development of abnormal and excessive movements known as L-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with L-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration Of L-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic L-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10-30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1-30 mg/kg) and NG-nitro-L-arginine (50 mg/kg), given 30 min before L-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat L-DOPA.-Induced dyskinesia. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.