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BACKGROUND: Osseointegration may be described as a direct contact between living bone and an alloplastic implant. It is thought that a period of undisturbed healing is required to ensure osseointegration. The length of the healing period is dependent on a number of factors, such as implant material, surface configuration, site preparation technique, bone quality, healing capacity of the osteotomy, and implant design. Elimination of the healing period offers distinct advantages in terms of cost of therapy and convenience to patients. Recently, a new one-piece implant design was proposed that provides improved stability of the implant to allow immediate support of an interim prosthesis. PURPOSE: This article presents the initial clinical experiences when the Altiva Natural Tooth Replacement one-piece implant was used in a human clinical trial. MATERIALS AND METHODS: This was a prospective multicenter study of the placement and immediate loading of the one-piece implant. A total of 142 implants were placed in the jaws of 93 patients. Implants were placed consecutively and were followed at specified intervals in three private clinical practices. Clinical performance was recorded relative to implant survival and prosthesis support. RESULTS: The implant survival rate was 93.7%, with similar responses in the maxilla (95.0%) and the mandible (92.7%). When implant failure occurred, it was observed as mobility without infection within 3 to 5 weeks of implant insertion. CONCLUSIONS: On the basis of this trial, there is promising evidence that this implant design can succeed at rates similar to other designs that require conventional healing times.

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OBJECTIVE: To study changes in viscoelasticity of a ligament due to an incomplete or a subfailure injury. DESIGN: An in vitro study of anterior cruciate ligament preparations. BACKGROUND: The viscoelastic properties are an inherent part of the physical characteristics of a ligament. An injury to a ligament alters both its elastic and viscous properties. Although the effects of several parameters on the mechanical properties of a ligament have been studied, there is no information in the literature concerning the effect of an incomplete or subfailure injury on its viscoelastic behavior. METHODS: Ten pairs of rabbit femur-anterior cruciate ligament-tibia specimens were used. A standardized relaxation (Relax) test was adopted to quantify the viscoelastic behavior, before and after a subfailure injury. One member of the pair was subjected to three sequential tests: Relax 1; Relax 2; and stretch to failure. The other member of the pair was subjected to other three tests: Relax 3; 80% subfailure injury, i.e. stretch of 80% of failure deformation; and Relax 4. RESULTS: We found that the relaxation test by itself (Relax 1 vs Relax 2), did not affect the viscoelasticity of the ligament. On the other hand, the 80% subfailure injury (Relax 3 vs Relax 4) affected the ligament viscoelastic behavior. The force was decreased by about 50% at time zero (10.46 vs 4.79 N, p = 0.014), and at 180 s (8.14 vs 4.11 N, p = 0.018). Fitting a three-element linear viscoelastic solid model to our data, we found the serial spring stiffness to decrease by about 50% (p = 0.01), the parallel spring remained unchanged, and there was a tendency for the dashpot coefficient to decrease (by 57%, p = 0.09). CONCLUSIONS: The 80% subfailure injury decreased the initial stiffness of the ligament, and tended to decrease its viscoelastic property. RELEVANCE: Subfailure or incomplete injuries of ligaments are more common than the complete injuries. The present study describes the effects, on both the elastic and viscous properties, of a ligament subjected to a subfailure injury.

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Despite the potential of type 1 interferons (IFNs) for the treatment of cancer, clinical experience with IFN protein therapy of solid tumors has been disappointing. IFN-beta has potent antiproliferative activity against most human tumor cells in vitro in addition to its known immunomodulatory activities. The antiproliferative effect, however, relies on IFN-beta concentrations that cannot be achieved by parenteral protein administration because of rapid protein clearance and systemic toxicities. We demonstrate here that ex vivo IFN-beta gene transduction by a replication-defective adenovirus in as few as 1% of implanted cells blocked tumor formation. Direct in vivo IFN-beta gene delivery into established tumors generated high local concentrations of IFN-beta, inhibited tumor growth, and in many cases caused complete tumor regression. Because the mice were immune-deficient, it is likely that the anti-tumor effect was primarily through direct inhibition of tumor cell proliferation and survival. Based on these studies, we argue that local IFN-beta gene therapy with replication-defective adenoviral vectors might be an effective treatment for some solid tumors.

