Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases

In an attempt to identify autoantigens of synovium in rheumatoid arthritis (RA), we constructed lambda phage expression cDNA libraries from synovium and screened them by IgG purified from synovial fluids, both of which were derived from RA patients. As a result of this unique combination of the libraries and probes, we cloned follistatin-related protein (FRP) as a novel autoantigen in systemic rheumatic diseases. FRP is a secreted protein containing a similar amino acid sequence to follistatin, an inhibitor of activin. FRP was first cloned as a transforming growth factor-beta1-inducible protein (called TSC-36) from a mouse osteoblastic cell line and was suggested to have some roles in the negative regulation of cellular growth. Immunoblotting analyses detected synovial fluid and serum anti-FRP antibodies of IgG class more frequently in RA than any other systemic rheumatic diseases and controls. Synovial fluid anti-FRP antibodies appeared in 44% of RA (n = 18) and none of osteoarthritis (OA) (n = 15) patients. Serum antibodies were detected in 30% of RA (n = 67), 17% of systemic sclerosis (n = 18), 10% of systemic lupus erythematosus (n = 51) and Sj?gren's syndrome (n = 10), and none of polymyositis/dermatomyositis (n = 13) patients and healthy subjects (n = 30). These antibodies recognized an EC domain, an extracellular Ca2+ binding module. In anti-FRP antibody-positive RA patients, serum C-reactive protein level and erythrocyte sedimentation rate were more elevated than negative patients (P < 0.05 and P < 0.01, respectively). FRP gene expression was higher in RA than OA synovium (P < 0.05). However, there was no difference between these groups in the amount of synovial FRP, suggesting its elevated turnover in RA. As follistatin inhibits activin, FRP might inhibit some growth factor-like molecule. Detection of anti-FRP antibodies, possibly having disease-promoting effects as the blocking antibodies, could be one of the markers for clinical evaluation of systemic rheumatic diseases.     

Arterial disease and thrombosis in the antiphospholipid syndrome: a pathogenic role for endothelin 1

PURPOSE: It has been proposed that inferior vena cava filter placement should be the initial treatment of deep venous thrombosis (DVT) or pulmonary embolus (PE) in patients with coexisting malignant disease. We have chosen instead to selectively place filters only in patients with either a contraindication to anticoagulation therapy or a subsequent complication from anticoagulation therapy. The treatment efficacy and mortality rates in patients with concomitant malignant disease and venous thromboembolism using this approach was determined. METHODS: We retrospectively reviewed all patients at our institution with malignant disease in whom venous thromboembolism developed between August 1991 through August 1996 and identified 166 patients with PE (n = 8), DVT (n = 147), and DVT/PE (n = 11). Of these patients, 138 (83.1%) were initially treated with anticoagulation therapy, and 28 (16.9%) had primary filter placement because of contraindications to anticoagulation therapy (10 for intracranial tumors, 11 for recent or upcoming operations, 6 for recent hemorrhage, and 1 for a malignant bloody pericardial effusion). RESULTS: Thirty-two (23%) of the 138 patients who initially underwent anticoagulation therapy subsequently required a filter for the following reasons: bleeding (n = 15, 10.9%); recurrent thromboembolism (n = 6, 4.3%); heparin-induced thrombocytopenia (n = 1, 0.7%); and perceived high risk for bleeding with continued anticoagulation therapy (n = 11, 8%). Both bleeding and recurrent thromboembolism developed in 1 patient. Sixty patients (36%) received filters. No major technical complications occurred from filter placement. Major recurrent thromboembolic complications developed in 10 patients: DVT (n = 6, 10%), PE (n = 2, 3.3%), inferior vena cava thrombosis and phlegmasia cerulea dolens (n = 1, 1.7%), superior vena cava thrombosis (n = 1, 1.7%). Venous gangrene developed in 1 patient with DVT. The 1-year actuarial survival rates for patients treated with filter and anticoagulation therapy were 35% and 38%, respectively (P = NS). CONCLUSION: In summary, our experience suggests that 64% of patients with malignant disease and venous thromboembolism are effectively treated with anticoagulation alone; 17% require primary filter placement for standard indications, and an additional 19% require subsequent filter placement because of complications (primarily bleeding) or failure of anticoagulation therapy. Although technical complications of filter placement are low, serious life-threatening or limb-threatening thromboembolic complications developed in 17% of patients. Survival was poor in all patients, regardless of treatment. These data support a conservative approach of routine anticoagulation therapy with selective filter placement.     

