Munchausen by proxy syndrome mimicking childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) is a chronic inflammatory multisystem autoimmune disease that requires multiple differential diagnoses. Munchausen by proxy syndrome (MBPS) is a form of child abuse, where a caregiver intentionally creates a medical history and induces or fabricates signs or disease in a patient. To our knowledge, there is no case report of MBPS mimicking cSLE diagnosis. We reported herein a 9-year-old male patient, with a history of multiple hospitalizations due to seizures with altered levels of consciousness. The mother reported malar rash, photosensitivity, alopecia, arthralgia, arterial hypertension, macroscopic hematuria, seizure and positive antinuclear antibodies. In the other service, he was treated with intravenous methylprednisolone, prednisone and mycophenolate mofetil. At 8 years and 8 months, he was admitted to our tertiary center with history of fever and macroscopic hematuria. Laboratory examinations were normal, including negative for antinuclear antibodies, anti-double stranded DNA, anticardiolipin, anti-Ro/SSA, anti-La/SSB, anti-RNP and anti-Sm antibodies. Multiple urine cultures revealed the presence of Enterococcus faecium, Acinetobacter sp., Stenotrophomonas maltophilia and Serratia marcescens, without any association with pyuria. At 8 years and 9 months, he was readmitted at emergency room with history of severe fever, headache, vomiting, photophobia, phonophobia and dizziness. The physical examination showed agitation, confusion, ataxic gait, slurred speech, horizontal nystagmus, painful facial expressions, tachycardia and weight loss. Brain magnetic resonance angiography and cerebrospinal fluid analysis were normal. During hospitalization, he had an acute episode of epistaxis and otalgia with excoriation in the auditory canal. At that moment, the suspicion of MBPS mimicking cSLE was raised and phenytoin intoxication was confirmed (peak phenytoin concentration was 45.4 mcg/mL, therapeutic range 10-20 mcg/mL). The mother and the patient were immediately separated, and she was replaced by another legal guardian. One week later, the neurological and other signs and symptoms were completely resolved. The child was placed under paternal custody with a court order and moved to another state. After that, the mother reported phenytoin use for her child and was referred to psychiatric follow-up. In conclusion, the first case of MBPS mimicking cSLE, resulting in multiple unnecessary examinations and treatments with delayed diagnosis was reported.

Novel, human cell line-derived recombinant factor VIII (human-cl rhFVIII; Nuwiq® ) in adults with severe haemophilia A: efficacy and safety.

INTRODUCTION: Nuwiq® [human cell line-derived recombinant factor VIII (human-cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line. AIM/METHODS: This prospective, open-label, multinational phase III study assessed the efficacy and safety of human-cl rhFVIII in 32 adult previously treated patients (PTPs) with severe haemophilia A during standard prophylaxis for ≥6 months and ≥50 exposure days. Efficacy in treating bleeds and during surgical prophylaxis was also assessed. RESULTS: Prophylactic efficacy, based on mean monthly bleeding rate, was rated as 'excellent' or 'good' in 97% of patients for all bleeds and in 100% of patients for spontaneous bleeds. Mean (SD) annualized bleeding rate was 2.28 (3.73) [median = 0.9] for all bleeds, 1.16 (2.57) [median = 0] for spontaneous bleeds and 1.00 (1.79) [median = 0] for traumatic bleeds. There were no bleeds in 50% of patients and there were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in treating 28 (100%) of 28 bleeds. Overall efficacy was rated as 'excellent' during four surgical procedures (three major, one minor) and 'moderate' during one major surgery. Incremental in vivo recovery (IVR) data were comparable with the one-stage and chromogenic assays. IVR was >2.0% per IU kg-1 for all measurements and stable over 6 months. No patients developed FVIII inhibitors and there were no treatment-related serious or severe adverse events. CONCLUSION: These results in adult PTPs indicate that human-cl rhFVIII is effective for the prevention and treatment of bleeds in adults with severe haemophilia A.

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.

BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry.

OBJECTIVE: The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. DESIGN: Prospective, multi-centre, large-scale, pan-European registry. SETTING: A total of 117 haemophilia centres in 13 European countries. POPULATION: Pregnancy-associated AHA. METHODS: Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. MAIN OUTCOME MEASURES: Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. RESULTS: The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. CONCLUSIONS: Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.

Cohort profile: the German ClinSurv HIV project--a multicentre open clinical cohort study supplementing national HIV surveillance.

