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Biomedical subjects

J J Jacobs

Publications and source records attributed to J J Jacobs.

At least 91 records · Page 5Linked to original sources
PubMed1995

The susceptibility of smooth implant surfaces to periimplant fibrosis and migration of polyethylene wear debris.

The purpose of this investigation was to establish whether the tissue response and migration of polyethylene debris differed at noncemented smooth and porous implant surfaces. This was accomplished through 3 separate but closely related studies: (1) a canine cylindrical implant model with smooth and porous surfaces exposed to polyethylene debris; (2) a canine total hip arthroplasty model analyzing the interface between bone and femoral implants with various porous-coating configurations; and (3) a histologic analysis of autopsy-retrieved, human, noncemented hip prostheses with noncircumferential porous coating. The cylindrical implant model involved the placement of split cylinders, 1/2 porous and 1/2 smooth, into the distal femur and proximal tibia of 4 dogs. Four control implants and 10 test implants (chronically exposed to simulated polyethylene debris with a mean size of 4.7 microns) were examined histologically as long as 30 weeks after surgery. The canine hip study involved the study of 54 noncemented hip prostheses at periods of 1, 6, and 24 months. The prostheses possessed 4 different porous surface configurations: 1 with circumferential porous coating, 2 with noncircumferential coating, and 1 without porous coating. The human retrieval analysis involved the study of 7 cadaveric femora (age, 6 months-5 years) implanted with a straight titanium-alloy prosthesis possessing proximal pads of titanium fiber metal on the anterior, posterior, and medial aspects. With all implants in all 3 studies, there was the common finding of bone ingrowth at the porous implant surface and a fibrous interface or periprosthetic cavity around the portion of the implant that was smooth surfaced. The periprosthetic cavity typically was encapsulated by a thin continuous shell of trabecular bone. In addition, polyethylene debris was found to have preferentially migrated along the smooth implant surfaces. In the longer-term canine and human hip retrievals, polyethylene particles in the micron size range were present within histiocytes, whereas larger particles as much as 100 microns were found within foreign-body giant cells. Of importance for the implants from all 3 studies, with the exception of some pronounced cavities on the lateral aspect of the human hip prostheses, the periimplant cavities around the smooth surfaces were not detectable radiographically. This study clearly established a fundamental principle of relative barriers to particulate debris migration. Smooth implant surfaces are more susceptible than porous surfaces to the development of a fibrous tissue filled periimplant cavity and the subsequent migration of polyethylene wear debris.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Reduction of DNA synthesis, pigment synthesis, pigmentation gene mRNA and resistance to UVB in human melanoma cells treated with analogues of a histamine (H2) agonist.

Two groups of S-[2-(N,N-dialkylamino)ethyl]isothiourea derivates which depigmented melanoma cells either with inhibition of tyrosinase (group 1, R = methyl, isopropyl) or without inhibition of tyrosinase (group 2, R = benzyl, phenyl) were studied. Treatment of human melanoma cells with non-lethal doses of group 1 drugs led to a reduction in the levels of mRNA for the pigmentation genes tyrosinase, tyrosinase-related protein-1 and Pmel 17. The group 1 drug S-[2-N,N-diisopropylamino)ethyl[isothiourea] (DINOR) (R = isopropyl) produced only moderate inhibition of DNA, RNA and protein synthesis in three cell lines during the first 24 hr of treatment, and there was no correlation between the extent of inhibition and long-term toxicity. A group 2 drug (R = benzyl) rapidly inhibited DNA synthesis in an amelanotic melanoma cell line (MM96E) sensitive to killing by the drug; association of the latter with inhibition of RNA or protein synthesis was less clear. MM96E cells were also sensitive to killing by reactive oxygen species. In pigmented melanoma cells (MM418), incorporation of [125I]thiouracil, a false precursor of melanin, increased during the first 24 hr of treatment with DINOR whereas a group 2 drug (R = phenyl) inhibited incorporation of [125I]thiouracil. Cells depigmented by treatment with drugs from either group suffered the same amount of DNA damage as pigmented cells after UVB irradiation, as judged by inhibition of DNA synthesis, but did not recover as well as pigmented cells, whether or not drug was present during recovery. The results suggested that (1) group 1 agents down-regulated message for several pigmentation genes, possibly at the transcriptional level; (2) the toxicity of group 2 drugs was related to reactive oxygen species; and (3) melanin protected cells from UVB by enhancing cellular recovery.