Efficacy of oral pyronaridine for the treatment of acute uncomplicated falciparum malaria in African children

Pyronaridine is a new antimalarial agent developed in China. In this randomized, unblinded study, the safety, tolerance, and clinical efficacy of pyronaridine (n = 44) were evaluated and compared with those of chloroquine (n = 44), the standard first-line antimalarial drug in most of Africa, in 88 Cameroonian children with acute uncomplicated falciparum malaria. The target sample size was determined to detect a 35% difference in in vivo resistance between the two treatment groups, with 95% power. Clinical and parasitological responses were monitored for 14 days on an outpatient basis. Seven children (3 treated with pyronaridine and 4 treated with chloroquine) were lost to follow-up and were excluded from the analysis. All 41 patients treated with pyronaridine were cured. Treatment failure was observed in 16 (40%) of the 40 children treated with chloroquine. In vitro assays indicated that 23 of 40 clinical isolates obtained from patients treated with pyronaridine were resistant in vitro to chloroquine. Side effects associated with pyronaridine intake were minor and transient. Pyronaridine is safe and well tolerated by symptomatic Cameroonian children, and it is highly efficacious in Africa, where chloroquine resistance is well established.     

Composition and function of peripheral blood stem and progenitor cell harvests from patients with severe active rheumatoid arthritis

High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 microg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 x 10(6)/kg, P = 0.03) and CD34+ cells (2.7 v 5.8 x 10(6)/kg, P = 0.003). However, there were increased proportions of CD14+ cells (P = 0.006) and CD14+ CD15+ cells (the phenotype of previously described 'abnormal' myeloid cells, P = 0.002) in the RA PBSCH which translated into 3.5- and 7-fold increases respectively on a per CD34+ cell basis. There were no differences in T-cell activation status as judged by proportions of CD4+ and CD8+ expressing CD45RA, CD45RO, HLA-DR and CD28 (RA PBSCH, n = 7, donor PBSCH, n = 5, P = 0.2-0.7). Phytohaemagglutinin responses determined fluorocytometrically with induction of CD69 expression were reduced in CD4+ and CD8+ cells following filgrastim administration in 3/3 RA patients tested. Compared with bone marrow as a potential source of CD34+ cells, PBSCH contained 11-fold more T cells (P < 0.0005), 8-fold more B cells (P < 0.0005) and 4-fold more monocytes (P = 0.02). In short-term methylcellulose culture there were no differences in colony counts (CFU-GM, CFU-GEMM, BFU-E) per CD34+ cell from PBSCH from RA patients (n = 11) and healthy donors (n = 10). Long-term culture initiator cells were cultured successfully from cryopreserved PBSCH from RA patients (n = 9). In conclusion, PBSCH from RA patients differed significantly in composition from normal individuals, but in vitro studies support normal stem and progenitor cell function. Changes in T-cell function occur during mobilization in RA patients. This work provides reassurance for the use of PBSCH as haematological rescue and baseline data for clinical trials of graft manipulation strategies in patients with RA.     

Radiologic progression in early rheumatoid arthritis treated with methotrexate

OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.     