BACKGROUND: New forms of HIV/AIDS therapy require new surveillance instruments to meet shifting public health demands. The Clinical Surveillance of HIV Disease (ClinSurv HIV) project was established in 1999 as a collaboration between major HIV treatment centres in Germany and the Robert Koch Institute (RKI). The project contributes to national HIV surveillance and focuses on the changing epidemiology of HIV/AIDS after the introduction of new therapies in 1995. METHODS: ClinSurv HIV is designed as an open multicentre observational cohort study of HIV-infected patients. Anonymized data on diagnoses, treatment and laboratory parameters are collected in a standardized format. Data are currently sampled biannually via 11 centres specializing in HIV diagnosis and care within the legal framework of the German Protection against Infection Act [Infektionsschutzgesetz (IfSG)]. RESULTS: A total of 14874 patients were enrolled in the study by 30 June 2009. Of these, 10221 patients (68.7%) were enrolled after 1 January 1999 and 6006 patients (40.4%) were known to have been diagnosed as positive for HIV before 1999. Evaluation indicators, such as the number of newly enrolled patients per half-year period, loss to follow-up, completeness of data per case, availability of data per possible clinical contact, and internal quality control parameters, show a very stable evolution in the cohort, which although open, can be observed. Comparison with the national HIV surveillance data suggests a high degree of representativeness according to major demographic variables. CONCLUSION: Bearing in mind the obvious strengths and weaknesses discussed, the German ClinSurv HIV cohort provides a broad range of research opportunities in the field of HIV/AIDS both within Germany and in international collaborative research.

Current CONtrolled Transmit And Receive Coil Elements (CONTAR) for Parallel Acquisition and Parallel Excitation Techniques at High-Field MRI.

A novel intrinsically decoupled transmit and receive radio-frequency coil element is presented for applications in parallel imaging and parallel excitation techniques in high-field magnetic resonance imaging. Decoupling is achieved by a twofold strategy: during transmission elements are driven by current sources, while during signal reception resonant elements are switched to a high input impedance preamplifier. To avoid B(0) distortions by magnetic impurities or DC currents a resonant transmission line is used to relocate electronic components from the vicinity of the imaged object. The performance of a four-element array for 3 T magnetic resonance tomograph is analyzed by means of simulation, measurements of electromagnetic fields and bench experiments. The feasibility of parallel acquisition and parallel excitation is demonstrated and compared to that of a conventional power source-driven array of equivalent geometry. Due to their intrinsic decoupling the current-controlled elements are ideal basic building blocks for multi-element transmit and receive arrays of flexible geometry.

[Influence of visual symptoms on subjective quality of vision after LASIK and pIOL implantation]. / Beeinflussung der subjektiven optischen Qualität nach LASIK und pIOL-Implantation durch visuelle Symptome.

OBJECTIVE: The aim of this study was to assess the influence of visual symptoms on subjective quality of vision (SQV) after laser in situ keratomileusis (LASIK) and implantation of an intraocular lens in the phakic eye (pIOL implantation). METHODS: Fifty-four myopic patients were included. Forty patients (67 eyes) had uneventful LASIK; in 14 patients (27 eyes) a pIOL was implanted. In the LASIK group the mean age was 37 ± 7 years (pIOL: 36 ± 8); the mean preoperative spherical equivalent was -5.64 ± 1.10 D (pIOL: -7.17 ± 1.39). One month postoperatively all patients completed a questionnaire that differentiated between right and left eye and between three lighting conditions (photopic, high-mesopic and low-mesopic). The intensity of the symptoms "glare", "haloes", "starbursts", "blurred vision", "ghosting" and the SQV were marked on a visual analogue scale (0-100). The influence of the symptoms on SQV was assessed using a multiple regression model. RESULTS: Under photopic conditions SQV was 22 ± 19 (pIOL: 16 ± 15), under high-mesopic conditions 21 ± 19 (pIOL: 14 ± 13) and under low-mesopic conditions 33 ± 21 (pIOL: 32 ± 19). The coefficients of determination for the three conditions were 0.74 (pIOL: 0.56), 0.68 (pIOL: 0.75) and 0.69 (pIOL: 0.42). After LASIK, the symptoms "glare" and "blurred vision" had the strongest impact on SQV. In the pIOL group, glare, ghosting, haloes and starbursts had a significant influence on SQV. CONCLUSIONS: The present study showed that two-thirds of the variance of SQV could be explained by the symptoms examined in the questionnaire. Blurred vision, ghosting and glare were the symptoms with the most significant influence.

