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Objective.To compare the efficacy of hydroxychloroquine, penicillamine, sodium aurothiomalate and auranofin in the treatment of active rheumatoid arthritis over a period of 5 yr. [ABSTRACT FROM PUBLISHER]

The concept of a dual articulation acetabular cup was developed by Prof. Bousquet in 1974. This concept has been shown to provide high stability after revision and primary total hip arthroplasty. The aim of our study was to evaluate the incidence of prosthetic instability in a consecutive homogeneous series of 384 primary dual mobility cups. Incidence of instability and implant survival were evaluated. Mean follow-up was 15.3 years (range, 12-20). There was no early or late instability. On the acetabular side there were 13 aseptic loosenings, 14 intraprosthetic dislocations, and seven polyethylene wear cases that required replacement of the liner. The cumulative survival rate of the dual-articulation acetabular cup using surgical revision for aseptic loosening as the endpoint was 95.9% +/- 4.1% at 18 years postoperatively. Our series proves the good long term behaviour of dual-articulation acetabular components in primary arthroplasty. Their excellent survivorship rate and the absence of episodes of prosthetic instability increase our confidence in this concept.

Purpose of the Study: As part of the 2006 symposium of the French Hip and Knee Society devoted to the dual mobility socket, we report a retrospective multicentric series of 438 first-intention total hip prostheses with a dual mobility socket at a mean 17 years follow-up. The purpose of our report was to ascertain the 15-year survival of this socket and analyze failures., Material and Methods: The series included 438 primary replacements. This was a homogeneous multicentric series. The cementless sockets were 80 Novae-1 titanium Serf cups and 358 Novae-1 stainless steel Serf cups. All stems were inserted without cement: 185 Pf((R)) stainless steel screwed Serf stems, 228 PRO titanium screwed Serf stems, and 25 Corail stems. The mobile polyethylene insert was retaining. All of the heads were 22.2-mm chromium-cobalt heads. Degenerative hip disease was the main etiology and mean follow-up was 17 years (range, 12-20). Mean age at implantation was 54.8 years (range, 23-87). The actuarial method with a 95% confidence interval was used to determine the 15-year cup survival rate., Results: At the last follow-up, none of the patients had presented an episode of early or late instability. Analysis of the socket at last follow-up showed 13 aseptic loosenings, 23 intraprosthetic dislocations, and seven replacements of the polyethylene insert for wear. The overall 15-year prosthesis survival rate was 89.2+/-8.7%. The overall 15-year socket survival rate was 96.3+/-3.7%., Discussion: The fact that, at last follow-up, none of the implants had shown instability confirms the long-term stability of the dual mobility socket. The results in terms of 15-year survival confirm earlier reports. The main cause of failure was cup fixation, which is the weak point of this technique with the initial Novae cup design, which did not have hydroxyapatite coating. The second leading cause was intraprosthetic dislocation, which can be divided into three main categories. The first is intraprosthetic dislocation in a context of pure wear with normal function of the dual mobility socket; the retaining feature of the insert loses its efficacy due to wear. The second category is intraprosthetic dislocation in a context of cup loosening with a third-body effect and increased retention wear, in which case we consider that cup loosening is the primary event leading to rapid secondary wear and subsequent intraprosthetic dislocation. The third category is intraprosthetic dislocation caused by a blockage in a context of fibrosis or impingement involving severe heterotopic ossifications. We had only two femoral failures related to aseptic loosening, most certainly related to use of noncemented implants, which limits the extension of granulomas to the polyethylene. Studying the three series from Saint-Etienne more specifically, where three different configurations were used, it would appear that the titanium cup has a better survival rate and that the titanium used for the thinner necks may be an unfavorable factor for intraprosthetic dislocation.