Tumor necrosis factor-alpha stimulates human Clara cell secretory protein production by human airway epithelial cells

OBJECTIVE: Low serum levels of mannan binding lectin (MBL) are associated with increased risk of recurrent infections. We determined whether there was an association between serum MBL levels and the course and prognosis of rheumatoid arthritis (RA). METHODS: MBL was analyzed in sera from 99 patients with RA who were included in a longterm prospective study. RESULTS: Compared with controls, a high fraction of patients lacked detectable MBL in serum (11 vs 3%; p = 0.025). Comparing patients with MBL serum levels above and below the median revealed that those with levels below the median were younger at onset of RA (p = 0.043) and had higher erythrocyte sedimentation rate (p = 0.006), joint swelling score (p = 0.019), limitation of joint motion score (p = 0.027), and annual increase in radiographic destruction score (p = 0.053). CONCLUSION: MBL insufficiency may be a contributing pathogenetic factor in RA.     

Long-term follow-up of childhood duodenal ulcers

PURPOSE: This study reports the long-term results in children who have duodenal ulcers diagnosed by endoscopy who were treated with H2-receptor antagonist. METHODS: The medical records of 32 children admitted into The Queen Mary Hospital with endoscopically proven duodenal ulcers between 1975 and 1988 were reviewed to evaluate the long-term outcome of childhood duodenal ulcers after initial treatment with H2-receptor antagonist (H2RA). Follow-up details were updated and patients who had been lost to follow-up were recalled. The age of the 22 boys and 10 girls at the time of diagnosis of the ulcers ranged from 3 to 16 years (mean, 11.8 yrs). The duration of follow-up ranged from 8.5 to 21 years (mean, 11.6 yrs). RESULTS: Their primary presentations included epigastric pain (n = 9, 28.0%); nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal bleeding (GIB, n = 6, 18.7%); unprovoked GIB (n = 12, 37.5%); perforation (n = 4, 12.5%); and pyloric obstruction (n = 1, 3.0%). All 13 patients who had NSAID-induced ulcers (pain and bleeding) responded to H2RA therapy and required no further treatment. All 14 patients who had unprovoked ulcers who presented with pain or bleeding did not respond to H2RA treatment. Ulcer healing was achieved only after eradication of Helicobacter pylori with antibiotics (n = 8) or definitive surgery involving either truncal vagotomy and pyloroplasty (VP, n = 4) or proximal gastric vagotomy (PGV, n = 2). The patient who had gastric outlet obstruction had vagotomy and antrectomy. All four patients who had perforation were initially treated with patch repair, but two had persistent ulceration despite H2RA treatment and required PGV. Complications developed in none of the four patients who had PGV, whereas two of the four patients with VP had problems (diarrhea, n = 1; bezoar obstruction, n = 1). CONCLUSIONS: Unprovoked childhood duodenal ulcer is associated with significant long-term morbidity and requires continued follow-up. The majority of the ulcers are resistant to H2RA treatment alone and ultimately require either eradication of H. pylori or surgery. In the absence of obstruction, PGV may be enough to resolve the ulcer diathesis.     

Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis

OBJECTIVE: To investigate thiopurine enzyme activities for their possible value in predicting the development of azathioprine (AZA)-related toxicity in patients with rheumatoid arthritis (RA). METHODS: Patients with longstanding RA (n = 33) were enrolled in a study of treatment with AZA. Before the initiation of AZA treatment and at months 1 and 6 of treatment, we measured activities of the purine key enzymes hypoxanthine guanine phosphoribosyltransferase, 5'-nucleotidase, purine nucleoside phosphorylase, and thiopurine methyltransferase (TPMT). Controls included patients with early RA (n = 24) and healthy volunteers (n = 42). RESULTS: Fourteen of the 33 patients rapidly developed severe side effects, most frequently gastrointestinal (GI) intolerance. Compared with the other groups, the group with adverse effects had significantly lower TPMT activities (P = 0.004). Seven of 8 patients with reduced ("intermediate") baseline TPMT levels developed toxicity, resulting in a significant relationship (P = 0.005) between toxicity and "intermediate" TPMT activity. Compared with "high" activity, baseline intermediate TPMT activity gave a relative risk of 3.1 (95% confidence interval 1.6-6.2) for the development of severe toxicity with AZA treatment. CONCLUSION: In RA patients, inherited intermediate TPMT activity seems predictive for the development of severe side effects of AZA. Clinicians should consider measuring TPMT prior to treatment initiation to improve the safety of AZA use. We hypothesize that GI intolerance may also be related to a thiopurine metabolic imbalance.     

