Pathogenic mechanisms in the rheumatoid nodule: comparison of proinflammatory cytokine production and cell adhesion molecule expression in rheumatoid nodules and synovial membranes from the same patient

OBJECTIVE: To investigate the production of proinflammatory cytokines and expression of cell adhesion molecules in the rheumatoid nodule. METHODS: Cytokine content (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], and IL-1 receptor antagonist [IL-1Ra]), at the messenger RNA (mRNA) and protein levels, and cell adhesion molecule expression were studied in 16 rheumatoid nodules and 6 synovial membranes. RESULTS: Macrophages in the rheumatoid nodules contained TNFalpha, IL-1beta, and IL-1Ra mRNA and protein, particularly in perivascular cells of the stroma and in the palisading layer. All cell adhesion molecules studied were expressed in both the rheumatoid nodules and synovial membranes, with increased expression of E-selectin in the rheumatoid nodule compared with the synovial membrane, and with the absence of vascular cell adhesion molecule 1 expression on cells of the palisading layer in the rheumatoid nodule. CONCLUSION: The presence of similar proinflammatory cytokines and cell adhesion molecules in the rheumatoid nodule and synovial membrane suggests that similar pathogenic processes result in the chronic inflammation and tissue destruction in these lesions.     

Biomechanical study of sternal closure using rigid fixation techniques in human cadavers

BACKGROUND: We believe rigid plate fixation may be superior to wire fixation in sternal closure, as rigid fixation used in the craniofacial skeleton has shown greater stability, lower postoperative pain, and accelerated bone healing. We hypothesize that sterna fixed with titanium plates are more stable mechanically than sterna fixed with wires. METHODS: The sterna from human cadavers were used in this two-phased study. Phase I compared wires to four-hole titanium straight plates. Phase II compared wires to four-hole titanium custom H plates. The sterna were tested biomechanically using all fixation methods. RESULTS: Phase I showed no statistically significant difference in the stiffness or lateral displacement between the wired and straight plated sterna. Phase II showed a statistically significant greater stiffness (p < 0.05) and less lateral displacement (p < 0.05) in the custom plated sterna over the wired sterna. CONCLUSIONS: Our results showed that custom titanium H plates were superior to wire fixation. Furthermore, our results established the importance of plate configuration in sternal fixation. Our study may have beneficial clinical implications, as decreased motion at the sternotomy site could mean less postoperative pain, a decreased incidence of infection, and accelerated bone healing.     

Ligand-induced endocytosis of the asialoglycoprotein receptor: evidence for heterogeneity in subunit oligomerization

Prostate cancer is the most common form of cancer in older men and the major cause of death from prostate cancer is metastatic disease. The matrix metalloproteinases (MMPs) play a significant role in the growth, invasion and metastasis of many tumors, including those of the prostate. We previously demonstrated that doxycycline, a synthetic tetracycline, inhibits MMPs and cell proliferation and induces apoptosis in several cancer cell lines. We also demonstrated that in an in vivo model of metastatic breast cancer in athymic mice doxycycline inhibits tumor size and regrowth after resection. In the present study, gelatinolytic activity in the human prostate cancer cell line, LNCaP, was suppressed and significant inhibition of cell growth occurred after exposure to 5 or 10 microg/ml of doxycycline, while cell growth was normal in untreated cells. Radioisotope incorporation into proteins was reduced by doxycycline. DNA fragmentation, consistent with apoptosis, was demonstrated in cells treated with doxycycline. These data suggest that doxycycline may have potential utility in the management of prostate cancer.     

