Whole-eye transplantation: a look into the past and vision for the future.

Blindness afflicts ~39 million people worldwide. Retinal ganglion cells are unable to regenerate, making this condition irreversible in many cases. Whole-eye transplantation (WET) provides the opportunity to replace diseased retinal ganglion cells, as well as the entire optical system and surrounding facial tissue, if necessary. Recent success in face transplantation demonstrates that this may be a promising treatment for what has been to this time an incurable condition. An animal model for WET must be established to further enhance our knowledge of nerve regeneration, immunosuppression, and technical aspects of surgery. A systematic review of the literature was performed to evaluate studies describing animal models for WET. Only articles in which the eye was completely enucleated and reimplanted were included. Study methods and results were compared. In the majority of published literature, WET can result in recovery of vision in cold-blooded vertebrates. There are a few instances in which mammalian WET models demonstrate survival of the transplanted tissue following neurovascular anastomosis and the ability to maintain brief electroretinogram activity in the new host. In this study we review in cold-blooded vertebrates and mammalian animal models for WET and discuss prospects for future research for translation to human eye transplantation.

Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group.

OBJECTIVE: To evaluate the efficacy and safety of diacerein, a drug with interleukin-1beta--inhibitory activity in vitro, in patients with knee osteoarthritis (OA). METHODS: A total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily). RESULTS: In the intent-to-treat population, 100 mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage. CONCLUSION: Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).

The clinical spectrum of the arthropathy associated with hidradenitis suppurativa and acne conglobata.

Patients with hidradenitis suppurativa/acne conglobata attending a university medical center were evaluated for the presence of an associated arthritis. Of 44 subjects, 21 had objective evidence of inflammatory arthropathy. Of these 21, all adults, 11 were women and 17 black Americans; clinically, 18 had peripheral arthritis, 15 axial arthropathy and 12 both. Clinical and laboratory findings were characteristic of those seen in other seronegative spondyloarthropathies, except for lack of association with HLA-B27.

Estrogens and osteoarthritis.

Clinical and laboratory observations suggest that a relationship exists between sex hormones and the development of osteoarthritis. The mechanisms whereby these hormones influence the pathophysiology of osteoarthritis have been explored. Tamoxifen, an estrogen antagonist, reduced erosive changes in meniscectomy-induced osteoarthritis in rabbits. By contrast, estradiol worsened it. There was no effect of either agent on the incidence of osteophytes in this model. Both estradiol and tamoxifen affected proteoglycan, prostaglandin, and proteoglycanase production by cartilage components. These observations suggest that cartilage is a sex hormone-sensitive tissue. This may have therapeutic implications in the future.

Fine specificity of serum anticollagen molecules in experimental immune synovitis.

Serum anticollagen antibodies to the native and denatured interstitial collagens were measured by solid phase radioimmunoassay (RIA) in a rabbit model of IgG-induced immune synovitis. Serum antibodies binding the native interstitial collagens and denatured type II collagen were observed in 100% of the animals tested (n = 6). Titerable antibodies to the alpha 1 (III) collagen polypeptide chain were observed in 83% of the animals, whereas serum antibodies to denatured type I collagen were observed in 33%. Inhibition studies showed that the observed serum anticollagen antibodies were conformationally dependent and collagen type specific. In addition these antibody populations varied in their affinities by as much as a factor of 2.81 for the specific substrates. Mean value of the average binding constants (Ka) for synovitis anticollagen antibodies binding native type II collagen was 5.47 X 10(6)mol; while the Ka determined for synovitis antibodies binding denatured type III collagen was 1.94 X 10(6)/mol. The data indicate that unique anticollagen antibody populations are expressed in the serum of animals with experimental IgG-induced chronic immune synovitis.

Idiopathic adolescent scoliosis--a prototype of degenerative joint disease. The relation of biomechanic factors to osteophyte formation.

A study was performed to evaluate the presence of degenerative joint disease (DJD) in idiopathic adolescent scoliosis (IAS) and correlate DJD with biomechanic factors. The average age of the subjects was 19 years (range, 12-30). Osteophytes reflecting the presence of degenerative joint disease occurred in apophyseal and/or intervertebral joints of 74% of 100 subjects. Osteophytes were correlated with curve angle and apical rotation. Compression forces are of pathogenic significance in the localization of osteophytes in IAS. IAS can serve as a naturally occurring prototype for the study of the influence of biomechanic factors on the pathogenesis of DJD.

Immunoglobulin G-induced experimental chronic immune synovitis: cell-mediated immunity to native interstitial collagen molecules and their constituent polypeptide chains.