Two centre evaluation of seven thyrotropin kits using luminescent detection

We compared seven thyrotropin luminescent immunometric assay kits in two centres, by use of panel sera from 438 patients: controls (n = 203) and different groups of subjects: hyperthyroidism (n = 42), hypothyroidism (n = 46), non-thyroidal illness (n = 102), geriatrics (n = 24) and selected patients previously treated for thyroid cancer and maintained on suppressive doses of L-thyroxine (n = 17), anti-thyrotropin antibody (n = 4). We did not observe any significant differences in analytical tests among the seven methods on the Probioqual control sera, Anemia control serum and human serum pools. The linearity of serial dilutions was found with all kits. Some variations were noticed at extreme dilutions. The within-assay precision was acceptable in all cases. The functional sensitivity limits were estimated from 20% compound precision profile: they ranged from 0.011 to 0.030 mU/l. In the clinical study, the seven assay demonstrated high diagnostic performance. Some interference by heterophilic antibodies were observed.     

Long-term (10-year) outcome in patients with unstable angina pectoris treated by coronary balloon angioplasty

OBJECTIVES: We sought to examine completed 10-year survival and event-free survival in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty. BACKGROUND: Patients with unstable angina are at increased risk for recurrent acute coronary events. METHODS: The study included 208 consecutive patients (133 with stable and 75 with unstable angina pectoris) undergoing angioplasty from 1984 to 1986. The balloon crossed the lesion in 185 patients (121 with stable and 64 with unstable angina pectoris). Angioplasty was performed in patients with unstable angina pectoris 12+/-15 days (median 8) after symptom onset. Patients with unstable angina pectoris were classified retrospectively into Braunwald class I (n=3), class II (n=20), class III (n=28), class B (n=52) and class C (n=12). Follow-up data were obtained from hospital charts, telephone interview and official death certificates where applicable. The study had >80% power to detect a clinically significant 20% difference in survival and a 20% difference in event-free survival between the stable and unstable patient groups. RESULTS: Despite similar baseline characteristics, early (40-day) mortality was slightly higher in patients with unstable angina (4.7% [3 of 64 patients] vs. 0.8% [1 of 121 patients], p=NS). Long-term outcome was not different, because survival curves were parallel thereafter (10-year survival was 83% for those with stable and 77% for those with unstable angina, p=NS). Survival free of myocardial infarction or coronary artery bypass graft surgery at 10 years was 53% in patients with stable and 47% in patients with unstable angina (p=NS), and survival free of infarction, bypass surgery or repeat angioplasty was 32% for both groups at 10 years. In patients with Braunwald class III unstable angina, 10-year survival was 80%, as compared with 85% in other patients with unstable angina, due to the early hazard (p=NS). Survival and event-free survival were similar in patients who had had a recent myocardial infarction (Braunwald class C) and in patients with acute electrocardiographic changes. Repeat hospital admissions were not more frequent in patients with unstable angina (3.1+/-3.5 vs. 3.0+/-2.6, p=NS). CONCLUSIONS: Ten-year survival and event-free survival were similar in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty, with no evidence of an increased rate of recurrent cardiovascular events in the unstable group.     

Comparison of results after transanal endoscopic microsurgery and radical resection for T1 carcinoma of the rectum

BACKGROUND: We compared the results of transanal endoscopic microsurgery and radical surgery in patients with T1 carcinomas of the rectum. METHODS: We performed a retrospective study (1985-96) to compare the results obtained in 103 patients with T1 rectal carcinomas (low-risk T1, n = 80; high-risk T1; n = 23) undergoing transanal endoscopic microsurgery and radical surgical therapy. RESULTS: The complication rate in patients undergoing local excision was 3.4% (two of 58); it was 18% (eight of 45) in the group treated with radical surgery. Two of 45 patients (3.8%) died after radical resection; there were no deaths after local excision. With regard to the actuarial 5-year survival rate, no difference was observed in the group with low-risk T1 carcinoma between patients treated with local excision (79%) and those who had radical resection (81%) (p = 0.72). In patients with high-risk T1 carcinoma, lymph node metastases were identified in four of 11 patients undergoing radical resection (36%). Four of 12 patients with high-risk T1 carcinoma treated by local excision developed recurrences, whereas none of the patients undergoing primary radical surgery had a recurrence. CONCLUSIONS: Transanal endoscopic microsurgery for the treatment of low-risk T1 carcinomas is associated with a significantly lower complication rate than radical surgical therapy. There is no difference in 5-year survival between local and radical surgical therapy in patients with low-risk T1 carcinoma.     