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Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed predominantly by prostate cancer cells. We have characterized four monoclonal antibodies that bind to the extracellular domain of PSMA (Liu et al., Cancer Res., 57: 3629-3634, 1997). Here we report that viable LNCaP cells internalize these antibodies. Laser scanning confocal microscopy reveals that the internalized antibodies accumulate in endosomes, and immunoelectron microscopy reveals that endocytosis of the PSMA-antibody complex occurs via clathrin-coated pits. In addition, a quantitative cell surface biotinylation assay demonstrates that PSMA is constitutively endocytosed in LNCaP cells and that anti-PSMA antibodies increase the rate of internalization of PSMA. These studies suggest that PSMA might function as a receptor mediating the internalization of a putative ligand. The availability of prostate-specific internalizing antibodies should aid the development of novel therapeutic methods to target the delivery of toxins, drugs, or short-range isotopes specifically to the interior of prostate cancer cells.

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STATEMENT OF PROBLEM: The success rates of osseointegrated implants used to restore patients who were irradiated for head and neck tumors are influenced by radiation-induced changes in the hard and soft tissues. PURPOSE: This article examined, by review of the literature, current perspectives on the restoration of irradiated patients using osseointegrated implants. RESULTS: In published reports that investigated both intraoral and extraoral applications, irradiation decreased implant success rates and the amount of reduction was dependent on the location within the craniofacial skeleton. The limited number of implants and patients in these studies precludes definitive conclusions regarding the efficacy of placing implants into irradiated tissues. The implants placed into the irradiated anterior mandible have demonstrated an acceptable implant success rate of 94% to 100% with a minimal risk of osteoradionecrosis. The efficacy of implants in the posterior mandible has not been examined. Implant success rates ranged from 69% to 95% in the irradiated maxilla for intraoral applications. Extraoral applications demonstrated excellent implant success rates in the temporal bone (91% to 100%). The rates in the anterior nasal floor have varied from 50% to 100%. The implant success rates in the frontal bone decreased as the length of the studies increased (96% to 33%). The long-term efficacy of implants in the irradiated frontal bone is poor.

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PURPOSE: A clinical study of 23 craniofacial implants placed in 8 irradiated and nonirradiated orbital detects was conducted over a 7-year period. MATERIAL AND METHODS: Implant-retained orbital prostheses were fabricated, implant success rate was determined, and the soft tissue responses were recorded at 6-month intervals. As a result of patient death, no data were gathered on three implants. A five-point scale was used to record the health of the peri-implant soft tissues and the patients were followed from 9 to 72 months. The unit of measure was a visit/site that was assigned for each instance an implant site was evaluated. Evaluations were conducted at 6-month intervals, and for the study period, there were 80 visit/sites. RESULTS: The study revealed that 42.5% (34/80) of the visit/sites demonstrated an absence of inflammation; 23.7% (19/80) of visit/sites demonstrated slight redness; 13.8% (11/80) demonstrated peri-implant red and moist tissues; 6.2% (5/80) demonstrated granulation tissue associated with the implants; and 13.8% (11/80) infection of the peri-implant soft tissues was noted. Implant success rate was 35% (7/20); implant success rate in the nonradiated patients was 37.5% (3/8) and the success rate for radiated patients was 33.3% (4/12). Implants placed in the orbital region demonstrated a high failure rate. Most implant failures occurred late as opposed to early in the study period. CONCLUSION: Orbital implants should be placed in patients who understand that long-term success rates may be low and require meticulous hygiene maintenance.