AHEAD. Advate in HaEmophilia A outcome Database.

The clinical picture of haemophilia A patients is often characterised by recurrent bleedings, in particular joint bleeds. Thus far, long-term data on the outcome of haemophilia A patients are scarce as regards the development of target joints, joint replacement, lost days from school or work due to bleedings, and the quality of life, as most previous studies were limited to the aspects of safety and efficacy. The Baxter-initiated AHEAD (Advate in HaEmophilia A outcome Database) study is a multi-centre, prospective, non-interventional observational study of haemophilia A patients. All patients with a residual FVIII activity of £5% who are being treated with ADVATE are eligible. There are no limitations in terms of patient age or treatment regimen. AHEAD is scientifically supported by a renowned interdisciplinary steering board and is intended to yield data on 500 patients in up to 30 haemophilia centres, collected during a period of four years. The large patient population has been chosen in order to ensure a valid database. The objective of the study is to record haemophilia-related arthropathies, which will be defined based on imaging techniques (e. g. MRI, X-ray, ultrasound) and the judgment of the attending physician. In addition, extensive data will be collected on joint replacement surgeries, pseudotumour development, bleeding-related pain, quality of life (age-related questionnaires: Haem-A-QoL, Haemo-QoL, SF10, SF12v2), risk factors (diabetes mellitus, arterial hypertension, nicotine abuse), blood group, gene mutation, physical activity, and on the efficacy and safety of Advate. The patient data will be entered into an electronic CRF system at the centres. Plausibility checks during data entry, regular monitoring visits, and the option of auditing all serve to ensure a high data quality for AHEAD. The first patient was enrolled in the study in early June 2010; recruitment is planned to continue until the end of 2011. The Ethics Committee of the University of Bonn has given its favorable opinion.

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

UNLABELLED: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

IgA-anti-Fab autoantibodies and disease progression in AIDS.

There is increasing evidence that autoimmune phenomena contribute to the pathogenesis of the acquired immunodeficiency syndrome (AIDS). We investigated the relationship between IgA autoantibodies directed against the Fab part of the IgG molecule and disease progression in 87 HIV-infected hemophilia patients. AIDS patients demonstrated a significantly higher serum IgA-anti-Fab activity than HIV-positive (HIV+) patients with AIDS-related complex (ARC) (P < 0.02), HIV+ patients without AIDS/ARC (P < 0.0001), HIV negative (HIV-) patients (P = 0.0001), or healthy controls (P < 0.0001). Moreover, an inverse association was observed between serum IgA-anti-Fab activity and CD4+ cell counts (r = -0.396, P < 10(-6)). This close association was confirmed in longitudinal studies of symptomatic patients. IgA-anti-Fab antibodies are suggested to play an important role in the immunopathogenesis of AIDS, and their determination may be helpful in the monitoring of HIV-infected patients.

Improving CD4+ lymphocyte counts in HIV-infected hemophilia patients. A favorable prognostic indicator?

CD4+ lymphocyte counts of 91 HIV+ hemophilia patients were monitored for a mean of 4 years (range: 15-69 months). CD4+ lymphocytes decreased in 55 but increased in 36 patients over time. The CD4+ cell increases were persistent in 5 patients, whereas they fluctuated in 31. Of the 36 patients with increasing CD4+ counts 3 developed AIDS and 1 LAS. The other 32 patients were clinically asymptomatic (CDC II), but had immunological abnormalities, such as increased serum neopterin (N = 18) and impaired in vitro T cell responses to pooled allogenic stimulator cells (N = 15) or mitogens (N = 18). In contrast, of the 55 patients whose CD4+ cells decreased, 24 developed AIDS and 5 ARC (P less than 0.0005). Only 2 of these 55 patients had normal mitogen stimulation in vitro and normal serum neopterin levels.

Association of immune complexes and plasma viral load with CD4+ cell depletion, CD8+ DR+ and CD16+ cell counts in HIV+ hemophilia patients. Implications for the immunopathogenesis of HIV-induced CD4+ lymphocyte depletion.