Comparison of phenytoin with auranofin and chloroquine in rheumatoid arthritis--a double blind study

OBJECTIVE: To evaluate efficacy of phenytoin in modifying the course of rheumatoid arthritis (RA) by comparing it to gold (auranofin) and chloroquine. METHODS: A double blind, randomized study of 6 months' duration was conducted at the Nizam Institute of Medical Sciences, Hyderabad, India. One hundred and thirty-two patients with active RA (defined by the 1987 ARA criteria) were entered into the study and randomized into 3 groups: phenytoin, chloroquine, or auranofin. RESULTS: Full data were evaluable in 100 patients who satisfactorily completed the protocol (phenytoin, 35; auranofin, 30; and chloroquine, 35). Twenty-four patients were noncompliant and did not take medication or return for evaluation; 8 patients had the drug withdrawn because of side effects before study completion. For each of the 3 drugs all clinical and laboratory variables improved when pre and posttreatment values (p < 0.05 to 0.001) were compared. There was a greater reduction in posttreatment mean morning stiffness in the chloroquine group than in the phenytoin and auranofin groups (p < 0.05). Posttreatment grip strength was also greatest in the chloroquine group. On the other hand, there were statistically significant decreases in IgM levels in both the phenytoin and auranofin groups (p < 0.001), but not with chloroquine. Among the 53 patients with a disease history of 3-6 months, global outcome was best with phenytoin (16/17), compared to chloroquine (12/18) and auranofin (12/18) (p < 0.03). However, there was no such difference in the 47 patients in all 3 groups with a disease history longer than 6 months. Eight patients had side effects (phenytoin, auranofin, 2; chloroquine, 1) requiring withdrawal of the drug. However, the incidence of side effects was not significantly different for the 3 drugs. CONCLUSION: Our data indicate that phenytoin is comparable to auranofin and chloroquine in its efficacy in RA and may be considered an alternative disease modifying agent for RA.     

The concurrence of rheumatoid arthritis and limited systemic sclerosis: clinical and serologic characteristics of an overlap syndrome

OBJECTIVE: The characteristics of 3 patients with longstanding rheumatoid arthritis (RA) and consecutive evolution of limited cutaneous systemic sclerosis (IcSSc) were evaluated and compared with those of patients with IcSSc alone (n = 20) or with RA alone (n = 120). METHODS: Clinical features of the different patient populations were compared. Serologic analyses included tests for antinuclear antibodies (ANA) and ANA subsets, in particular anticentromere antibodies (ACA) and anti-heterogeneous nuclear RNP (hnRNP)-A2/RA33 (anti-A2/RA33). RESULTS: The 3 patients with RA developed IcSSc 11, 29, or 50 years after the onset of RA. Features of IcSSc were Raynaud's phenomenon, sclerodactyly, and telangiactasias in all 3 patients, and esophageal dysmotility in 1 patient. Rheumatoid factor (RF) and anti-A2/ RA33 were each found in 2 patients, and 1 of these patients was seropositive for both RF and anti-A2/RA33. ACA titers were positive in all cases. However, similar to the development of RA prior to IcSSc, the occurrence of autoantibodies typical of RA preceded the occurrence of ACA, at least in 2 of the patients. Using affinity-purified antibodies, cross-reactivities between anti-centromere protein A (CENP-A) and anti-CENP-B antibodies with anti-A2/RA33 antigens were seen in the 2 anti-A2/RA33-positive patients. Such cross-reactivities were not found in IcSSc patients without concomitant RA. Epitope mapping revealed that both autoantibody specificities recognized the known major epitopes: anti-CENP-B reacted with the C-terminal region and anti-A2/RA33 with the second RNA binding domain in the N-terminal region of hnRNP-A2. CONCLUSION: The RA-lcSSc overlap syndrome in these 3 patients with longstanding RA was characterized by an incomplete CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) syndrome. The study demonstrated the presence of autoantibodies typical of both diseases and cross-reactivity of ACA with hnRNP-A2/RA33 in the sera of these patients.     

