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PubMed2006

Auditory outcomes in tumor vs. nontumor patients fitted with auditory brainstem implants.

Auditory brainstem implants (ABIs) are currently indicated for patients older than 12 years with neurofibromatosis type 2 (NF2) who had bilateral schwannoma removed. Over the last 10 years, we have extended the indications for ABIs to nontumor children and adult patients with cochlear or cochlear nerve injuries or malfunctions who would not benefit from a cochlear implant. We have provided ABIs for patients with cochlear nerve aplasia and other injuries, and patients in whom any benefit was, or would be, severely compromised as in extensive cochlear ossification. In the present chapter we report our recent findings in adult ABI patients and compare the psychophysical and speech perception outcomes in tumor with those in nontumor patients. We demonstrate that the ABI can stimulate the central auditory system in a way that gives the ability of open set speech understanding, and can thus be indicated in nontumor adult patients who are not candidates for a cochlear implant. From April 1997 to January 2006, a total of 80 patients, 62 adults and 18 children, were fitted with ABIs in the University of Verona ENT Department; age ranged from 14 months to 70 years. Twenty-six patients had NF2 with bilateral vestibular schwannoma removal, and 54 had nontumor diseases of the cochlear nerve or cochlea. The retrosigmoid approach was used in all patients. All patients had a functioning implantation, and no complications were observed during the operation, activation as well as long-term use of the ABI. All patients, except 1 (NF2), reported auditory sensations with activation of various numbers of electrodes (from 5 to 21). Different electrodes elicited different pitch sensations. At 1 year after implantations nontumor adults scored from 12 to 100% in open set speech perception tests (average 59%), and tumor (NF2) patients scored from 5 to 30% (average of 11%). The differences between these results are statistically significantly (p < 0.01). To investigate the cause of the differences in performance between tumor and nontumor ABI recipients, a series of psychophysical tests were done consecutively in 39 adult patients with implants (25 nontumor and 14 tumor patients) from May 1999 to April 2004 and with a follow-up of at least 1 year. The outcome of this study shows that: (1) The ABIs allow most tumor and nontumor patients to experience improved communication as well as awareness of environmental sounds. (2) Nontumor patients had better hearing outcomes than tumor patients when the variation in the auditory benefit with the ABI in relation to the patient's underlying pathological conditions were taken into consideration. (3) A significant number of nontumor patients are able understand speech at a level comparable to that of the most successful cochlear implant users including conversational telephone use. (4) The ABI represents the tool for hearing rehabilitation in patients with profound hearing loss who cannot be fitted with cochlear implants.

Adolescent↗
PubMed2006

Matrix metalloproteinase-9 induces the formation of cartilage canals in the chondroepiphysis of the neonatal rabbit.

BACKGROUND: An investigation of matrix metalloproteinase-9 (MMP-9) and its influence on vascular invasion in the secondary ossification center at the chondroepiphysis of developing long bones was undertaken. The effect of MMP-9 was compared with that of basic fibroblast growth factor (b-FGF), a potent angiogenic factor, and we assessed the chorioallantoic membrane (CAM) culture as a model for angiogenesis in osteochondral tissue. METHODS: Seventy-two femoral and seventy-two humeral heads of thirty-six four-day postnatal rabbits were dissected immediately after each animal was killed. Solutions of MMP-9, b-FGF, and phosphate-buffered saline solution were applied, and the femoral and humeral chondroepiphyseal explants were incubated for ten days in CAM culture. This was used as an in vivo model to investigate the growth of blood vessels into the femoral and humeral heads of the neonatal rabbit. The explants were harvested from the CAM culture and analyzed histologically. A three-day incubation was also performed to look for early signs of vascular ingrowth into the cartilage matrix. RESULTS: One hundred and twenty epiphyses from thirty rabbits were placed onto CAM culture successfully; of these, two were harvested at three days to assess early changes and 118 were harvested at ten days. Forty of the 118 cultures were still viable when harvested after ten days, giving a 33% yield. Both MMP-9 and b-FGF caused an increased vascular invasion into the chondroepiphysis. New blood vessels derived from the chorioallantoic membrane within cartilage canals were more numerous in MMP-9 treated epiphyses, and larger canals were more commonly seen when compared with a control group. CONCLUSIONS: These findings confirmed that b-FGF is angiogenic at the chondroepiphysis. Matrix metalloproteinase-9 appears to be implicated in vascular invasion and induces the formation of new cartilage canals at the chondroepiphysis. The CAM culture model was a useful model for investigating angiogenesis in osteochondral tissue. CLINICAL RELEVANCE: This study adds to the understanding of the complex biochemical interaction that occurs in cartilage when the advancing vasculature begins growing into the chondroepiphysis. A better knowledge of this angiogenic process will enable a better understanding of the pathological failure or disturbance of vasculogenesis, which results in dysplastic growth disorders and osteonecrosis.