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BACKGROUND: Expression of Major Histocompatibility Complex (MHC) class I and II antigens are critical for the cellular immune response. Loss of MHC expression represents one mechanism by which cancer cells escape immune recognition. PURPOSE: To define MHC class I and II expression by prostate cancer (PCa) in vivo and in vitro and the ability to modulate MHC expression in vitro with IFN-alpha and -gamma. METHODS: Frozen tissue sections of 25 benign prostatic hyperplasia (BPH) and 18 PCa specimens were studied by immunohistochemistry. PCa cell lines LNCaP, PC-3, and DU-145 were studied by FACS, ELISA, and cytospin. Class I was detected by monoclonal antibody (mAb) W6/32, and class II by mAb 13.17. The effects of IFN-alpha and -gamma were assessed by testing the three cell lines in the presence or absence of varying concentrations of the cytokine for varying incubation times. RESULTS: Class I was strongly expressed by 24/25 BPH specimens; 4/18 (22%) PCa were homogeneously class I-positive, while 5/18 (28%) were heterogeneously positive and 9/18 (50%) were class I-negative. PC-3 and DU-145 expressed normal levels of class I, while LNCaP expressed only low levels. All line except LNCaP demonstrated significant up-regulation of class I with either IFN-alpha or -gamma. Class II expression was not seen in BPH epithelium nor in 17/18 PCa. Class II could be only weakly induced in the three PCa lines. CONCLUSIONS: These findings confirm prior studies demonstrating that class I expression is commonly lost or diminished in PCa. In addition, class II up-regulation by IFN-gamma appears very limited in relation to other normal or neoplastic epithelium. IMPLICATIONS: The present findings, taken together with previous studies, are most consistent with the expression of neoantigens by PCa, which are recognized and appropriately eliminated by the cellular immune system. This selective pressure favors outgrowth of cells which down-regulate or lose class I and/or class II expression. Understanding PCa immunobiology will help in the development of effective immunotherapy for this disease.

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Prostate-specific membrane antigen (PSMA), initially defined by monoclonal antibody (mAb) 7E11, is a now well-characterized type 2 integral membrane glycoprotein expressed in a highly restricted manner by prostate epithelial cells. 7E11 has been shown to bind an intracellular epitope of PSMA that, in viable cells, is not available for binding. Herein, we report the initial characterization of the first four reported IgG mAbs that bind the external domain of PSMA. Competitive binding studies indicate these antibodies define two distinct, noncompeting epitopes on the extracellular domain of PSMA. In contrast to 7E11, these mAbs bind to viable LNCaP cells in vitro. In addition, they show strong immunohistochemical reactivity to tissue sections of prostate epithelia, including prostate cancer. These mAbs were also strongly reactive with vascular endothelium within a wide variety of carcinomas (including lung, colon, breast, and others) but not with normal vascular endothelium. These antibodies should prove useful for in vivo targeting to prostate cancer, as well as to the vascular compartment of a wide variety of carcinomas.

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A clinical study of 23 craniofacial implants placed in 11 nasal defects was conducted over a 7-year period. Implant-retained nasal prostheses were fabricated, implant success rate was determined, and the soft tissue responses were recorded at 6-month intervals. No data were gathered on two implants because of patient death. The implant success rate was 71.4% (15/21) but varied significantly by anatomic site. The implant success rate in the glabella was 0% (0/4), whereas the success rate in the anterior nasal floor was 88.1% (15/17). All implant failures occurred within the first year of loading. A five-point scale was used to record the health of the peri-implant soft tissues, and the patients were followed up from 6 to 74 months. The unit of measure was a visit/site, and a unit was assigned for each instance an implant site was evaluated. Evaluations were conducted at 6-month intervals for a total of 76 visit/sites for the study period. The results revealed that 85.5% (65/76) of the visit/sites demonstrated an absence of inflammation; 10.5% (8/76) of the visit/sites demonstrated slight redness; 1.3% (1/76) demonstrated peri-implant red and moist tissues; 2.6% (2/76) demonstrated granulation tissue associated with the implants; and 0% (0/76) demonstrated infection of the peri-implant soft tissues. Severe soft tissue reactions around implants placed in the anterior nasal floor are rare.