Molecular epidemiology of malaria in Yaoundé, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum

It has been postulated that chloroquine resistance may be associated with a single point mutation at codon 86 of the Plasmodium falciparum multidrug resistance 1 (pfmdr 1) gene. Using a simple and rapid molecular technique involving polymerase chain reaction and restriction fragment length polymorphism, the frequency of the Asn-to-Tyr mutation associated with chloroquine resistance was established among 129 clinical isolates obtained from indigenous patients in Yaoundé, Cameroon. The results showed that 110 of 129 isolates display a mutant codon. The other clinical isolates had either a pure wild-type Asn-86 codon (n = 12) or mixed Asn/Tyr alleles (n = 7). In vitro drug assays were performed to compare the genotype and phenotype in 102 clinical isolates. Of these isolates, 86 displayed pure Tyr-86 mutant codon; 48 (56%) mutant isolates were chloroquine-resistant (50% inhibitory concentration [IC50] > 100 nM), as expected, but 38 (44%) mutant isolates were chloroquine-sensitive (IC50 < 100 nM). Three chloroquine-resistant isolates and seven chloroquine-sensitive parasites carried a wild-type Asn-86 codon. Mixed alleles were found in six isolates (four chloroquine-sensitive and two chloroquine-resistant isolates). Our results did not confirm previous observations on the possible association between chloroquine resistance phenotype and genotype based on the pfmdr 1 gene.     

Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre

Between 1947 and 1992, 1403 patients with 1432 salivary gland tumours were treated at the Christie Hospital, Manchester. There were 1194 epithelial neoplasms: parotid, 1082 (91 per cent); submandibular, 47 (4 per cent); minor glands, 65 (5 per cent). The commonest histological diagnoses were pleomorphic adenoma (n = 776) and adenolymphoma (n = 159). A total of 244 carcinomas were seen (adenoid cystic carcinoma, n = 75). Treatment was primarily surgical, conservative where possible, and determined by tumour extent and not histology. Adjuvant radiation therapy was used in over half the definitively treated malignancies. The recurrence rate following the treatment of 551 new parotid pleomorphic adenomas was 1.6 per cent at median follow-up 12.5 (range 1-34) years, increasing to 15 per cent in the secondarily referred group (n = 170). For patients with definitively treated primary salivary carcinomas (n = 148), the disease-free survival rate at 5, 10 and 15 years was 58, 47 and 45 per cent respectively. Using multivariate analysis, clinical stage was the most important predictor of survival; the 10-year survival rate for stages I-IV was 96, 70, 47 and 19 per cent respectively.     

Effect of pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary artery disease. Coronary Artery Regression Study (CARS) Group

To evaluate the effect of pravastatin on progression of coronary atherosclerosis in normocholesterolemic patients with coronary artery disease (CAD), 90 patients with CAD and serum cholesterol levels of 160 to 220 mg/dl were randomized into a pravastatin (10 mg/day) group (n = 45) and control group (n = 45) in a 2-year study. The proportions of patients with progression (an increase of > or = 15% in percent stenosis) and regression (a decrease of > or = 15% in percent stenosis) of coronary atherosclerosis were compared between the 2 groups. Of 90 patients, 80 (89%) had a final angiogram: the pravastatin (n = 39) and control group (n = 41). Percent changes in total cholesterol, low-density lipoprotein cholesterol, and apoprotein B levels were significantly greater in the pravastatin group than in the control group (total cholesterol -11 +/- 12% vs 3 +/- 15%, p < 0.01; low-density lipoprotein cholesterol -18 +/- 16% vs 4 +/- 21%, p < 0.01; apoprotein B -5 +/- 20% vs 6 +/- 20%, p < 0.05). The proportion of patients with progression of coronary atherosclerosis was significantly smaller in the pravastatin group than in the control group (21% vs 49%, p < 0.05). The proportion of patients with disease regression did not differ in the 2 groups (3% vs 2%, p = NS). In conclusion, this study indicates that cholesterol-lowering therapy with pravastatin can prevent the progression of coronary atherosclerosis even in normocholesterolemic patients with established CAD.     