In vitro cell-mediated immune responses to homologous rabbit immunoglobulin G (IgG), purified protein derivative (PPD), native Type I, II, and III collagen, and denatured Type I, II, and III collagen were studied in an IgG-induced animal model of immune synovitis. Immune response was measured as augmented [3H]thymidine incorporation by spleen cells on exposure to antigen. Immune responses were observed in vitro after 72 hr of culture with antigen, while a majority of responses to antigens occurred after 96 hr of incubation. Separation of spleen cell subpopulations showed that measured immune responses were of T-cell origin. In vitro cell-mediated immune responses were observed for native and denatured collagen in splenic cell cultures from six of seven synovitic rabbits (P less than 0.01) but not in control spleen cell cultures derived from normal, adjuvant-primed or IgG-immune nonsynovitic rabbits. The incidence of cellular reactivity to incubation with native interstitial collagens was as follows: Type I, 43%; Type II, 43%; Type III, 57%. The incidence of in vitro immune responses to denatured collagens in cultures derived from rabbits with synovitis was: Type I, 50%; Type II, 50%; Type III, 67%. The relatively high incidence of immune response to both native and denatured collagens suggests that immunity to structural components of the synovial membrane and the adjacent surface of articular cartilage may play a role in the inflammation observed in immune synovitis.

IgG-induced experimental immune synovitis: hormonal modulation of in vitro splenic immune responses to homologous antigens.

The effect of oestrogen or anti-oestrogen administration on gross pathology and in vitro cell-mediated immune responses to homologous IgG, native and denatured interstitial collagens and PPD was studied in an IgG-induced rabbit model of immune synovitis. During induction of synovitis, rabbits were administered oestradiol valerate (0.075 mg/kg/day) or tamoxifen, an anti-oestrogen (2.0 mg/kg/day, high dose or 0.5 mg/kg/day, low dose) or placebo injections. Low dose tamoxifen administration was associated with significant improvement P less than 0.05 in immune synovitis with regard to gross pathology, when compared to placebo and the oestradiol treatment group. High dose tamoxifen treatment was not associated with significant improvement in observed synovitis. With regard to cell-mediated immune responses, spleen cells derived from immune synovitis rabbits were observed to increase 3H-thymidine uptake on incubation with native or denatured homologous collagens. Modulation of these immune responses to antigens was observed in anti-oestrogen treated rabbits with immune synovitis. In vitro cell-mediated immune responses to denatured type I, II and III collagens, PPD, as well as native type II and III collagens were not observed in the low dose tamoxifen treatment group. However, in vitro immune responses to these antigens were observed in spleen cell cultures from immune synovitis rabbits treated with either high dose tamoxifen or oestradiol valerate. The data suggest that in vivo anti-oestrogen administration can modulate the in vitro cell-mediated immune response to connective tissue constituents observed in immune synovitis. Concomitant with reduced immune responses is a significant reduction in the observed lesions of the inflammatory response.

Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy.

Five patients who presented with arthritis as the sole manifestation of hereditary hemochromatosis and 51 family members were studied. Studies included clinical evaluation for the presence of arthritis and hemochromatosis, roentgenography of hands, knees, and pelvis, serum iron and serum ferritin measurements, complete HLA typing for 50 of the A and B loci, and, when indicated, liver biopsy. Arthritis occurred in 45 percent of persons with hemochromatosis. Although typical involvement of second and third metacarpophalangeal joints was observed in all five patients and some family members, two with typical arthritis did not have characteristic radiographic changes, two had constitutional symptoms without arthropathy, and one had unilateral hand changes. A specific HLA haplotype (A2/B17 in Family 1 and A29/B15 in Family 2) correlated with hereditary hemochromatosis but not with the arthropathy. Phlebotomy alleviated the early constitutional symptoms but did not help advanced arthritis. Anti-inflammatory drugs, intraarticular injections of glucocorticoids, and resection osteotomies of metacarpal heads were other treatment modalities.

Estradiol and tamoxifen stimulation of lapine articular chondrocyte prostaglandin synthesis.

The effect of estradiol and tamoxifen on prostaglandin (PG) synthesis by rabbit articular chondrocytes in secondary monolayer cultures was investigated. Radioimmunoassay for PGE2, PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane B2 was performed on media from cultures containing estradiol and tamoxifen (10-12M-10-7M). Radiometric thin-layer chromatography was also carried out. The time course of estradiol/tamoxifen effect on chondrocyte PG synthesis was evaluated and its relationship to cell density in culture examined. Estradiol stimulated the synthesis of PGs by chondrocytes. Stimulation was noted at picomolar concentrations of estradiol without further stimulation at markedly higher concentrations. In time studies, after a lag, the effect of estradiol was present fully by 5 hrs, remained steady for 24 hrs and then declined by 48 hrs. Estradiol stimulation of PG synthesis was dependent upon chondrocyte culture plating density. Tamoxifen stimulated chondrocyte PG synthesis to relatively lower levels than estradiol. The characteristics of estradiol/tamoxifen stimulation of chondrocyte PG synthesis suggest a mechanism involving estradiol cytoplasmic receptors.