Purpose of the Study: Within the framework of the 2007 symposium of the French Hip and Knee Society devoted to the dual mobility socket, we report a retrospective multicentric series of 438 first-intention total hip prostheses with a dual mobile socket at 17 years mean follow-up. The purpose of our report was to ascertain the 15-year survival and analyze failures., Material and Methods: The series included 438 first-intention prostheses. This was a homogeneous multicentric series. Sockets were: 80 Novae-1 titanium Serf cups and 358 Novae-1 stainless steel Serf cups. All stems were inserted without cement: 185 Pf) stainless steel screwed Serf stems, 228 PRO titanium screwed Serf stems, 25 Corail stems. The mobile polyethylene insert was retaining. All of the heads were 22.2mm chromium-cobalt heads. Degenerative hip disease was the main etiology and mean follow-up was 17.18 years (range: 12-20). Mean age at implantation was 54.8 years (range: 23-87). The actuarial method with 95% interval of confidence was used to determine the 15-year cup survival., Results: At last follow-up, none of the patients had presented an episode of early or late instability. Analysis of the socket at last follow-up showed: 13 aseptic loosenings, 23 intraprosthetic dislocations, and seven replacements of the polyethylene insert for wear. The overall 15-year prosthesis survival was 89.2+/-8.7%. The overall 15-year socket survival was 96.3+/-3.7%., Discussion: The fact that at last follow-up none of the implants had exhibited instability confirms the long-term stability of the dual mobility socket. The results in terms of 15-year survival confirm earlier reports. The main cause of failure was cup fixation, which is the weak point of this technique with the initial Novae cup, which did not have hydroxyapatite coating. The second leading cause was intraprosthetic dislocation, which can be divided into three main categories. The first is intraprosthetic dislocation in a context of pure wear with normal function of the dual mobility; the retaining feature of the insert looses its efficacy due to wear. The second category is intraprosthetic dislocation in a context of cup loosening with a third-body effect and increased retention wear, in which case we consider that the cup loosening is the primary event leading to secondary rapid wear and subsequent intraprosthetic dislocation. The third category is intraprosthetic dislocation cause by a cam effect in a context of fibrosis or impingement involving a large calcification. We have had only two femoral failures by aseptic loosening, most certainly related to use of noncemented implants, which limits the extension of granulomas to the polyethylene. Studying more specifically the three series from Saint-Etienne where three different configurations were used, it would appear that the titanium cup has a better survival and that the titanium used for the thinner necks would be an unfavorable factor for intraprosthetic dislocation.

Purpose of the Study: MacFarland fractures are known to have poor prognosis. There is a major risk of misalignment due to the formation of an epiphysiodesis bridge. The purpose of this study was to evaluate the functional and radiological outcome of these fractures in a retrospective series of patients., Material and Methods: We analyzed retrospectively the cases of 26 patients (14 boys and 12 girls), mean age 11 years 6 months (range 7-15) with MacFarland fractures. The Salter and Harris classification was Salter III (n = 17) and Salter IV (n = 9). Surgery was used for 21 patients and cast immobilization for five. Mean follow-up was 28.4 months (19-63 months). None of the children were lost to follow-up. Outcome was noted good (no stiffness, no pain, no limp, no misalignment, no surgical complication, no healing problem), fair (stiffness and/or pain and/or limp and/or healing problem without misalignment, no surgical complication), or poor (misalignment or surgical complication)., Results: The three-months postoperative assessment showed three patients with ankle pain, five with stiff ankles, one with a medial problem (snapping) and two with wound healing complications. The long-term outcome was considered good for 24 patients and fair in two (one wound adherence and one hypertrophic scar tissue). There were no poor outcomes., Discussion: We used surgery more than is generally reported by other teams, opting for surgery when the displacement was 1 mm rather than the 2 mm used by others. Surgical treatment was arthrotomy in all cases to achieve anatomic reduction under direct view, followed by osteosynthesis. For some, this therapeutic scheme may be considered too surgical. In order to achieve anatomic reduction, we use an epiphyseal lag screw for cancellous bone to achieve better compression of the fracture line. A washer is also used to improve compression and maintain perfect reduction. Theoretically, the washer could raise the risk of perichondral virola and consequently an iatrogenic epiphysiodesis bridge, but we have not had any problems in our experience. Arthrotomy did not lead to ankle stiffness, which is feared by some, in any of our patients.

Objectives: To describe the changes in functional ability (FA) taking place over 5 yr in patients with rheumatoid arthritis (RA) starting disease-modifying anti-rheumatic drug (DMARD) therapy, to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment., Methods: Three hundred and sixty-six patients with active RA were studied as part of a 5-yr randomized controlled study of DMARD therapy. FA was assessed by Health Assessment Questionnaire (HAQ) score every 6 months. Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr. The independent variables used were age, sex, visual analogue scale (VAS) pain, Ritchie articular index, C-reactive protein (CRP), Larsen score and log-transformed morning stiffness (EMS)., Results: Mean HAQ score was 1.64 at baseline, improved by 21% at 1 yr and gradually returned towards baseline levels by 5 yr. At baseline only 34% of variance in HAQ score could be explained; the most significant explanatory variables were the Ritchie articular index and CRP. At 5 yr the variance explained was 60%. The Ritchie articular index remained the strongest factor followed by VAS pain, log(10) EMS and Larsen score., Conclusions: Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr. The most consistent factor affecting function was joint tenderness. Global pain and duration of EMS were of lesser importance. Disease activity measures such as the CRP exerted an influence in the earlier, more active stages of disease: radiographic damage assumed greater importance as the arthritis progressed.