Animals↗
PubMed1987

[Two cases of heterotopic bone formation in the kidney and clinico-pathological study of 36 cases reported in Japan].

We report two cases of heterotopic bone formation in the kidney. One patient was a 54-year-old man who consulted his family physician with the complaint of fever-up and nocturia. X-ray examination revealed a calcification in the left kidney and location of the pelvis for outside. Therefore, abdominal CT scan and selective renal angiography were performed. As a malignant renal tumor with hypovascularity could not be neglected, left nephrectomy was performed on August 18, 1980. Grossly, the resected kidney was 230 g in weight and had a 8 X 3 cm mass with a white cut surface and bone-like tendency. Histopathologically, a well-developed bone with erythropoietic bone marrow was found outside of the renal capsule. The other patient was a 52-year-old man with the complaint of painful swelling of left scrotum and lumbago. X-ray examination revealed bilateral renal stones and left ureteral stone. Bilateral nephrolithotomy and left ureterolithotomy were performed, and some stones and a part of bilateral renal pelvis which was bony hard and white in color were resected. Histopathologically, there were well-developed bone formation and infiltration of inflammatory cells in renal pelvic membrane. Among 36 reported cases in Japan, 16 cases were in male and 20 cases in female patients. Our second case was the first cases of bilateral renal heterotopic bone formation complicated with bilateral renal stones in 5 reported cases with renal stones. Including our first case, 5 cases which had heterotopic bone formation in renal capsule have been reported.

Humans↗
PubMed2006

Distribution of SPARC during neovascularisation of degenerative aortic stenosis.

OBJECTIVE: To examine the hypothesis that degenerative aortic stenosis (AS) is associated with the development of blood vessels and the expression of the secreted protein, acidic and rich in cysteine/osteonectin (SPARC), a matricellular protein that is involved in ossification, the modulation of angiogenesis and the production of metalloproteinases. METHODS: 30 surgically excised AS valves and 20 normal aortic valves were studied. RESULTS: Blood vessels were detected in the aortic valves from patients with degenerative AS, whereas normal valves were avascular structures. Blood vessels in AS valves expressed endothelial nitric oxide synthase, CD34 and von Willebrand factor (vWF). Blood vessels were located in three distinct regions: near calcified nodules, under the leaflet border and in rich cellular areas forming cell islands. Blood vessels were predominantly present in early and intermediate grades of calcification. Cell islands were densely populated by CD45-positive cells where endothelial cells (CD34+, vWF+) forming cord-like structures were present. Immunoblotting detected SPARC only in AS valves and immunohistological analysis located SPARC in mature blood vessels. The proportion of blood vessels positive for SPARC was higher in valves with a lower grade of calcification. In cell islands, SPARC was distributed to mature blood vessels and to macrophages, where it co-located with matrix metalloproteinase-9, whereas no expression was detected in endothelial cells forming cord-like structures. CONCLUSION: The localisation of SPARC to mature blood vessels and its predominant expression in AS valves with a lower calcification grade suggest that the spatial and temporal distribution of this matricellular protein is tightly controlled to participate in the neovascularisation of AS valves.

Aged↗
PubMed1995

A protocol for the management of failed alloplastic temporomandibular joint disc implants.

PURPOSE: This is a retrospective evaluation of a protocol for management of failed alloplastic temporomandibular joint (TMJ) disc implants. PATIENTS AND METHODS: The criteria for implant failure were defined as any one or combination of the following symptoms and signs: TMJ pain, jaw hypomobility, occlusal changes, and radiographic evidence of bone pathology related to the implant. The protocol consisted of removal of the implant, aggressive joint debridement, recontouring of the articulating surfaces, and placement of a pedicled temporalis muscle/fascia flap (TF) for joint lining. Arch bars and maxillomandibular guiding elastics were used if extensive condylar recontouring was necessary. No attempt was made to reconstruct the condyle or correct occlusal abnormalities at the time of implant removal. All 27 patients (42 joints) treated by this protocol during the study period were included for evaluation. There were 24 Proplast/Teflon (PTI) (Vitek, Inc, Houston, TX), 11 Silastic (SI) (Dow Corning, Midland, MI), and 7 Christensen Fossa implants (CFI) (TMJ Implants, Golden, CO) implants removed. RESULTS: The mean follow-up period was 38.3 months (range, 3 to 65 months). Pain was well controlled in 24 of 27 patients (88.9%). Preoperative and postoperative mean maximal incisal opening (MIO) was 32.1 mm and 39.8 mm, respectively. Two patients (7.4%) required a second TMJ operation for persistent pain and limitation of opening. To date, 7 patients (25.9%) have required a secondary procedure (unilateral vertical ramus osteotomy, n = 1; Le Fort I osteotomy, n = 6) to correct occlusal prematurity on the operated side or bilateral open bite. The remaining patients have required no additional surgical treatment. CONCLUSIONS: The results of this study indicate that a proposed protocol is an effective means of controlling pain and improving jaw motion in patients with failed alloplastic TMJ disc implants.