Blotting, Northern↗
PubMed1994

Dimaprit analogues inhibit tyrosinase via a disulphide breakdown product independently of the histamine H2 receptor.

Histamine displayed specific and saturable binding to membrane fractions of the human melanoma cell line MM96E (Kd = 72.4 nM and Bmax = 487 fmol/mg protein). There was weak competition with isothioureas that inhibit tyrosinase in intact cells: dimaprit (an H2 agonist) nordimaprit and S-[2-(N,N-diisopropyl)ethyl]isothiourea (DINOR). Under culture conditions, rapid, pH-dependent hydrolysis of the isothioureas occurred, with cleavage to urea and a thiol which spontaneously oxidised to the disulphide. The H3 agonist imetit, which also inhibited tyrosinase, behaved similarly. The disulphide breakdown product of DINOR but not the thiol inhibited tyrosinase activity in intact MM96E cells to a similar extent as DINOR itself. Isothioureas with more bulky substituents, however, were stable in culture and did not inhibit tyrosinase. The results show that (a) certain histaminergic drugs exert effects via a disulphide hydrolysis product independently of the histamine H2 receptor, and (b) beta-aminoethyldisulphides are depigmenting agents.

Biotransformation↗
PubMed1994

Transcriptional regulation of differentiation, selective toxicity and ATGCAAAT binding of bisbenzimidazole derivatives in human melanoma cells.

To study the relationship between the structure of minor groove ligands and their affinity for specific DNA sequences that regulate gene transcription, three analogues of the A-T-specific DNA minor groove ligands Hoechst 33258 and Hoechst 33342 were synthesized with 5, 8 or 12 carbons in an aliphatic chain attached to the phenolic oxygen of the molecule. There was a striking bimodal relationship between toxicity to HeLa cells and the lipophilicity of the five analogues, toxicity being low for the compounds with a free hydroxyl (Hoechst 33258) or a 12-carbon substituent, yet high for the 5-carbon analogue. Selective killing of human melanoma cells compared with normal fibroblasts was observed for the Hoechst analogue with a 12-carbon chain attached. Hoechst 33258 itself was selectively toxic for the MM96E melanoma cell line compared with other cell lines, induced a highly dendritic morphology, increased tyrosinase activity and tyrosinase mRNA but decreased the level of gp75 (TRP-1) mRNA; message for a third pigment gene, Pmel-17, was unchanged. Tyrosinase activity was decreased in the resistant A2058 melanoma cell line and transcription was affected to a lesser extent than in MM96E. Expression of gp75 protein and two intermediate filament proteins was inhibited by Hoechst 33258 in MM96E cells. There was no major difference in the amount of 125I-Hoechst 33258 taken up by sensitive and resistant cells. Of the five derivatives studied, the parent drug Hoechst 33258 and the 2-carbon analogue (Hoechst 33342) were found to have the most inhibitory effect on affinity of octamer binding proteins for the ATGCAAAT consensus sequence found in the promoter region of certain genes associated with proliferation and differentiation. In contrast to Distamycin A (also an A-T-specific minor groove ligand), Hoechst 33258 displaced proteins already bound to the octamer motif. The G-C ligand chromomycin A3 exhibited a different spectrum of cell toxicity and tyrosinase stimulation compared with Hoechst 33258. Chromomycin A3 but not Hoechst 33258, strongly inhibited the zinc-dependent transcriptional activity of the sheep metallothionein-Ia promoter in reporter gene assays of transfected cells. Since the six metal-responsive elements of the promoter are GC-rich, this provides independent evidence for the sequence-specificity of transcriptional inactivation by one of these drugs in melanoma cells. Overall, the results suggest that Hoechst 33258 acts by inhibiting the transcription of specific genes, cell lines evidently differing in the accessibility to drugs of certain A-T-rich sequences.

Base Sequence↗
PubMed1994

Macrophage/particle interactions: effect of size, composition and surface area.