Introduction: The clinical diagnosis of dry-eye is confirmed by a suitable test of tear production and the technique commonly used today to diagnose dry eye is the Schirmer's test (ST). Although the ST is easy to perform it gives variable results, poor reproducibility and low sensitivity for detecting dry eyes. Another test, the tear break up time (TBUT) is used to assess the stability of tears which if abnormal may also cause symptomatic dry-eye. We present the results of both these tests and a new test, which shows greater sensitivity than the ST in detecting aqueous tear deficiency. The fluorescein meniscus time (FMT) is a new test developed in conjunction with one of the authors (CL) and the Department of Ophthalmology at the University Hospital of Wales. The FMT is a measure of the rate at which a fluorescent tear meniscus is formed using 2% sodium fluorescein, a stopwatch and suitable illumination with a slit lamp., Method: An open controlled study in 62 patients and 51 controls was conducted to compare the ability of ST, FMT and TBUT to detect dry-eye in a group of patients diagnosed with rheumatoid arthritis and symptomatic dry eyes for a minimum period of 6 months. A separate control group of 15 subjects was tested on three separate occasions to assess the reproducibility of the FMT test., Results: All three tests showed a statistically significant difference between the patient and control populations; Mann-Whitney P < 0.001. There was a correlation between the right and left eye for all three tests in the control group (ST r(2) = 0.77, FMT r(2) = 0.98, TBUT r(2) = 0.94). This correlation was markedly reduced for FMT and TBUT in the patient population and was in keeping with the symptoms reported as being worse on one side in a proportion of the patients (FMT r(2) = 0.52, TBUT r(2) = 0.54, ST r(2) = 0.75). A correlation with age was also observed for all the three tests in the control group (ST r(2) = 0.74, FMT r(2)= 0.92, TBUT r(2) = 0.51), but not in the patient population (ST r(2) = 0.06, FMT r(2) = 0.18, TBUT r(2) = 0.03). A significant correlation was observed between the ST and FMT in both the control (ST vs FMT r(2) = 0.65) and patient population (ST vs FMT r(2) = 0.44). There was no value greater than 200 seconds for FMT recorded in the control group. Using this value to define an abnormal FMT, 85% of the patients (72% of the eyes tested) had an abnormal result. This was in contrast to 35% of patients (26% of the eyes tested) with abnormal results detected by ST. Using ANOVA and Student's paired t-test, there were no significant differences between the three sets of values recorded serially over 3 months to assess the reproducibility of the FMT. The average standard error of the mean was 2.72% and the average co-efficient of variation 4.07%., Conclusion: Our study suggests that the FMT is a more sensitive test with good reproducibility compared to the Schirmer's test. The FMT correlates with the ST and suggests that both tests measure aqueous tear deficiency. The FMT therefore is a better alternative to ST currently being used to test aqueous tear deficiency.

Objective: To investigate the association between serum soluble interleukin 2 receptor (sIL-2R) levels and radiological changes in patients with early rheumatoid arthritis (RA)., Methods: sIL-2R levels from 155 patients with active RA were measured by immunoassay over a 2 year period and the associations with radiological change and other measures of disease activity were analyzed., Results: The area under the curve for sIL-2R is weakly associated with the change in the modified Larsen score over a 2 year period; this is weaker than the association of radiological change with serum C-reactive protein., Conclusion: We found no significant association of sIL-2R levels with erosive change in early RA.

We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.

