Tissue plasminogen activator (tPA) activity is a novel and early marker of asymptomatic LEAD in type 2 diabetes

Introduction

Lower extremity arterial disease (LEAD) is often one of the first signs of a generalized atherosclerotic disease in type 1 and type 2 diabetic subjects.

Materials and methods

We studied 143 diabetic subjects at 30-70 years of age, M/F 69/74, 74 with type 1 and 69 with type 2 diabetes, without previously known or suspected lower extremity arterial disease. The relationship between early asymptomatic lower extremity arterial disease and blood levels of HbA1c, lipids and fibrinolysis markers (tPA-activity, tPA mass, PAI-1 activity, tPA-PAI-1 complex) was assessed. In parallel, a group with non-diabetic subjects (n = 80) was studied.

Results

35 (24%) diabetic subjects were classified as having sign(s) of LEAD, defined as having at least one reduced peripheral blood pressure measurement, 28% in type 1 vs 20% in type 2 diabetic subjects (p = NS). In univariate logistic regression analyses age, glycemic level (HbA1c), male gender (only in type 1 diabetic subjects), hypertension and tPA activity (only in type 2 diabetic subjects) were positively associated with LEAD. When markers of fibrinolysis were entered into a multivariate model adjusting for age, hypertension, and HbA1c, only tPA activity remained independently associated with LEAD (p = 0.01) and this was also found in type 2 diabetic subjects (p = 0.05). In type 1 diabetic subjects the increase in odds ratio was non-significant.

Conclusions

Tissue plasminogen activator (tPA) activity may be an independent and early marker for asymptomatic lower extremity arterial disease in diabetic subjects, particularly in type 2 diabetes. Thus an altered fibrinolytic activity could be an early marker of atherosclerosis development in the lower extremities but the cause-effect relationship remains unclear.     

Osteomalacia in a patient with primary intestinal lymphangiectasis (Waldmann's disease)

Primary intestinal lymphangiectasis (PIL), also known as Waldmann's disease, is a rare protein-losing enteropathy characterized by abnormal enlargement of the lymphatic ducts in the bowel wall. The symptoms usually start in early infancy. We report a case of osteomalacia in a 63-year-old patient with delayed-onset of PIL, for which she was on dietary treatment. She presented with a 3-year history of mechanical pain in the back and pelvis. Mild ascites and edema with functional impairment of the lower limbs were noted. The neurological evaluation was normal. Blood tests showed hypocalcemia, hypophosphatemia, alkaline phosphatase elevation, and evidence of intestinal malabsorption. Radiographs of the pelvis disclosed a fracture, Looser's zones in the iliopubic rami and left femoral neck, and a washed-out appearance of the vertebras. Dual-energy X-ray absorptiometry showed bone loss with T-score values of -1.2SD at the lumbar spine and -2.5SD at the femoral necks. A diagnosis of osteomalacia related to vitamin D deficiency was given. Serum 25-OH-vitamin D was 18.2ng/ml (normal, 20-40ng/ml) and serum parathyroid hormone was 620pg/ml (normal, 15-65pg/ml), suggesting secondary hyperparathyroidism. Intramuscular vitamin D was given, together with oral calcium and an adequate diet. At follow-up 8 months later, small improvements were noted in the symptoms and absorptiometry findings.     

Partial deletion of CYP2B6 owing to unequal crossover with CYP2B7

OBJECTIVE: To evaluate the possibility of copy number variation (CNV) of CYP2B6. METHODS: We investigated CNV in 226 HIV-1-infected individuals by quantitative PCR. Identification of a candidate CNV prompted characterization of the size of deletion by assessment of absence of exons, mapping of the recombination site by sequencing, and by southern blot. The functional consequences of CNV were assessed in silico (predicted protein), and in vivo, by evaluation of plasma drug levels of the CYP2B6 substrate efavirenz. RESULTS: Analyses identified one white individual carrying a heterozygous deletion of exons 1-4 of CYP2B6. We identified a approximately 68 kb deletion between CYP2B7 and CYP2B6, and mapped the crossover to a homologous region in intron 4 of both genes. The new hybrid allele, named CYP2B6*29, carries two amino acid substitutions, Q172H and M198T, previously associated with impaired enzyme function. Consistent with the functional prediction, the average of efavirenz area under the curve values of the patient was mean+/-SD, 81.64+/-23.62, versus 47.75+/-19.73 mug h/ml for individuals with an extensive metabolizer phenotype. CONCLUSION: CYP2B6*29 represents a new mechanism of genetic variation at the CYP2B6 locus, underscoring the highly polymorphic nature of this isoenzyme.     