Redo aortic grafting after treatment of aortic graft infection

PURPOSE: This study was performed to determine the indications, operative strategy, and hemodynamic benefit of redo aortic grafting procedures after earlier excision of an infected aortic graft. METHODS: Among 164 patients treated for aortic graft infection, 15 later underwent redo aortic grafting procedures an average of 18 months (range, 1 to 59 months) after removal of an infected aortic graft. Redo grafting procedures were performed for leg ischemia (n = 11) or infection (proven, n = 3; suspected, n = 1). The new aortic graft originated either from the distal thoracic aorta (n = 5) or from the juxtarenal aortic stump (n = 10). Follow-up averaged 56 months (range, 7 to 110 months). RESULTS: All patients survived the redo grafting procedure. In the eleven patients who had ischemic symptoms, redo grafting procedures uniformly resulted in symptomatic improvement with an increase in ankle-brachial indexes (0.78 +/- 0.34 vs 0.50 +/- 0.29; p = 0.02). A graft limb occlusion developed in two of these patients (3 and 6 months), but no limbs were amputated. In the four patients who had proven or suspected extraanatomic bypass graft infection, there was one graft limb occlusion (29 months) and one amputation (17 months). Overall, recurrent graft infection occurred in three of 15 patients and may be more frequent in patients who have a proven extraanatomic bypass graft infection (2 of 3 vs 1 of 12; p = 0.08). Infection accounted for two of the three graft limb occlusions and two of the three late deaths. Recurrent infection was not associated with early (< 1 year) regrafting procedures, and culture results did not correlate with the microbiologic features of the primary infection. CONCLUSIONS: Redo aortic grafting procedures can be performed safely and at relatively early intervals (6 to 12 months) after removal of the infected aortic graft. The procedure reliably relieves ischemic symptoms of the hemodynamically inadequate extraanatomic bypass graft. Reinfection remains a risk after redo aortic grafting procedures, particularly when treating established extraanatomic bypass graft infection.     

Antibodies to beta 2-glycoprotein-I: urea resistance, binding specificity, and association with thrombosis

The aim of the present study was to evaluate the urea resistance and binding characteristics of anti-beta 2-glycoprotein I (anti-beta 2GPI) antibodies using standard anticardiolipin (aCL) and anti-beta 2GPI enzyme immunosorbent assays (ELISAs). Sera from patients with antiphospholipid syndrome (APS) (n = 22) and non-APS (n = 24), positive in a standard aCL ELISA, were tested in an anti-beta 2GPI ELISA performed in polystyrene-irradiated ELISA plates. Urea resistance aCL and anti-beta 2GPI ELISAs were performed by measuring the ability of antibodies to recognize antigen in the presence of 2 M urea. The serum dilution after urea treatment (D) expressed as a percentage of the serum dilution without urea treatment (D(o)) corresponding to the same optical density was defined as residual activity (RA = 100 D/D(o)). The higher the RA, the higher the resistance of the antibodies to urea. APS compared to non-APS sera had higher aCL binding (absorbance values ranging between 0.180 and 1.400; median, 0.717 vs 0.120-1.273; median, 0.250, respectively; P < 0.004). Six APS patients' sera had low aCL levels but they expressed RA > or = 30%. Anti-beta 2GPI antibodies were detected in 15 of 22 APS vs 3 of 24 non-APS patients (P < 0.03); RA > or = 30% was detected in 15 of 22 APS vs 1 of 23 non-APS patients (P < 0.004). Using a CL affinity column, antibodies were purified from three APS anti-beta 2GPI negative and three non-APS anti-beta 2GPI-positive patients and tested in a aCL ELISA, using highly purified bovine serum albumin (BSA) as a blocking agent (modified ELISA); reactivity was not detected in two APS and one non-APS sera. On the contrary, the reactivity of the purified antibodies was high when beta 2GPI was incubated with CL in the ELISA plates; thus some anti-beta 2GPI negative sera from APS patients recognized the CL/beta 2GPI complex, rather than CL or beta 2GPI alone. In conclusion, anti-beta 2GPI antibodies are common in the APS patients, but a number of such patients recognize the CL/beta 2GPI complex and not CL or beta 2GPI. Antibodies to either beta 2GPI or the CL/beta 2GPI complex derived from APS sera present a high resistance to urea. Anti-beta 2GPI antibodies of low urea resistance exist in a minority of non-APS patients with autoimmune disease.     