In this study, we sought to determine whether liposomal preparations containing a phospholipid conjugate of methotrexate and dimyristoylphosphatidylethanolamine (MTX-gamma-DMPE) incorporated within their lipid membranes are effective in suppressing established joint inflammation in a monoarticular model of arthritis in the rat. Arthritis was induced in the right knee joint of Lewis rats. The rats were treated with a single intra-articular injection of either free methotrexate (MTX), liposomal MTX [MTX-multilamellar vesicles (MLV)-1.2 microns or MTX-small unilamellar vesicles (SUV)-100 nm], control liposomes (E-LIPO) or saline into the inflamed knee 7 days after arthritis induction. There was no significant difference in knee swelling in MTX-, saline- and E-LIPO-treated rats up to 21 days after treatment. However, MTX-MLV treatment produced a significant reduction in knee swelling (26.5 +/- 6.0%: mean +/- S.E.M.) 1 day after intra-articular injection compared with MTX (3.5 +/- 3.5%) and MTX-SUV (14.4 +/- 2.4%), respectively. Over the next 20 days, knee swelling in MTX-MLV-treated rats fell progressively and almost returned to normal. MTX-MLV treatment also inhibited the cellular infiltration associated with the arthritis. Large multilamellar liposomal preparations of MTX-gamma-DMPE are more effective than free MTX and MTX-SUV in suppressing inflammation. Their differential effects in treating the antigen-induced arthritis model are related to their retention within the joint space.

In this study we evaluated the comparative efficacy of free and liposomally conjugated methotrexate on both disease induction and suppression of acute inflammation in rat adjuvant-induced arthritis. Rats were given either empty liposomes (E-LIPO), free methotrexate (MTX) or the liposomally conjugated methotrexate (MTX-LIPO) at a dose of 100 micrograms/day for 7 consecutive days by the intravenous route. When MTX treatment was initiated on the day of arthritis induction the drug suppressed but did not abolish the development of joint inflammation. Free MTX had no significant anti-inflammatory effect upon an established arthritis when dosing was commenced on day 11 post-adjuvant induction. Conversely, MTX-LIPO did not affect the progression of the arthritis when dosing was started on day 0, but exerted a significant anti-inflammatory effect on an established arthritis. MTX-LIPO treatment was significantly less haematotoxic than free MTX.

Small unilamellar vesicles containing clodronate (SUVc) injected intravenously will deplete splenic macrophages and the degree of histological depletion can be assessed by determining the clearance and uptake of monoclonal antibody coated erythrocytes. Splenic Fc dependent clearance, assessed in decomplemented animals, provides a more sensitive index of the effects of large multilamellar liposome encapsulated clodronate (MLVc) and SUVc than does the clearance of complement coated erythrocytes on macrophage depletion in the spleen. MLVc were more efficient than SUVc in inducing a reduction in the number of red pulp macrophages within the spleen. Receptor specific red cell uptake in the spleen could be used as an alternative to histology when assessing splenic macrophage depletion. Encapsulation of clodronate is crucial to its depleting effect since the free drug in saline does not change splenic macrophage number or function.

Clodronate, encapsulated within small unilamellar vesicles (SUVc) will deplete hepatic macrophages after intravenous injection. Functional studies, using probes to evaluate hepatic Fc and C3b uptake, showed a close correlation between the inhibition of receptor-mediated uptake and the depletion of hepatic macrophages. Twenty milligrams of clodronate encapsulated within SUVc produced > or = 90% inhibition of uptake and clearance of Fc- and C3b-coated erythrocytes and a comparable reduction of hepatic macrophage numbers. Inhibition of macrophage receptor-mediated uptake of these erythrocytes was closely related to the reduction in macrophage numbers. Repopulation of macrophages within the liver took place over 2 weeks. At 1 week after depletion, although repopulation was taking place, receptor-mediated function remained suppressed. In a preliminary experiment, treatment of rats with adjuvant arthritis with 20 mg clodronate encapsulated in SUV suppressed the inflammation and reversed the course of the disease, while treatment with 20 mg free clodronate in saline or 20 mg clodronate in multilamellar vesicles (MLVc) did not.

The effect of a novel liposomal preparation containing a phospholipid conjugate of methotrexate (MTX-LIPO) upon macrophage mediator release was investigated in normal and arthritic rats ex vivo. Peritoneal macrophages isolated from MTX-LIPO-treated arthritic rats and stimulated with lipopolysaccharide produced significantly less tumor necrosis factor (TNF) and prostaglandin (PGE2) than did macrophages isolated from saline-treated controls. In the same experimental system, free methotrexate only inhibited prostaglandin release, but it was more potent than MTX-LIPO in this respect. Additional studies are presently underway to investigate the effect of MTX-LIPO and MTX treatment upon the lipopolysaccharide-induced rise in plasma levels of various proinflammatory mediators in vivo. Haematopoietic toxicity was demonstrated in blood isolated from rats treated with free MTX, and this was as characterized by a significant reduction in reticulocyte count compared with MTX-LIPO and saline-treated rats.