Particulate wear-debris are detected in histiocytes/macrophages of granulomatous tissues adjacent to loose joint prostheses. Such cell-particle interactions have been simulated in vitro by challenging macrophages with particles dosed according to weight percent, volume percent, and number of particles. Each of these dosage methods has inherent shortcomings due to varying size and density of challenging particles of different compositions. In this study we challenged P388D1 macrophages with titania and polystyrene particles (< 2 microns), with dosage based on the ratio of the surface area of the particles to the surface area of the cells. The effect of size and composition on (1) the bone resorbing activity, (2) fibroblast proliferation, and (3) secretion of IL-1 and PGE2 was determined. Macrophage response to particulate debris appears to be dependent on particle size, composition, and dose as given by surface area ratio. P388D1 macrophages challenged with titania particles released IL-1, but did not stimulate fibroblasts. Inhibition of macrophage DNA synthesis at higher surface area ratios suggests cell damage or death. Particle-stimulated cells increased bone resorption up to 125% of controls but released only basal levels of PGE2. Macrophages stimulated by wear particles are expected to synthesize numerous factors affecting events in the bone-implant interface. Using the concept of surface area ratio allows us to study and compare such cellular responses to wear particles in a standardized manner.

Animals↗
PubMed1994

Response of three murine macrophage populations to particulate debris: bone resorption in organ cultures.

Particulate wear debris from bone cement or prosthetic components can stimulate macrophages to cause bone resorption. We compared the effect of particle composition (titanium and polymethylmethacrylate as inherent components of prosthetic materials or bone cement and polystyrene as a reference material) on the secretion of interleukin-1 and prostaglandin E2 by peritoneal macrophages and monocyte/macrophage cell lines (P388D1 and IC-21) and on the bone-resorbing activity of conditioned medium harvested from these particle-challenged macrophages. Titanium particles (1-3 microns) in peritoneal macrophage cultures exhibited significantly enhanced bone-resorbing activity measured as 45Ca release, whereas polymethylmethacrylate and polystyrene exhibited this effect to a greater extent in the P388D1 and IC-21 monocyte/macrophage cultures. Although exogenous prostaglandin E2 and recombinant human interleukin-1 could significantly increase the 45Ca release and indomethacin significantly reduced both the spontaneous calcium efflux and active 45Ca release from calvarial bones labeled in vivo, the levels of interleukin-1 and prostaglandin E2, alone or together, did not always correlate with the bone-resorbing activity of conditioned media. Thus, the actual levels of potent bone-resorbing agents (prostaglandin E2 and interleukin-1) measured in conditioned tissue culture media did not necessarily reflect the bone-resorbing capability. An important result of this study is that different macrophage populations may respond differently to the same microenvironmental signal, which in our investigation was particulate wear debris of differing composition and size.

Animals↗
PubMed1994

Intergranular corrosion-fatigue failure of cobalt-alloy femoral stems. A failure analysis of two implants.

Two modular hip implants with a cobalt-alloy head and a cobalt-alloy stem were retrieved after a fracture had occurred in the neck region of the femoral component, eighty-five and seventy months after implantation. Both implants failed less than one millimeter distal to the taper junction between the head and the stem (outside of the taper). The fracture surfaces of the implant were investigated with the use of scanning electron microscopy, to determine the nature of the failure process. The fractures occurred at the grain boundaries of the microstructure and appeared to be the result of three factors: porosity at the grain boundaries; intergranular corrosive attack, initiated both at the head-neck taper and at the free surface; and cyclic fatigue-loading of the stem. The corrosive attack of the free surface was initiated, in part, by the egression of surface grains and by the ingression of fluid into the intergranular regions. Sectioned surfaces showed extensive intergranular corrosive attack in the prosthetic neck localized in the region of the head-neck taper junction and penetrating deeply into the microstructure.

Aged↗
PubMed1994

Migration of corrosion products from modular hip prostheses. Particle microanalysis and histopathological findings.