Significance of the detection of Epstein-Barr virus DNA in lymph nodes in patients with Hodgkin's disease.

Epstein-Barr virus (EBV) DNA is frequently identified in benign and malignant lymphoproliferative conditions. As shown by in situ hybridization studies viral DNA is localized within malignant cells as well as benign lymphocytes. Clonal and nonclonal EBV genomes are present in Hodgkin's disease (HD), lymphomas of the immunocompromised host and reactive lymph node hyperplasia. Lytic infection with formation of linear genomes is observed in the same conditions but appears to be infrequent in HD as shown by quantitation of mRNA coding for viral capsid antigen. Expression of the oncogene LMP (latent membrane protein) is seen in Sternberg-Reed (SR) cells and immunoblasts of AIDS-related lymphoma and infectious mononucleosis (IM). In HD, the region of the BNLF1 oncogene coding for the amino terminal and transmembrane domains (associated with oncogenic function) of LMP appears to be homogeneous whereas the region coding for the intracytoplasmic (carboxy terminal) domain of LMP is heterogeneous. Cytological similarities between SR cells and immunoblasts of IM and AIDS-related lymphomas are consistent with the hypothesis that the BNLF1 oncogene is one possible inducer of morphological features of SR cells. Whether chromosomal integration of EBV DNA is an important factor in activation of such a transforming activity remains to be elucidated. EBV DNA positive and negative HD cases with numerous SR cells lack significant mRNA expression of the two recombinase activating genes (RAG-1 and RAG-2). Therefore the SR cells appear to be derived from lymphocytes beyond the pre-B-cell or common thymocyte stage which may or may not subsequently become infected by EBV.     

Atteinte articulaire du pied au cours de la maladie de Behçet

Résumé: But: étudier les atteintes cliniques du pied et de la cheville au cours de la maladie de Beh?et (MB) et rechercher les signes radiologiques de cette atteinte. Patients et méthodes: Cinquante-six malades atteints d'une MB (critères de l'international study group for Beh?et's disease) ont été recrutés par le biais des consultations externes de rhumatologie et de médecine interne. Quatorze femmes et 42 hommes, d'age moyen 41,46 ± 13,35 ans (14 et 83 ans). Ils étaient interrogés par un rhumatologue sur les différentes manifestations de la MB et spécialement sur l'atteinte articulaire. L'examen des pieds a recherché une douleur à la palpation, un gonflement, une synovite, un érythème, une augmentation de la chaleur, une diminution de la mobilité articulaire et/ou des déformations. Des radiographies des pieds (face et 3/4) et des chevilles (face et profil) et des sacro-iliaques ont été demandées à chacun d'eux. Vingt ont effectué ces examens qui ont été analysés par le même radiologue. Résultats: L'ancienneté moyenne de la maladie de Beh?et est de 6,7 ± 5,6 ans (1 à 20 ans). Dix-neuf patients (33,9 %) ont présenté dans leurs antécédents au moins une poussée d'arthrite. Trente-deux (57,1 %) présentent dans leur histoire de maladie des arthralgies, 19 (33,9 %) avaient des douleurs articulaires des pieds. Vingt-deux (39,3 %) patients avaient des arthralgies des chevilles. Une douleur de la cheville et/ou du pied sans arthrite a été notée dans 25 cas (44,6 %): des douleurs plantaires dans dix cas (17,9 %) dont neuf (13,8 %) avaient des talalgies, des douleurs du médiopied dans quatre cas (7,1 %), des tarsométatarsalgies dans six cas (10,7 %) et des métatarsalgies dans 12 cas (21,4 %). Quatre patients présentaient lors de l'examen des signes cliniques inflammatoires du pied. Trois patients présentaient des déformations à type d'hallux valgus isolé, un avait un avant-pied triangulaire et un autre avait un quintus varus isolé. Les radiographies ont montré des lésions radiologiques dans 57,1 % des cas. Une sacro-iliite était constatée chez trois patients. Conclusion: La maladie de Behc?et peut s'accompagner d'une localisation périphérique en particulier celle du pied à l'origine dans certains cas d'une atteinte destructrice.      