OBJECTIVE: There is evidence that HIV induces CD4+ depletion in part by the formation of immune complexes (IC) that attach to CD4+ blood lymphocytes. In the present study we examined the relationship of IC-coated CD4+ blood cells with retroviral replication in HAART-treated patients. PATIENTS AND METHODS: 52 hemophilia patients were studied from 1997 to 1999. Lymphocyte subsets, IgM, IgG and gp120 on CD4+ blood cells, in vitro responses of lymphocytes to mitogens, plasma neopterin and plasma viral load were measured. RESULTS: Patients with detectable viral replication and without ICs on CD4+ blood lymphocytes had a lower viral load (4100 versus 21000 HIV-1 mRNA copies/ml; P = 0.079) and higher CD4+ cell counts (310/microl versus 161/microl; P = 0.035) than patients with ICs on circulating CD4+ lymphocytes. Among patients with < 80 HIV-1 mRNA copies/ml, IC- individuals had slightly higher CD4+ lymphocyte counts than IC+ patients (384/microl versus 316/microl; n.s.). Further evidence for the clinical relevance of the ICs was obtained when 18 patients who had an undetectable viral load at previous investigations were analyzed. Among patients with a stable undetectable viral load, CD4+ counts increased in 6 of 8 IC- but in none of 2 IC+ individuals. In patients whose viral load increased during the observation period, 5 of 6 IC- but none of 2 IC+ individuals showed higher CD4+ cell counts. Impaired virus killing is suggested by lower CD16+ (35/microl versus 107/microl; P = 0.016), higher CD3+ DR+ (178/microl versus 66/microl; P = 0.006), and higher CD8+ DR+ (142/microl versus 34/microl; P = 0.017) cell counts in IC(-) patients compared to IC- patients without detectable viral load. Strong retroviral replication induced strong T cell dysfunctions. Fewer CD3+ 25+ blood lymphocytes (19/microl versus 47/microl; P = 0.006) and a lower in vitro response of T lymphocytes to the mitogens Con A (RR: 0.3 versus 1.2; P=0.023) and CD3 mab (RR: 0.5 versus 2.4; P = 0.012) was observed in IC+ patients with detectable versus undetectable viral load. CONCLUSION: Our data suggest that ICs on circulating CD4+ blood lymphocytes are primarily associated with CD4+ lymphocyte depletion whereas the plasma viral load is primarily associated with decreased T lymphocyte activation, lower CD16+ counts, and higher CD8+ DR+ lymphocytes which might be the effector cells for virus elimination.

Sequential occurrence of IgM, IgM/IgG, and gp120-IgM/IgG complement complexes on CD4+ lymphocytes in relation to CD4+ blood lymphocyte depletion in HIV+ hemophilia patients: results of a 10-year study.

The concept of autoimmune mechanisms playing an integral role in the pathogenesis of HIV disease is rapidly gaining ground. In this study, we determined IgM and IgG antibodies, complement fragments and gp120 on the surface of CD4+ lymphocytes using double-fluorescence flow cytometry. Sequential analysis demonstrated an inverse relationship of autoantibodies and CD4+ lymphocyte counts in the peripheral blood. HIV+ patients without autoantibodies (16/104 = 15%) had the highest CD4+ blood cell counts (324 +/- 264/microliters; mean +/- SD). CD4+ counts were successively lower in patients with complement-fixing IgM (243 +/- 240/microliter), complement-fixing IgG and IgM (139 +/- 138/microliter), or gp120-IgM/IgG complement complexes on the surface of CD4+ cells (38 +/- 45/microliter, P = 0.03). Individual patient profiles show that IgM autoantibodies typically are formed early after HIV infection and appear to deplete CD4+ lymphocytes very slowly, whereas complement-fixing IgG autoantibodies are generated at a later stage and deplete CD4+ lymphocytes more efficiently. The presence of both soluble gp120 and complement-fixing autoantibodies on CD4+ lymphocytes is associated with very low CD4+ cell counts and coincides with progression to terminal disease. Early during HIV infection autoantibody production is rather unstable, but it becomes more stable with disease progression and persists in advanced stages of the disease. These data suggest that autoantibody formation against CD4+ lymphocytes is a pathogenic mechanism for CD4+ cell depletion.

Reduction of viral load and immune complex load on CD4+ lymphocytes as a consequence of highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patients.