A phospholipid conjugate of methotrexate was synthesized and liposomally formulated in order to determine whether such a formulation could modulate the severity of experimentally induced arthritis in the rat. Lewis rats were immunized with Mycobacterium butyricum and after the onset of joint inflammation were treated intravenously with methotrexate liposomes (MTX-LIPO). This preparation was significantly better in reducing established joint inflammation than comparable doses of the free drug or empty liposomes of identical lipid composition. Haematopoietic toxicity associated with MTX-LIPO was significantly less than seen with comparable doses of the free drug.

We report the clinicopathologic, immunohistochemical, and electron microscopic study of two cases of juxtaglomerular cell tumor of the kidney with a hitherto unreported dominant papillary pattern. Both tumors were associated with high blood pressure that did not respond to medical therapy, but that returned to normal after removal of the kidney. They were well delineated, tan, and had no necrosis. The cores of the papillary structures consisted of polygonal cells found to express renin by immunohistochemistry and to contain renin protogranules by electron microscopy. The papillary fronds were covered by one layer of cuboidal epithelial cells that did not stain for renin and had ultrastructural features reminiscent of the collecting duct epithelium. These tumors must be differentiated from malignant papillary tumors of the kidney, such as papillary clear cell carcinoma, transitional cell carcinoma, and collecting duct carcinoma.

Sucrose feeding over a long period has been reported to induce glomerular basement membrane (GBM) thickening and insulin resistance in normal rats. These effects are attributed to the fructose moiety of the sucrose molecule, to Cu deprivation or both. Consequently, our aim was to evaluate the long-term effects of fructose feeding with normal or high amounts of Cu on body weight, plasma lipids, blood glucose regulation, GBM thickening and insulin binding to adipocytes. Four groups of eight Sprague-Dawley rats were fed for 10 weeks on a diet containing 570 g carbohydrate/kg supplied either as starch (S), dextrose (D), fructose (F) or fructose-starch (1:1, w/w; FS), and an adequate amount of Cu (12 micrograms Cu/g diet). A fifth group was fed on diet F supplemented with 24 micrograms Cu/g diet (FCu). After 10 weeks the epididymal adipose tissue and kidney weights expressed per 100 g body weight (relative weight) were heaviest in the F and FCu groups (P < 0.0001, ANOVA). The GBM thickness was within the normal range in the five groups but significantly higher in group D (1.95 (SE 0.04) nm and lower in group FS (1.79 (SE 0.02) nm when compared with group S (1.85 (SE 0.03) nm; P < 0.05). Insulin binding to adipocytes (expressed per cell) was lowest in the F and FCu groups, intermediate in groups D and FS and highest in group S (P < 0.05). Fasting plasma insulin level was higher in group F than in the FCu and FS groups (P < 0.05), whereas fasting plasma glucose, total cholesterol and triacylglycerol levels remained within the normal range in all groups. We conclude that in normal rats a 10-week fructose-rich diet with an adequate amount of Cu produced deleterious metabolic effects on adipose tissue, insulin binding to adipocytes, and plasma insulin, but not on GBM thickening even though kidney weight was significantly increased. However, a moderate fructose intake mixed with other sugars did not have adverse effects.

Arylamine N-acetyltransferase catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-acetylation is subject to a polymorphism and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate polymorphic substrates in vivo. Previously, slow acetylation has been linked to four distinct polymorphic N-acetyltransferase (pnat) alleles each of which contains one or more point mutations within the coding region of the pnat gene. One new rare slow variant of pnat has been identified by cloning and sequencing the pnat DNA from an individual whose NAT phenotype was determined by in vivo acetylation of the polymorphic substrate sulphamethazine. This allele, designated S1c, differs from the wild type fast allele at nucleotide positions 341 and 803. A second new rare slow allotypic variant, designated S3, has been identified by resistance of the pnat specific DNA to digestion with the restriction enzymes Fok I and Bam HI. A method of genotyping individuals for the arylamine N-acetyltransferase (NAT) polymorphism is presented which correctly predicts the phenotype of greater than 95% (21 of 22) of individuals as measured by the extent of acetylation of sulphamethazine in urine. This refined genotyping method was applied to a clinical population of 48 Caucasians with classical or definite rheumatoid arthritis each receiving daily between 150 and 500 mg of the anti-rheumatic drug, D-penicillamine. There is no difference in the N-acetyltransferase phenotype of the individuals who developed proteinuria and the control group with no adverse effects.