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This study presents the results of 10 consecutive patients treated with unilateral bone augmentation of the maxillary sinus floor using particulated mandible harvested from the symphysis. Endosseous titanium implants (Brånemark) were placed 6 months after the transplant procedure. Thirty self-tapping implants were placed with a mean follow-up period of 26 months (range 12 to 46 months). Bone biopsy specimens were obtained from the donor site and the residual alveolar process at the time of grafting. A second biopsy specimen was obtained from the grafted site after 6 months of healing (at time of implant placement), and a third biopsy specimen was obtained after 12 months of healing (at time of abutment placement). Histomorphometry was performed on microradiographs using a computerized image analysis system. The bone volume fraction at the donor site before particulation was 58% +/- 19%, and the volume fraction at the residual alveolar process was 45% +/- 15%. The mean volume fraction of bone in the grafted area increased from 40% +/- 12% after 6 months of healing to 48% +/- 10% after 12 months. Histology of the retrieved bone biopsy specimens revealed normal healing and bone maturation in all samples.

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We have previously shown that the tat protein of HIV-1 can be used as a carrier to promote the intracellular delivery of heterologous proteins. Here we have tested if the tat-delivery technology can be used to direct MHC class I presentation of native protein, using ovalbumin (OVA) as a model system. We show that a tat-ovalbumin conjugate (tatOVA) can be delivered into cells and that subsequent processing and presentation occurs, resulting in effective and specific killing of these target cells by an OVA specific cytotoxic T-lymphocyte (CTL) line. Comparison with the E.G7 line that expresses the OVA gene indicates that tat-mediated delivery is as efficient as endogenous expression in this system. Tat-mediated antigenic protein delivery may be useful both as a research technique and, potentially, as a therapeutic or prophylactic vaccine.

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A clinical study of 40 craniofacial implants placed in 13 auricular defects was conducted over a 6-year period. Implant-retained prostheses were fabricated, the implant success rate was determined, and the soft tissue responses were recorded at regular intervals. All of the implants became osseointegrated and none demonstrated failure during the study period. A five-point scale was used to record the health of the peri-implant soft tissues and the patients were followed up for up to 69 months. The results were as follows: 55.1% of the visit/sites demonstrated an absence of inflammation; 32.3% of the visit/sites demonstrated slight redness; 4.7% demonstrated red and moist peri-implant tissues; 5.5% demonstrated granulation tissue associated with the implants; and in 2.4% of the implants, infection of the peri-implant soft tissues was noted. Good patient hygiene compliance combined with thin and immobile peri-implant soft tissues resulted in minimal soft tissue complications.

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From 1987 to 1990, 28 patients were treated with titanium implants (Brånemark flange fixtures) in the craniofacial area for the support of craniofacial prosthesis or anchorage of bone-conduction hearing aids in the Orofacial Implant Center at the University of California, Los Angeles (UCLA). A total of 88 implants were placed, of which 22 were placed in previously irradiated areas. Twenty-three of the implants were placed in the orbital area, 37 in the mastoid area, 20 in the nasal area, and eight in various other craniofacial regions. Seven implants were lost in four different patients. The proper location and positioning of implants in specific areas of the craniofacial regions, as well as soft-tissue complications and management, are discussed.