Pneumocystis pneumonia in 3 non HIV patients

We report 3 cases of pneumocystis pneumonia (PCP) in 2 female and 1 male patients (mean age=50 years) free of human immunodeficiency virus (HIV) infection. One female patient presented with breast neoplasm the other with Wegener's granulomatosis, the male patient with lymphoma. All patients were taking immunosuppressive treatment at the time of infection. Persistent cough, dyspnea, and severe hypoxemia were the most characteristic clinical signs. All patients presented with lymphopenia (average CD4-cell count=275/mm3), two with hypoalbuminemia, and one with renal failure. In all cases, the microscopic analysis of bronchoalveolar lavage was used to establish the diagnosis. All patients were treated with trimethoprim and sulfamethoxazole and a tapering dose of corticosteroids. Outcome was favorable for 1 patient, 1 was transferred to the intensive care unit for acute respiratory failure, and 1 died.     

Association of serum levels of aggrecan ARGS,NITEGE fragments and radiologic knee osteoarthritis in Tunisian patients

ObjectivesProteolytic degradation of aggrecan is a hallmark of the pathology of osteoarthritis. The aim of this study was to develop enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of specific aggrecan fragments generated by aggrecanases-mediated cleavage. We investigated the relationships between these two aggrecan degradations fragments and urinary CTX-II levels.MethodsThe competitive ELISAs employ a polyclonal antibody raised against the aggrecan fragments containing two neoepitopes NITEGE³⁷³ and ³⁷⁴ARGSVI. We measured serum levels of ARGSV and NITEGE in 125 women with knee osteoarthritis (mean ± SD age of 53.6 ± 7.6 years, mean ± SD disease duration of 3.6 ± 3.8 years), and 57 women age-matched controls.ResultsAggrecan neoepitopes assays showed an intra- and inter-assay imprecision (CV) lower than 20% for both tests and good linearity. Median serum ARGSVI (by 18%; P = 0.002), and NITEGE (36.4%; P < 0.001) levels were significantly decreased in patients with knee osteoarthritis compared with controls. Minimal joint space width was negatively correlated with ARGSVI (r = –0.368, P = 0.04) and NITEGE (r = –0.274, P = 0.038) in knee osteoarthritis patients. Median urinary CTX-II levels were significantly increased by 39.5% (P = 0.001) in knee OA patients compared with controls.ConclusionMarkers of degradation aggrecan were analyzed for the first time in an African osteoarthritis population. These markers can be used to monitor aggrecanase activity in human joint disease. Their combination with CTX-II can improve clinical investigation of patients with osteoarthritis patients.     

Systemic lupus erythematosus in Tunisia. A multicentric study. About 295 cases

PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disease with a great clinical polymorphism. Wide variety of genetic, hormonal, immunological and environmental contributes to release the disease. Our objective was to describe and precise the epidemiological, clinical and immunological profile of this disease in Tunisia. METHOD: It is a retrospective study conducted by the Tunisian society of internal medicine during the period from January 1990 to December 1999. All patients fulfilled at least four of the revised American Rheumatism Association's criteria for SLE. RESULTS: Two hundred and ninety-five SLE have been examined (271 women, 24 men). The most frequent clinical manifestations were: articular 90%, malar rash 62%, photosensitivity 46%, seritis 32% and glomerulonephritis 56%, dominated by WHO class III and IV: 60 cases (renal biopsy was performed in 95 patients). Neurological features were observed in 14.5%. The abnormal laboratory findings were leucocytopenia 45%, lymphopenia 47%, thrombocytopenia 16% and hemolytic anemia in 6.7%. Antinuclear antibodies, anti-ds DNA and anti-Sm were at 92%, 74% and 57%, respectively. Eighty-three percent of patients were treated by steroids, and in 52 cases (18%), we added immunosuppressive drugs. Two hundred and eighteen patients were followed up with a mean follow-up duration of 51 months. Twenty-eight percent were in complete remission and in 60%, the SLE was active. In contrast, death occurred in 29 cases. CONCLUSION: Our study confirmed the clinical polymorphism of SLE, the great similarity with other studies apart the world, the gravity of renal and cardiac features and the infectious complications induced by corticosteroids.