Migration of solid corrosion products from the modular head-neck junction of fifteen total hip replacements to the periprosthetic tissues was studied. The devices and tissues were recovered at the time of a revision procedure or at autopsy after a mean of sixty-four months (range, eight to ninety-seven months). The prostheses had a cobalt-chromium-alloy head coupled with a cobalt-chromium-alloy or a titanium-alloy stem. The solid corrosion product was identified by electron microprobe analysis and Fourier transform infrared microprobe spectroscopy as a chromium orthophosphate hydrate-rich material. The product was present at the junction of the modular head and neck and as particles within the periprosthetic tissues as early as eight months postoperatively. In several hips, it was also present on the polyethylene bearing surface. The particles in the tissues ranged in size from less than one to 500 micrometers. They were present within histiocytes or were surrounded by foreign-body giant cells in the pseudocapsule of the hip joint; in the membranes of the femoral bone-implant interface; and at sites of femoral endosteal erosions, with and without loosening of the femoral component.

Adult↗
PubMed1994

Composition and morphology of wear debris in failed uncemented total hip replacement.

Interfacial membranes collected at revision from 11 failed uncemented Ti-alloy total hip replacements were examined. Particles in the membranes were characterised by electron microscopy, microchemical spectroscopy and particle size analysis. Most were polyethylene and had a mean size of 0.53 micron +/- 0.3. They were similar to the particles seen in the base resin used in the manufacture of the acetabular implants. Relatively few titanium particles were seen. Fragments of bone, stainless steel and silicate were found in small amounts. Most of the polyethylene particles were too small to be seen by light microscopy. Electron microscopy and spectroscopic techniques are required to provide an accurate description of this debris.

Aged↗
PubMed1993

Inhibition of melanogenesis in human melanoma cells by novel analogues of the partial histamine (H2) agonist nordimaprit.

A series of analogues of the weak histamine (H2) agonist S-[2-(N,N-dimethylamine)ethyl] isothiourea (nordimaprit) was produced to investigate the possibility that bulky substituents on the tertiary amine of nordimaprit would enhance potency for depigmentation and killing of melanoma cells. Cell survival studies showed that neither an increase in lipophilicity nor an increase in size of these groups produced selective toxicity, with only the N,N-diisobutyl derivative being more effective than the N,N-diisopropyl derivative in killing the constitutively pigmented human melanoma cell line MM418. The most hydrophobic analogue, the N,N-dibenzyl derivative, was also the most toxic to all cell lines tested. The association of toxicity with lipophilicity was confirmed by the piperidine derivative having greater toxicity than the less hydrophobic morpholine analogue. The ability to decrease tyrosinase activity was lost when lipophilicity and size of the N-terminal groups were increased, but these analogues produced marked depigmentation, even greater than that found with either nordimaprit or the diisopropyl derivative. Surprisingly, an increase in tyrosinase activity was achieved, the most potent agent being the N-ethyl-N-anilino analogue which caused complete depigmentation (0.6% of control) and elevated tyrosinase activity (148%) in MM418 cells after 1 month of treatment. This indicates that nordimaprit and its derivatives possess two different mechanisms of depigmentation, the first being tyrosinase dependent and the second being tyrosinase independent. The latter pathway is yet to be elucidated but appears to require a high degree of hydrophobicity.

Cell Line↗
PubMed1993

In vivo corrosion of modular hip prosthesis components in mixed and similar metal combinations. The effect of crevice, stress, motion, and alloy coupling.

One hundred forty-eight retrieved modular hip prostheses of both mixed (Ti-6Al-4V/Co-Cr) and similar (Co-Cr/Co-Cr) metal combinations were examined and positive evidence of corrosive attack was found in the conical taper region between head and stem. Significant corrosion was observed in both mixed and similar metal combinations with 16% of necks and 35% of heads (for mixed-metal cases), and 14% of necks and 23% of heads (for similar-metal cases) showing moderate to severe corrosive attack. There was a significant correlation between the percentage of prostheses with moderate to severe corrosion and the duration of implantation for both mixed and similar metal cases, indicating that this corrosion process is progressive in time. Moderate to severe corrosion was seen as early as 2.5 and 11 months (mixed and similar metals, respectively). Scanning electron microscopy and x-ray analysis identified several forms of corrosive attack in the cobalt-based component of the taper. These included, for both mixed and same metal combinations: preferential dissolution of cobalt, fretting, and pitting; mixed metals only: the formation of a Ti-Cr-Mo interfacial phase and interdendritic corrosion; and for similar metals: intergranular attack adjacent to grain boundaries enriched in molybdenum and silicon. It is hypothesized that the restricted crevice environment, coupled with high cyclic stresses which cause repeated fracture of the passive oxide films in the taper, result in an unstable electrochemical environment within the crevice for both the cobalt alloy and Ti-alloy passive films. The passivity of these alloys is subsequently lost and active attack of the taper results. Also, the repeated fracturing of the passive films will result in large amounts of corrosion products being formed. This corrosion and particulate accumulation could result in loss of mechanical integrity of the implants in vivo, create particles for third body wear, and release particles into the surrounding tissues.