Regulation of skeletal muscle perfusion during exercise

OBJECTIVE: To compare the composition and mechanical properties of the newly developed bladder acellular matrix graft (BAMG) with the normal urinary bladder in rat, pig and human. MATERIALS AND METHODS: Rat, pig and human urinary bladders were harvested and divided into control and experimental groups. For the latter, BAMGs were prepared, and light and transmission electron microscopic studies performed. Strips from the normal bladders and the BAMGs (10 in each group) were tested under tension, and the ultimate tensile strength, maximum strain, and elastic modulus were determined from stress/strain curves. RESULTS: Both types I and III collagen, as well as elastic fibres, were observed as major components of the matrix scaffold. There were more collagen type I fibres in the rat than in the pig and human BAMGs, whereas the pig, and particularly the human, both showed higher levels of type III collagen and elastic fibres. These different matrix scaffold patterns were confirmed by electron microscopy. Results from biomechanical testing showed no significant differences for strength, strain or elastic modulus between BAMG and control bladder strips, except in the rat where the maximum strain values were significantly lower. CONCLUSION: There are variations in the acellular matrix structure with similar biomechanical properties between the BAMG and the normal urinary bladder in three different species. These results may underscore the potential of the BAMG. Furthermore, this in vitro model provides a suitable method to study the mechanical properties of the urinary bladder and may serve as a diagnostic tool for various investigations.     

Diabetic-like retinopathy: early and late intervention therapies in galactose-fed rats

PURPOSE: To determine whether the diabetic-like thickening of retinal capillary basement membrane (RCBM) that develops in the galactose-fed rat model of diabetic ocular complications could be halted or ameliorated after 4 or 8 months of galactosemia by treatment with ARI-509, a potent new aldose reductase inhibitor (ARI), or by withdrawal of the galactose diet. METHODS: Weanling female Sprague-Dawley rats were randomized into eight groups and fed laboratory chow plus 50% starch, control group (CON); 50% D-galactose, galactose-fed group (GAL); 50% D-galactose with ARI-509 at 25 mg/kg or 10 mg/kg body wt per day, high-dose prevention group (HDP) and low-dose prevention group (LDP), respectively; 50% D-galactose for 4 or 8 months and then intervention by addition of ARI-509 (25 mg/kg body wt per day), 4-month intervention group (4IN) and 8-month intervention group (8IN), respectively; or 50% D-galactose for 4 or 8 months and then intervention by withdrawing galactose and replacing it with the 50% starch diet, 4-month galactose withdrawal group (4GW) and 8-month galactose withdrawal group (8GW), respectively. After 4, 8, 16, and 24 months of the experimental diets, the levels of carbohydrates in tissues and the extent of RCBM thickening in capillaries of the outer plexiform layer were determined in all groups. RESULTS: Retinal polyol was reduced by 95% in all ARI-treated groups and by 100% in the 4GW and 8GW groups after withdrawal of the galactose. The mean RCBM thickness increased rapidly in GAL rats, becoming almost two times greater (189 +/- 9.4 nm) than in CON rats (103 +/- 3.4 nm) by 24 months. Treatment with ARI-509 in high and low doses (HDP, LDP) initiated with the introduction of the galactose diet significantly prevented RCBM thickening at all time points (P < 0.05). In contrast, intervention by withdrawing galactose from the diet or by adding the high dose of ARI-509 had no significant effect (P < 0.05) on RCBM thickening until the 24-month time point (4IN, 166 +/- 10.3 nm; 8IN, 161 +/- 8.2 nm; 4GW, 136 +/- 5.1 nm; 8GW, 163 +/- 9.6 nm). CONCLUSIONS: Both early and late interventions decreased RCBM thickening compared with that in untreated GAL rats. The decreased thickening, however, was not evident until 16 to 20 months after the intervention. Because RCBM thickening is one of the earliest changes in diabetic and galactosemic retinopathy, the findings suggest that RCBM thickening and possibly subsequent retinal lesions are caused by early biochemical alterations induced by the galactose diet that are not readily reversed. The delayed response to therapy is consistent with that observed in the Diabetes Control and Complications Trial. The cumulative evidence indicates that intervention should begin as early after onset of diabetes as possible, and long follow-up periods should be used to evaluate efficacy.