BACKGROUND AND OBJECTIVES: Human immunodeficiency virus (HIV)-induced immune complex load on circulating CD4+ blood lymphocytes is associated with dysfunction and depletion of CD4+ lymphocytes and with increased monocyte/macrophage function. It was investigated whether HAART reduces both the viral load in plasma and the number of immune complex-coated CD4+ lymphocytes in the blood, and whether CD4+ counts are associated with viral load and/or immune complex load. MATERIALS AND METHODS: Twelve HIV+ hemophilia patients before and after conversion to HAART (group 1); eight HIV+ hemophilia patients without antiretroviral therapy (group 2). HIV-1 RNA copies in plasma using NASBA/Nuclisens kits; CD4+ lymphocytes coated in-vivo with immune complexes using flowcytometry on whole blood samples; in-vitro responses of immune complex-coated T lymphocytes in cell culture assays. RESULTS: After conversion to HAART there was a significant reduction of viral load, CD4+ gp120+, CD4+ IgM+, and CD4+ IgG+ circulating blood lymphocytes and plasma neopterin, paralleled by a significant increase of CD4+ and CD8+ counts. The percentage of immune complex-coated CD4+ lymphocytes of converted patients was significantly associated with CD4+ counts, in-vitro responses to concanavalin A (Con A), pokeweed mitogen (PWM), phytohaemagglutinin (PHA), anti-CD3 and pooled allogeneic stimulator cells, and with plasma neopterin levels. CONCLUSION: HAART reduces viral load and HIV-induced immune complex load on circulating CD4+ blood lymphocytes. The results of this study can be interpreted to suggest that HAART increases CD4+ lymphocyte counts in part by counteracting HIV-induced autoimmune phenomena.

Association of viral load in plasma samples of HIV-infected hemophilia patients with autoantibodies and gp120-containing immune complexes on CD4+ lymphocytes.

OBJECTIVE: We investigated whether the induction of antilymphocyte autoantibodies and immune complexes is associated with the activity of HIV replication. METHODS: Viral HIV-1 RNA was measured in the plasma samples of 84 HIV+ hemophilia patients and correlated with the IgM, IgG, IgM/IgG and IgM/IgG/gp120 load of circulating CD4+ lymphocytes, CD4+ and CD8+ cell counts, plasma neopterin levels and in vitro T-cell responses to mitogens and pooled allogeneic stimulator cells. RESULTS: Compared to patients with no immune complexes, on circulating CD4+ lymphocytes, viral load was increased in patients with IgM, IgM/IgG or IgM/IgG/gp120 complexes. Sequential analysis of HIV+ patients showed that peaks of retroviral activity were associated with the subsequent formation of CD4+ lymphocyte-reactive IgM and IgG autoantibodies and gp120-containing immune complexes. CONCLUSION: The induction of autoantibodies and immune complexes attached to CD4+ lymphocytes is associated with periods of increased viral activity in HIV-infected patients.

Increased soluble Fas in HIV-infected hemophilia patients with CD4+ and CD8+ cell count increases and viral load and immune complex decreases.

Previous studies interpreted increases of soluble Fas (sFas) in the plasma during disease progression in HIV-infected patients as evidence of increased apoptosis of CD4(+) lymphocytes. We studied whether sFas and sFas ligand (sFasL) plasma levels are associated with CD4(+) and CD8(+) lymphocyte counts, plasma viral load, and IgM, IgG, C3d, and gp120 complexes on circulating CD4(+) blood lymphocytes in long-term surviving HIV-infected hemophilia patients, most of whom were receiving HAART. Twenty-six hemophilia patients who were infected with HIV in the early 1980s were investigated in 1997, 1998, and 1999. HAART was initiated in 1996 and 1997 in most patients. Lymphocyte subpopulations and immune complex-coated CD4(+) lymphocytes in the blood were investigated by flow cytometry, plasma viral load (HIV-1 mRNA copies/ml plasma) was tested with HIV-1 QT Nuclisens kits, sFas (ng/ml) and sFasL (ng/ml) plasma levels were measured with MBL ELISA kits, and the in vitro response of patient lymphocytes was tested in cell cultures. During the period from 1997 to 1999 we observed an increase in sFas plasma levels (p = 0.003) as well as in CD4(+) (p = 0.004) and CD8(+) (p = 0.023) cell counts; a decrease in IgG (p = 0.047), C3d (p = 0.024), and gp120 (p = 0.001)-coated CD4(+) lymphocytes in the blood; and a decrease in the number of impaired mitogen stimulation assays (p = 0.013). sFas was negatively associated with viral burden (r = -0.662, p = 0.0002) as well as with CD4(+)IgM(+) (r = -0.554, p = 0.004), CD4(+)IgG(+) (r = -0.431, p = 0.031), CD4(+)C3d(+) (r = -0.551, p = 0.041), and CD4(+)gp120(+) (r = -0.430, p = 0.041) blood lymphocytes, CD8(+)DR(+) cell counts (r = -0.700, p = 0.016), and impaired in vitro responses of patient lymphocytes to PHA (r = -0.475, p = 0.016). sFasL was negatively associated with total lymphocyte counts (r = -0.433, p = 0.027), as well as with absolute numbers of CD3(+) (r = -0.492, p = 0.011) and CD8(+) (r = -0.432, p = 0.027) cells. We conclude that, contrary to expectations, sFas plasma levels increased in long-term surviving HIV-infected hemophilia patients receiving HAART, concomitant with increases in CD4(+) and CD8(+) cell counts. Increased sFas may reflect the growing pool of T lymphocytes that recovers because of a decreasing viral burden and a decreasing immune complex load of CD4(+) lymphocytes.