Adult↗
PubMed2004

[Fluorine as a factor in premature aging].

The use of fluorine compounds in various areas of medicine, particularly in dentistry, as well as in agriculture and industry became very popular in the second half of the 20th century. Fluorine owed this widespread acceptance to observations that its compounds stimulate ossification processes and reduce the prevalence of caries. Unfortunately, growing expectations overshadowed the truth regarding interactions of fluoride on the molecular level. The fact was often ignored that fluoride is toxic, even though laboratory data stood for a careful approach to the benefits of usage. Excessive exposure to fluoride may lead to acute poisoning, hyperemia, cerebral edema, and degeneration of the liver and kidneys. Acute intoxication through the airways produces coughing, choking, and chills, followed by fever and pulmonary edema. Concentrated solutions of fluorine compounds produce difficult to heal necrotic lesions. In spite of these dramatic symptoms, acute intoxications are relatively rare; the more common finding is chronic intoxication attributable to the universal presence of fluorine compounds in the environment. The first noticeable signs of excessive exposure to fluoride in contaminated water, air, and food products include discolorations of the enamel. Dental fluorosis during tooth growth and loss of dentition in adulthood are two consequences of chronic intoxication with fluorine compounds. Abnormalities in mineralization processes affect by and large the osteoarticular system and are associated with changes in the density and structure of the bone presenting as irregular mineralization of the osteoid. Fluorine compounds also act on the organic part of supporting tissues, including collagen and other proteins, and on cells of the connective tissue. These interactions reduce the content of collagen proteins, modify the structure and regularity of collagen fibers, and induce mineralization of collagen. Interactions with cells produce transient activation of osteoblasts, stimulate fibroblasts to produce collagenase, and trigger toxic reactions in osteocytes and chondrocytes of trabecular bone. Growing deformations of the skeleton reduce mobility and result in permanent crippling of the patient. Fluoride increases the mass of non-collagen proteins such as proteoglycans and glucosaminoglycans, accelerating skin aging even though protein biosynthesis is generally suppressed. The final outcome includes progressive vascular lesions and disorders of energy metabolism in muscles. In conclusions, the use of fluoride, particularly by dentists and pediatricians, must be controlled and adapted to individual needs. It is worth remembering that fluoride: is the cause of disability due to bone deformations and abnormalities in the musculoskeletal system; reduces the incidence of caries but do not protect against tooth loss; exerts an adverse effect of metabolic processes in the skin; accelerates calcification of vessels and thus reduces their elasticity; inhibits bioenergetic reactions, in particular oxidative phosphorylation, reducing physical activity of muscles. These findings suggest that fluorine may be yet another factor in accelerated aging and revive the dispute started more than two and half thousand years ago whether aging is a physiologic or pathologic process. The understanding of factors modifying the process of aging is the basis for preventive measures aimed at extending life and maintaining full psychosocial activity.