The cardiovascular system is one of those target-organ systems of senescence where the effects of physiological ageing meet the consequences, accumulated with time, of pathological disorders. In man, these two processes are not easily disentangled, and despite the advances achieved in ultrasonic techniques the approach of structural parameters remains difficult. On the other hand, the morphological and functional unicity of the vascular wall in different species is such that observations made in animals are relevant. In rats, the structure-function relationship can be determined by histomorphometric analysis of the myocardium and vascular wall under standardized conditions of treatment. As the animals get older, the cardiac mass, related or not to body-weight, increases while the cardiac efficacy decreases. Hypertrophy of the heart is accompanied by a change in the enzymatic property of myosin. Simultaneously, the walls of the greater arteries become thicker, more rigid and less compliant, hypertrophy of the smooth muscle cells being an essential component of vascular wall thickening. At the same time, the collagen fraction and the amount of collagen-bound calcium increase. The elastic component decreases, at least relatively, and the elastin-collagen ratio clearly diminishes with age. Altogether, these alterations are not different from those observed in human arterial hypertension. They result in a lesser permeability of the tunica media, facilitate the accumulation in the subendothelium of lipidic and/or proteinic compounds originating in plasma and constitute a link between ageing and atheromatous processes.

Clodronate (dichloromethylene bisphosphonate) encapsulated within liposomes and administered intravenously eliminates resident macrophages within the liver and spleen. Macrophage depletion in the rat requires 20 mg of the encapsulated drug, and so far this has only been achieved using large multilamellar vesicles (MLV). Recent studies have shown that small unilamellar vesicles (SUV) when injected intravenously accumulate at inflamed joint sites in both animal models of arthritis and patients with rheumatoid arthritis; multilamellar vesicles were not able to do so. If phagocytic cells, such as macrophages, are responsible for SUV sequestration, then SUV containing clodronate may be targeted to the inflamed joint and may eliminate the macrophage population leading to reduction in the state of inflammation. We have adapted an existing technique to radiolabel clodronate with 99mTechnetium to use as a tracer to determine its encapsulation within liposomes, a technique that has advantages over other current methods. We have achieved a high-encapsulation efficiency of the drug within MLV and produced SUV containing sufficient clodronate to deplete macrophages in rats in a small enough volume to administer it intravenously as a single dose.

A 59 year old woman with selective IgA deficiency associated with oligoarthritis and glomerulonephritis is described. She was seropositive for rheumatoid factor and renal histological examination showed a focal glomerulonephritis. High titre rheumatoid factor and a focal glomerulonephritis were also present in the only other well documented report of selective IgA deficiency and renal disease. Histological examination of the kidney suggested that the glomerulonephritis was mediated by immune complexes.

Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney, while the liver is the main extrarenal site of Epo production. Within these organs, the cells synthesizing Epo were identified by using in situ hybridization in hypoxic animals with an increased Epo mRNA expression. Epo-producing cells in the kidney were peritubular cells, most likely endothelial cells of the cortex and outer medulla. Glomerular and tubular cells were not labeled. In three patients with renal adenocarcinomas associated with polycythemia, in situ hybridization showed a strong labeling of the tumor cells. Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor located in the kidney. This oxygen sensor has been recently shown to be an heme protein. At the Epo gene level, studies to identify cis-acting DNA sequences, and trans-activation factors for inducible kidney and liver Epo expression are being pursued.