Role of surgery in the treatment of brain metastases in patients with breast cancer

BACKGROUND: Patients whose brain metastases from breast cancer are treated nonsurgically have a median length of survival ranging from 2.5 to 7.5 months, and a median time to recurrence ranging from 2 to 5 months. Patients treated with radiotherapy have a median length of survival ranging from 3 to 4 months. Those treated with chemotherapy have a median length of survival ranging from 5.5 to 7.5 months. METHODS: We conducted a retrospective analysis on 63 patients treated over a 10-year period. Only patients who underwent surgery for nonrecurrent brain metastases were studied. Sixty-one patients (97%) underwent surgery within 2 weeks of diagnosis of the brain metastases. RESULTS: The median length of survival was 16 months (95% confidence interval [CI] 11 to 22 months), and the 5-year survival rate was 17% (CI 9% to 29%). Brain metastases recurred in 27 patients at a median interval of 15 months (CI 12 to 24 months). Eleven patients had local recurrence, 10 had distal recurrence, and seven developed leptomeningeal disease. Significant prognosticators of length of survival were age (p = 0.011), menopause status (p = 0.10), postoperative radiotherapy (p = 0.054), preoperative neurologic status (p = 0.011), and preoperative systemic disease status (p = 0.0003). Systemic disease status had a significant effect on the length of survival but not on the time to recurrence.     

Epidemiologic and actual importance of entero-hemorrhagic E. coli in Northern Bavaria (1996)

OBJECTIVES: To compare peripheral type 1 (T1) and type 2 (T2) T cell activities in rheumatoid arthritis (RA) patients with that found for osteoarthritic (OA) patients and healthy controls and to correlate peripheral T1/T2 cell activity in RA with parameters of the disease. METHODS: Peripheral blood mononuclear cells were isolated from patients with RA (n = 66), OA (n = 19), and healthy controls (n = 15). Primary T cell activity in these mononuclear cells was enhanced by means of anti-CD3/anti-CD28, which mimicks stimulation of T cells by activation of the T cell receptor and a major co-stimulatory signal. Interferon gamma (IFN gamma) production and interleukin 4 (IL4) production in the three groups were quantified as measures of T1 and T2 cell activity, respectively, and compared. Serum tumour necrosis factor alpha (TNF alpha), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and joint destruction assessed radiographically of RA patients were determined as parameters of disease activity and correlated with T1/T2 cell activity. RESULTS: Peripheral T cells from RA patients produced significantly less IFN gamma and more IL4 than T cells from both age and sex matched OA patients and healthy controls. Moreover, in RA patients both a decrease in IFN gamma and an increase in IL4 production correlated with an increase in serum TNF alpha, ESR, CRP, and joint destruction. CONCLUSIONS: These results suggest a role for differential T cell activity in RA. In view of the intra-articular T1 cell predominance the results might be explained by selective T1 cell migration into the joint or peripheral suppression of T1 cell activity.