Aging↗
PubMed1997

Limb swelling in patients who have fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a rare heritable disorder of connective tissue characterized by progressive heterotopic ossification of soft tissues and by congenital malformation of the great toes. Limb swelling has also been noted, yet little is known about this complication of fibrodysplasia ossificans progressiva. To determine the prevalence of limb swelling in this condition, the authors reviewed detailed medical records on 74 patients (25 males, 49 females; age range, 1-49 years) who had a documented history of fibrodysplasia ossificans progressiva. The study population included more than 90% of all patients known to have fibrodysplasia ossificans progressiva in the United States. Acute swelling of the limbs occurred in association with flareups of the condition in nearly all cases. Acute swelling in the upper limbs was focal and nodular in contrast to acute swelling in the lower limbs, which was more diffuse. Acute swelling in the upper limbs occurred in all 74 patients whereas acute swelling in the lower limbs occurred in 47 of the 74 patients (64%). Two of the 74 patients who had acute swelling in the lower limbs (4%) had a documented episode of deep vein thrombophlebitis. Chronic swelling in the upper limbs occurred in 9 of the 74 patients (12%) and was not seen before the age of 12 years. Chronic swelling in the lower limbs occurred in 36 of the 74 patients (49%) and was not seen before the age of 9 years. The intense angiogenesis and edema seen on histopathologic evaluation of preosseous fibrodysplasia ossificans progressiva lesions may play a role in the pathogenesis of the limb swelling. The data show an age related prevalence of limb swelling in fibrodysplasia ossificans progressiva and suggest a model for understanding the complex pathways leading to limb swelling in this disorder.

Adolescent↗
PubMed2003

Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts.

Vascular endothelial growth factor (VEGF) released by osteoblasts plays an important role in angiogenesis and endochondral ossification during bone formation. In animal studies, we have reported that shock waves (SW) can promote osteogenic differentiation of mesenchymal stem cells through superoxide-mediated signal transduction (Wang, F. S., Wang, C. J., Sheen-Chen, S. M., Kuo, Y. R., Chen, R. F., and Yang, K. D. (2002) J. Biol. Chem. 277, 10931-10937) and vascularization of the bone-tendon junction. Here, we found that SW elevation of VEGF-A expression in human osteoblasts to be mediated by Ras-induced superoxide and ERK-dependent HIF-1alpha activation. SW treatment (0.16 mJ/mm(2), 1 Hz, 500 impulses) rapidly activated Ras protein (15 min) and Rac1 protein (30 min) and increased superoxide production in 30 min and VEGF mRNA expression in 6 h. Early scavenging of superoxide, but not nitric oxide, peroxide hydrogen, or prostaglandin E(2), reduced SW-augmented VEGF-A levels. Inhibition of superoxide production by diphenyliodonium, an NADPH oxidase inhibitor, was found to suppress VEGF-A expression. Transfection of osteoblasts with a dominant negative (S17N) Ras mutant abrogated the SW enhancement of Rac1 activation, superoxide synthesis, and VEGF expression. Further studies demonstrated that SW significantly promoted ERK activation in 1 h and HIF-1alpha phosphorylation and HIF-1alpha binding to VEGF promoter in 3 h. In support of the observation that superoxide mediated the SW-induced ERK activation and HIF-1alpha transactivation, we further demonstrated that scavenging of superoxide by superoxide dismutase and inhibition of ERK activity by PD98059 decreased HIF-1alpha activation and VEGF-A levels. Moreover, culture medium harvested from SW-treated osteoblasts increased vessel number of chick chorioallantoic membrane. Superoxide dismutase pretreatment and anti-VEGF-A antibody neutralization reduced the promoting effect of conditioned medium on angiogenesis. Thus, modulation of redox reaction by SW may have some positive effect on angiogenesis during bone regeneration.

Cell Differentiation↗
PubMed2025

Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.

This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that are keratin-positive. Our study cohort consists of 6 men and 6 women, with a mean age of 32 years. The tumors arose in the extremities (n = 9) and proximal limb girdle (n = 3) and were equally distributed between deep and superficial soft tissues. Patients reported dull painless masses of several months to >10 years duration (mean: 2.9 years). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumor's mean size was 5.7 cm. Histologically, the tumors were composed of uniform, eosinophilic myoid spindled cells growing in sheets and intersecting fascicles, surrounded by mature lamellar and/or woven bone. Also present was an admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins, and 50% (5/10) showed focal staining for S100; however, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n = 10); however, whole transcriptome sequencing (n = 8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in 4 tumors. Dual fluorescence in situ hybridization probes for SRSF7::NFATC3 successfully confirmed this fusion and identified a fifth case, which had not undergone whole transcriptome sequencing but was negative by a targeted RNA fusion panel. Methylation profiling (n = 8) demonstrated a shared epigenetic profile distinct from other entities. Clinical follow-up (n = 11) showed no evidence of recurrence after primary excision with a mean of 41.6 months. In summary, we describe a novel soft tissue tumor designated "ossifying spindled and epithelioid tumor" as a descriptive histologic term that also emphasizes its close radiologic mimic, ossifying fibromyxoid tumor. All cases have behaved in a benign fashion without recurrence following simple excision. Awareness of this entity is important, so that it can be distinguished from other neoplasms that have more aggressive biological potential.

Humans↗