The relative contributions of the hemodynamic and morphological (vascular and cardiac) modifications induced by long-term administration of an angiotensin I-converting enzyme inhibitor, quinapril, to the drug's long-lasting preventive effects vis-à-vis genetic hypertension development (GHD) have been investigated in young spontaneously hypertensive rats (SHRs). Two groups of SHRs were given quinapril (10 mg/kg/day) or distilled water from 5 to 20 weeks of age. The drug was then stopped, but observations continued for another 7 weeks. At selected times systemic and regional hemodynamic parameters as well as cardiac and vascular morphological effects were investigated. During the treatment period, quinapril partially opposed GHD and limited the early rise in total peripheral and regional vascular resistances observed in control animals. Quinapril's partial preventive effect vis-à-vis GHD persisted, but faded after treatment withdrawal. From a morphological point of view, quinapril strongly opposed aortic wall hypertrophy as evidenced by significant reductions in media thickness and wall to lumen ratio and by a significant increase in aortic nuclear density. Quinapril also limited vascular fibrosis development. At the cardiac level, quinapril reduced heart weight to body weight ratio and opposed myocardial hypertrophy and cardiac collagen synthesis. All these vascular and cardiac morphological changes were delayed (starting after 9-15 weeks of treatment) as compared to quinapril's hemodynamic effects. Finally, the drug's vascular and cardiac antihypertrophic properties persisted after treatment withdrawal. In conclusion, our data indicate that the early systemic and regional hemodynamic effects of quinapril initiate its antihypertensive action, but the drug-induced delayed and prolonged vascular morphological changes later take over and may be partly responsible for quinapril's residual blood pressure lowering effects after treatment withdrawal.

A 27-year-old female with seropositive rheumatoid arthritis of onset at age 18 years developed progressive aortic valve incompetence requiring urgent aortic valve replacement. Rheumatoid aortic valve disease may be more rapidly progressive than aortic valve disease from other causes and awareness of this by the monitoring physicians may help to avoid the possible complications.

Human atheromatous aorta segments as well as presumably disease-free control aorta were obtained at autopsy. They were incubated with solutions of various purified dicarboxylic porphyrins including hematoporphyrin (HP) and hydroxyethylvinyldeuteroporphyrin (HVD), and with solutions of Photofrin. Selective labelling of the atheroma was shown by macroscopic and microscopic observations of the characteristic porphyrin fluorescence associated with the atheromatous plaques. The time dependence of the uptake, monitored by absorption spectrophotometry or by high performance liquid chromatography, was inferred from the disappearance of the porphyrins in the incubation medium. Significant binding was observed in the absence of albumin or serum proteins. The uptake of HP was less than that of the more hydrophobic compounds HVD or Photofrin when these porphyrins were used alone. The presence of albumin or serum drastically reduces atheroma labelling. Some competition between HP and HVD for binding sites is also seen. The present results do indicate that hydrophobic porphyrins have an intrinsic affinity for atheroma and that they can be taken up through passive processes. Taking into account previous data on animal models (Photochem. Photobiol. (1989), 731-737), it appears however that, in vivo, interactions with proteins and pharmacokinetics will primarily determine plaque labelling.

An experimental in vivo model of aortic aneurysm was established by perfusing an isolated segment of rat abdominal aorta with pancreatic elastase. Ten rats were used in each protocol. Saline-perfused aortas developed no aneurysmal dilations. Elastase-perfused aortas contained aneurysms in the perfused area and a total loss of elastic tissue. Control aortas contained no elastic tissue lesions. There was a quantitative relation between the amount of elastase perfused and aneurysm formation: 1-2 units induced neither macroscopic nor microscopic lesions; 3-6 units induced microscopic elastic tissue damage without macroscopic aneurysm; and more than 6 units produced aneurysmal dilation in all cases. In situ elastase secretion by macrophages was induced by perfusing rat aortas with thioglycollate-activated macrophages or with thioglycollate alone. There was aortitis without true aneurysm and a total loss of elastic tissue in the vicinity of activated macrophages within the aortic media. Perfusion of infra-aneurysmal amount of elastase (1 or 2 units) or thioglycollate plus plasmin (2 units) always induced a large aneurysm, whereas plasmin alone induced neither macroscopic nor microscopic lesions. These morphological results were supported by the significantly elevated elastolytic activity within the aortic wall of animals perfused with thioglycollate plus plasmin 9 days, after perfusion (207.6 +/- 54.8 micrograms elastin-rhodamine lysed/18 hr; control rats, 25.43 +/- 11.13). The results suggest that the presence of elastase within the aortic media leads to aneurysm formation. Activated macrophages within the aortic media may be responsible for elastase secretion and elastic tissue destruction. Plasmin may enhance elastase activity and aggravate the aneurysmal lesion.