Factor V Leiden mutation in postthrombotic and non-postthrombotic venous ulcers.

OBJECTIVE: To determine the prevalence of the factor V Leiden mutation in patients with postthrombotic and non-postthrombotic venous ulcers. DESIGN: Case-control study. SETTING: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. PARTICIPANTS: Seventy-three consecutive outpatients and inpatients with venous ulcers and 45 age- and sex-matched control subjects (matched to the 42 patients with postthrombotic syndrome). MAIN OUTCOME MEASURES: Frequency of postthrombotic and non-postthrombotic findings in patients with venous ulcers. Prevalence of the factor V Leiden mutation in these different subgroups. RESULTS: Postthrombotic syndrome was identified as the cause of 42 (58%; 95% confidence interval [CI], 45%-69%) of 73 venous ulcers, and the remainder were caused by primary valvular insufficiency. In postthrombotic ulcers, the prevalence of the factor V Leiden mutation was 38% (95% CI, 24%-54%) (16/42), which corresponds to an odds ratio of 13.2 (95% CI, 2.8-62.3; P<.001). In non-postthrombotic venous ulcers, the prevalence was 16% (95% CI, 5%-34%) (5/31), which corresponds to an odds ratio of 3.2 (95% CI, 1.0-10.0; P =.07). CONCLUSIONS: The factor V Leiden mutation is highly prevalent in patients with postthrombotic venous ulcers. Even patients with non-postthrombotic venous ulcers show a moderately elevated prevalence of the factor V Leiden mutation. Some of the latter might be misclassified because of near-to-perfect revascularization after asymptomatic deep venous thrombosis. However, as long as the therapeutic consequences of the factor V Leiden mutation are not established, systematic screening cannot be recommended in patients with venous ulcers.

Thyroid peroxidase (TPO) as a tumor marker in the follow-up of differentiated thyroid carcinomas with surgical and ablative radioiodine therapy. An assessment after evaluation.

The clinical significance of serum thyroid peroxidase (TPO) for differentiated thyroid carcinomas(DTA) is estimated differently. In our preliminary studies it was found that TPO presented information extending those that from hTG. For further clarification a prospective follow-up study was performed including 66 female and 14 male total thyroidectomized patients with DTA for the time course of TPO and human thyroglobulin (hTg) in relation to the ablative radioidine therapy (ART). In 34/50 evaluable cases TPO levels showed an approximately analogous time course with hTg. In relation to the extension of residues, some cases presented increasing of TPO and hTG after radioiodine treatment. 6/7 patients suffering from extended postoperative residues with high anti hTg levels but without elevated TPO concentrations showed distinctly elevated TPO values. Therefore, TPO seems to be an indicator for the destruction of normal thyroid cells or thyroid tumor cells. The clinical value of TPO seems to be in the time being limited to DTA due to false negative hTg values. However, it should be possible that TPO can did the evaluation of thyroid specific therapy.

Efficacy of chemical dependency treatment as a function of combat in Vietnam.

Traumatized combat veterans frequently attempt to escape the chronic anxiety, insomnia and nightmares characteristic of post-traumatic stress disorder by self-medicating with alcohol and drugs. The elimination of alcohol and drugs through chemical-dependency treatment, therefore, might be expected to precipitate an exacerbation of stress symptoms and predispose veterans to new cycles of abuse. The relationship between combat and post-treatment substance abuse has not been subjected to empirical study. This paper examines treatment-completion and post-treatment abstinence rates (treatment efficacy) as a function of level of combat when combat veterans are provided trauma-oriented therapy concurrently with treatment for chemical dependency. The experimental results suggest that, under these conditions, treatment efficacy does not vary with level of combat. The absence of combat-level effects is explained in terms of the interactive dynamics of chemical-dependency and post-traumatic stress disorder.