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This study used histomorphometric analysis to quantitate the bone composition of four different sinus grafting materials biopsied at the time of implant installation. The study consisted of five patients in whom eight bone biopsies were obtained from seven grafted sites. The grafting materials consisted of hydroxylapatite (HA) granules mixed with cortical chin bone, HA mixed with demineralized bone powder, HA alone, and cortical chin bone alone. Histomorphometry was performed using backscattered scanning electron microscopy images and a computerized image analysis system. The biopsy cores yielded 46 sections from which a total of 255 fields, measuring 2.0 mm x 2.0 mm each, were imaged and analyzed. The biopsy cores contained 44.4% bone after grafting with HA granules and chin bone, 59.4% bone after grafting with chin bone alone, 20.3% bone after grafting with HA granules alone, and 4.6% bone after grafting with HA granules and demineralized bone powder. The small number of biopsies did not permit analysis of statistical significance. However, this study demonstrated the feasibility of correlating mineralized tissue composition of different sinus grafting materials with clinical outcome after dental implant installation.

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Vascular cell adhesion molecule-1 (VCAM1) is a member of the immunoglobulin (Ig) superfamily which interacts with the integrin very late antigen-4 (VLA4). The VCAM1/VLA4 interaction mediates both adhesion and signal transduction and is thought to play an important role in inflammatory and immune responses in vivo. VCAM1 cDNAs cloned from mouse, rat, rabbit, and human libraries contain six, seven, or eight extracellular Ig-like domains generated by alternate splicing, but to date shorter forms have not been found. We have cloned a novel cDNA encoding only the three N-terminal domains of murine VCAM1 followed by a unique C-terminal tail generated by alternate splicing of a previously undescribed exon. This truncated form of murine VCAM1 (3D-VCAM1) is expressed in COS cells as a functional adhesion molecule which is lost from the cell surface following treatment with phosphatidylinositol-specific phospholipase C. 3D-VCAM1 is found only in endotoxin-treated but not control murine and rat tissues. Thus in rodents alternate splicing of the VCAM1 gene generates a unique truncated inflammation-specific phosphatidylinositol-linked form of VCAM1.

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This paper reviews the outcome of 2,194 Brånemark implants placed in 540 patients by one of the authors over a 6-year period. The overall failure rate of 5.92% is consistent with other studies; however, when patients were subdivided into smokers and nonsmokers, it was found that a significantly greater percentage of failures occurred in smokers (11.28%) than in nonsmokers (4.76%) (P < .001). These differences were significant for all areas except the posterior mandible. While failure rates decreased with increasing implant length, failure rates for each implant length were consistently higher in smokers than in nonsmokers. The possible mechanisms of failure in smokers are discussed, and a protocol for cessation of smoking around the time of surgery is proposed.

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Vascular cell adhesion molecule-1 (VCAM1) is a member of the immunoglobulin (Ig) superfamily which interacts with the integrin very late antigen-4 (VLA4). The VCAM1/VLA4 interaction mediates both adhesion and signal transduction and is thought to play an important role in inflammatory and immune responses in vivo. The major form of human VCAM1 contains seven extracellular Ig-like domains, with domain 1 designated as the most N-terminal. We have examined the relationship between human VCAM1 structure and function using a combination of domain truncation mutants and proteolytic fragmentation of recombinant soluble VCAM1. We have characterized two regions of VCAM1, localized to domains 4 and 5, which are highly sensitive to proteolytic cleavage, localized the epitope of the blocking monoclonal antibody 4B9 to domain 1, and found that domains 1-3 are sufficient for both its adhesive function and its ability to initiate T cell activation.

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Vascular cell adhesion molecule-1 (VCAM1) is a member of the immunoglobulin (Ig) superfamily which interacts with the integrin very late antigen 4 (VLA4). We have cloned the cDNAs for both murine and rat VCAM1 from endotoxin-treated lung libraries. Both sequences encode proteins with seven extracellular Ig-like domains, which show 75.9% and 76.9% identity, respectively, with human VCAM1. Both murine and human cell lines show VLA4-dependent binding to COS cells transiently expressing murine and rat VCAM1. Two mAbs, M-K/1 and M-K/2, which recognize an antigen on murine bone marrow stromal cell lines, bind to murine VCAM1 expressed in COS cells and block VCAM1-dependent adhesion, confirming that these mAbs recognize murine VCAM1.

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