Alloys↗
PubMed1993

Bone resorption activity of particulate-stimulated macrophages.

Particulate wear debris from bone cement or prosthetic components can stimulate macrophages to cause bone resorption in a dose-dependent manner. This bone resorption activity of particulate-stimulated macrophages is associated with increased levels of both prostaglandin E2 (PGE2) and interleukin-1 (IL-1). In this study we compared the effect of particulate size, concentration, and composition on the secretion of IL-1 and PGE2 by peritoneal macrophages and on the bone-resorbing activity of conditioned medium (CM) harvested from particulate-challenged macrophages. Particulates (titanium, Ti; polymethylmethacrylate, PMMA; and polystyrene, PS) only with phagocytosable size stimulated peritoneal macrophages to secrete IL-1 and PGE2 in a dose- and time-dependent manner. Ti particles (1-3 microns) exhibited significantly enhanced bone-resorbing activity measured as 45Ca release. The maximum bone-resorbing response was observed at a concentration of 0.1% Ti (approximately 10-15 Ti particulates per cell), which also corresponded with the highest IL-1 levels measured in particulate-challenged CM. This was measured using either conditioned media from Ti-stimulated macrophages or in cocultures of calvarial bone and macrophages in the presence of Ti. Exogenous PGE2 and recombinant human IL-1 could significantly increase the 45Ca release; indomethacin (IM) significantly reduced both the spontaneous calcium efflux and active 45Ca release from in vivo labeled calvarial bones. However, IM and/or anti-IL-1 antibodies could suppress only partly the macrophage-mediated bone resorption, indicating that, in a macrophage-bone coculture system, factors other than PGE2 and IL-1 also may regulate particulate-induced bone resorption, probably involving multiple cell types.

Animals↗
PubMed1993

A quantitative study of bone and soft tissues in cementless porous-coated acetabular components retrieved at autopsy.

The authors examined 11 cementless acetabular components of one design retrieved at autopsy and made observations concerning tissue ingrowth and local tissue reaction, radiographic-histologic correlation, and the distribution of particulate wear debris. The cups were hemispherical in design with a commercially pure titanium fiber-metal porous coating. All of the prostheses were implanted with screws. The implants were in place for an average of 41 months (range, 5 weeks to 75 months). Ten of the cups had bone ingrowth, with the average volume fraction being 12.1 +/- 8.2%. There were no differences in the amount of bone ingrowth when the component was partitioned into nine anatomic regions. However, there was more bone adjacent to screw holes through which screws were inserted compared with empty screw holes. As the number of radiolucent zones increased on the clinical radiographs less bone ingrowth was observed histologically. The amount of metal debris in holes with screws and holes without screws was similar. In the longest term cases, polyethylene debris was noted within empty screw holes, but no granulomatous reactions or osteolytic processes were observed.

Acetabulum↗
PubMed1993

Primary total hip reconstruction with a titanium fiber-coated prosthesis inserted without cement.

A prospective study was done of the intermediate-term clinical and radiographic results of 121 total hip arthroplasties in which a Harris-Galante porous titanium-fiber-coated prosthesis was inserted without cement in 110 patients. The average age at the time of the operation was forty-nine years (range, twenty to seventy years). The average duration of follow-up was sixty-seven months (range, fifty-five to seventy-nine months). The average preoperative Harris hip score was 55 points, and the average postoperative score was 93 points. One acetabular component was revised due to recurrent dislocation. Eleven femoral implants were unstable, and of these, four were revised. Cortical erosion was present around the distal part of the femoral stem in nine patients (8 per cent) who had stable implants, and one of these femoral implants was revised because the erosion was extensive. Survivorship analysis at five years revealed a 97 per cent chance of survival (95 per cent confidence limit, 0.937 to 1.0) of the Harris-Galante femoral-stem implant inserted without cement.

Acetabulum↗