Intraarticular hyaluronic acid injection and synovial prostaglandins in experimental immune synovitis.

In vitro studies suggest that synovial fluid hyaluronic acid may have a role in reducing joint inflammation. The effect of intraarticular injection of sodium hyaluronate in a model of experimental immune synovitis was assessed. In addition, tissue prostaglandin content of synovia with and without immune synovitis was compared. Intraarticular hyaluronic acid administered at 2 doses was not effective in reducing the induced inflammation. With immune synovitis there was an increase in the total synovial prostaglandins. When related to total prostaglandins, prostacyclin was decreased, prostaglandin F2 alpha and thromboxane were increased and prostaglandin E2 was the same in synovitis as compared to controls.

Pathologic and metabolic responses of experimental osteoarthritis to estradiol and an estradiol antagonist.

Tamoxifen, an estradiol antagonist, and estradiol were separately evaluated in a rabbit experimental osteoarthritis. Cartilage from anatomically defined regions of individual rabbit knees was assayed for sulfate and thymidine incorporation. Tamoxifen reduced erosive osteoarthritic pathology, while estradiol worsened it. There was no effect on the incidence of osteophytes. Metabolic studies in organ culture showed no changes relating to treatment. The results suggest that specific medical therapy for osteoarthritis is within the realm of possibility.

Spondyloarthropathy associated with hidradenitis suppurative and acne conglobata.

We evaluated 10 patients with hidradenitis suppurative or acne conglobata who developed arthritis. In contrast to patients with acne fulminans and arthritis, all our subjects were adults over 22 years of age; nine were black; and four were women. Nine patients had episodic inflammatory oligoarthritis affecting mainly larger joints of the upper and lower extremities. Eight patients had roentgenographic evidence of peripheral arthritis, four with erosions. Nine had clinical axial arthropathy, but roentgenograms showed abnormalities of the axial skeleton in all 10 patients. Pyoderma gangrenosum, erythema nodosum, conjunctivitis, urethritis, and oral and penile ulcers occurred in some patients. Rheumatoid factor was negative in all patients; the erythrocyte sedimentation rate was elevated in nine; five had chronic anemia; four had circulating immune complexes; and complement components were elevated in four. There was no increased incidence of HLA-B27 or other HLA-B7 cross-reacting antigens. A temporal relation of skin and joint disease activity was suggested. We report a spondyloarthropathy associated with hidradenitis suppurativa and acne conglobata. Clinical and laboratory manifestations suggest the arthropathy may be reactive to chronic cutaneous infection.

Arthropathy, hypouricemia and normal serum iron studies in hereditary hemochromatosis.

A patient manifesting the arthropathy of hemochromatosis without abnormal serum iron studies is described. Hemochromatosis was confirmed by liver biopsy. This case serves to emphasize the diagnostic value of the characteristic arthropathy of hemochromatosis. Our observations in this patient support the hypothesis that the pathogenesis of hereditary hemochromatosis differs from that of acquired iron overload states. The concurrent presence of hypouricemia is explored in this patient and in 18 other patients with hereditary hemochromatosis. Men with hereditary hemochromatosis were found to have lower serum uric acid levels than expected. In our patient, a renal defect in tubular reabsorption of uric acid appears responsible for hypouricemia. The apparent association of hemochromatosis and hypouricemia deserves further investigation.

A trial of intraarticular orgotein, a superoxide dismutase, in experimentally-induced osteoarthritis.

Intraarticular injections of orgotein, a metalloprotein with superoxide dismutase activity, did not ameliorate experimentally-induced osteoarthritis in the rabbit. Reduction of sulfate incorporation by cartilage of operated osteoarthritic knees with injection of saline-sucrose placebo and orgotein in saline-sucrose vehicle was observed. Repeated intraarticular injections of both orgotein in a sucrose-saline vehicle, and sucrose-saline placebo administered separately induced a severe synovitis in both osteoarthritic and normal knees.

Effects of estrogen on cartilage and experimentally induced osteoarthritis.

Estradiol valerate did not ameliorate experimentally induced osteoarthritis in the rabbit. Both normal and osteoarthritic cartilage were susceptible to estradiol suppression of proteoglycan synthesis. Protoeglycan concentration was not diminished with estradiol, suggesting estradiol suppression of proteoglycan catabolism. The severity of osteoarthritis was unchanged despite markedly decreased proteoglycan catabolism. The severity of osteoarthritis was unchanged despite markedly decreased protoeglycan synthesis in the estrogen treated animals. Osteophyte proteoglycan metabolism differed from other osteoarthritic lesions. Differences in the metabolism of femoral and tibial articular cartilage were observed.