In situ hybridization was used to investigate the presence of mRNAs of three members of the serine protease inhibitor (serpin) superfamily, angiotensinogen (AG), alpha 1 protease inhibitor (alpha 1PI), and antithrombin III (ATIII) in normal human liver. The probes were full length 35S radiolabeled complementary DNAs of human AG, alpha 1PI, and ATIII. The three mRNAs were found to be uniformly distributed in all hepatocytes, with no evidence of any special distribution, but the signal was more intense for alpha 1PI than for AG and ATIII. Kupffer cells, biliary epithelial cells, and vascular cells were all negative. The same tissue was studied by peroxidase-antiperoxidase immunohistochemistry using specific antibodies against AG, alpha 1PI, and ATIII. No significant amounts of any of the proteins, alpha 1PI, AG, or ATIII were detected in frozen or fixed sections of normal liver. This study indicates that these proteins are not stored in the normal human hepatocyte, but that their genes are actively expressed and that in situ hybridization is the only technique presently available to detect their presence.

Seventeen surgical biopsy specimens of the axillary or subclavian artery were obtained from patients who had inflammatory, nonatherosclerotic arterial lesions and were studied retrospectively. Initial roentgenologic clinical, and histologic findings were evaluated and compared with final diagnosis. Histological examination suggested Takayasu's disease in 11 patients whereas the roentgenologic and clinical signs led us to suspect Takayasu's disease in only eight instances. Takayasu's disease was confirmed in these eight cases later in the course of the disease. In six patients subclavian artery biopsy specimens showed lesions consistent with Horton's disease in contrast to roentgenologic and clinical signs which suggested Takayasu's disease. In five patients, the final diagnosis was Horton's disease and in one, the diagnosis remained unknown. Of 13 patients who had revascularization procedures, bypasses remained patent in patients followed from nine months to 16 years (mean: 68 months). Histopathologic criteria are more reliable than roentgenologic or clinical signs in the diagnosis of Takayasu's disease. The subclavian artery is frequently involved in Takayasu's disease and is a desirable site for retrieval of diagnostic specimen when a revascularization procedure is entertained.

We report the eleventh illustrated case of primary liposarcoma of the heart in a 28-year-old man. The tumor arose from the mitral valve and the left ventricle and was revealed by a solitary brain metastasis 1 year before. The primary tumor and the metastasis were surgically removed. The cardiac and brain neoplasms were myxoid liposarcoma, as confirmed by histochemical, immunohistochemical, and ultrastructural studies. Although review of the literature points out the poor survival of patients with malignant liposarcoma of the heart, no recurrence or metastasis was observed after a 6-month follow-up.

Clinical cardiac manifestations are rare in the course of acquired immunodeficiency syndrome (AIDS), but cardiac lesions can be found at autopsy in 60% of cases. Myocardium and pericardium are the most frequently involved. Cardiac involvement in opportunistic infections, Kaposi's sarcoma, and non Hodgkin's malignant lymphomas usually reflects systemic dissemination of the disease. Idiopathic myocarditis and hypertrophic cardiomyopathy may also occur and may be related to human immunodeficiency virus. Dysautonomia and drug-induced cardiac lesions have also been reported. Cardiac involvement of acquired immunodeficiency syndrome in children is characterized by possible lesions of conduction tissue.

In this study, colonic biopsy specimens from 87 subjects (37 men and 50 women; mean age 51 +/- 14 years) were investigated by a new method of quantitation morphometric analysis. Subjects were classified in 3 groups: I, control group (25 cases); II, constipation and/or abdominal pain (36 cases); III, diarrhea (26 cases). All biopsy specimens were considered normal by both colonoscopic and microscopic observations. Morphometric analysis was performed with a specialized automated image processor. Complete analysis of 1 biopsy specimen required about 10 minutes. Glandular area showed no difference in the ascending, transverse, and descending colonic sites in the three groups. By contrast, the rectal glandular area was significantly larger than those from the 3 colonic sites in all groups (p less than 0.001). The mean cellular density in the control group was 172.7 +/- 24 nuclei/unit area of lamina propria at all biopsy sites. The cellular densities of groups II and III were significantly increased in the ascending colon as compared with the group I subjects (195.1 +/- 22.8, p less than 0.01 and 198.2 +/- 24.7 p less than 0.001, respectively). The cellular density in group III was significantly increased in the other sites as compared with group I (p less than 0.01). Morphometric analysis does provide a definition of the normal range of the lamina propria cellularity and can identify mild abnormalities in patients in whose both colonoscopy and conventional histologic interpretation have been considered as normal by experienced endoscopists and pathologists. A statistical increase in cellular density in groups of patients with clinical symptoms should be regarded as consistent with the concept of microscopic colitis and detectable by morphometry. Such a method reduces interobserver bias and permits objective comparison of groups.