B-cell anomalies in systemic lupus erythematosus

Systemic lupus erythematosus is a non-organ-specific autoimmune disease characterized biologically by B lymphocyte hyperactivity and the production of autoantibodies directed against various cellular components, in particular nuclear antigens. Different strains of mice spontaneously develop a lupus-like disease and constitute a guidelight for human SLE. Both polyclonal B cell stimulation and clonal expansion induced by self-antigens participate in B cell hyperactivity observed in human and mouse SLE. B cells are hyperactive to various stimuli, in particular those delivered by T cells through surface molecules or cytokines. The consequences are an increased production of immunoglobulins and the development of autoantibodies thought to induce the major part of tissue lesions. B cells also participate in the pathological process as antigen-presenting and cytokine-secreting cells. An intrinsic defect of B cells is suspected to be responsible for B cell anomalies as illustrated by certain spontaneous murine models of SLE (motheaten mice) and by lupus-like syndromes observed in mice rendered deficient for genes controlling the B-cell receptor (BCR) signaling pathway. Genome wide scan analysis of various lupus strains allowed to identify several loci predisposing to lupus among which certain are associated with B cell hyperactivity suggesting that the intrinsic defect is inherited.     

Assessing pharmacokinetic marker correlates of outcome,with application to antibody prevention efficacy trials

The Antibody Mediated Prevention efficacy trials are the first studies to evaluate whether passive administration of a broadly neutralizing monoclonal antibody can prevent human immunodeficiency virus (HIV) acquisition. The trials randomize 4600 HIV-negative volunteers to receive 10 infusions of the monoclonal antibody VRC01 or placebo. The primary objective compares the incidence of HIV infection between the study groups. The secondary objective assesses whether and how a marker defined as the serum concentration of VRC01 over time associates with the instantaneous rate of HIV infection, using a two-phase sampling design, a pharmacokinetic model for the time-concentration curve, and an estimator of HIV infection times. While a Cox model with a time-dependent covariate constitutes an important approach to this problem, the low interindividual versus intraindividual marker variability limits its power, motivating us to develop two alternative methods that condition on outcome status: (1) an indirect method that checks whether HIV-infected cases have unexpectedly long times from the most recent infusion to the estimated infection date and (2) a direct method that checks whether the marker itself is unexpectedly low at estimated infection dates. In simulations and a pseudo Antibody Mediated Prevention application, we find that method (2) (but not (1)) has greater power than the Cox model. We also find that the quality of the infection time estimator majorly impacts method performance, and thus, incorporating details of an optimized estimator is critical. The methods apply more generally for assessing a time-dependent longitudinal marker as a correlate of risk when the marker trajectory is modeled pharmacokinetically.     

Generation and Characterization of ALX-0171, a Potent Novel Therapeutic Nanobody for the Treatment of Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is an important causative agent of lower respiratory tract infections in infants and elderly individuals. Its fusion (F) protein is critical for virus infection. It is targeted by several investigational antivirals and by palivizumab, a humanized monoclonal antibody used prophylactically in infants considered at high risk of severe RSV disease. ALX-0171 is a trimeric Nanobody that binds the antigenic site II of RSV F protein with subnanomolar affinity. ALX-0171 demonstrated in vitro neutralization superior to that of palivizumab against prototypic RSV subtype A and B strains. Moreover, ALX-0171 completely blocked replication to below the limit of detection for 87% of the viruses tested, whereas palivizumab did so for 18% of the viruses tested at a fixed concentration. Importantly, ALX-0171 was highly effective in reducing both nasal and lung RSV titers when delivered prophylactically or therapeutically directly to the lungs of cotton rats. ALX-0171 represents a potent novel antiviral compound with significant potential to treat RSV-mediated disease.     

A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors

BACKGROUND: In patients with type 2 diabetes mellitus, all therapeutic options should be evaluated for their effect on cardiovascular risk factors, in addition to glycemic control. We conducted a meta-analysis of randomized controlled trials of pioglitazone hydrochloride and rosiglitazone maleate in patients with type 2 diabetes to evaluate their effect on glycemic control, lipids, blood pressure, and weight. METHODS: Randomized controlled trials of patients with type 2 diabetes that compared pioglitazone or rosiglitazone with placebo for 12 weeks were included. Primary analysis was to compare thiazolidinediones with placebo. Secondary analysis was to identify whether treatment with pioglitazone differed from rosiglitazone in any outcomes. We calculated weighted mean differences and 95% confidence intervals. RESULTS: Twenty-three randomized controlled trials were identified. Both thiazolidinediones demonstrated similar hemoglobin A(1c) level decreases of 1.0% to 1.5% and similar increases in body weight of approximately 3.0 kg. Pioglitazone significantly lowered triglyceride level (-40 mg/dL [-0.45 mmol/L]; 95% confidence interval [CI], -53 to -26 mg/dL [-0.60 to -0.29 mmol/L]), increased high-density lipoprotein cholesterol (HDL-C) level (+4.6 mg/dL [+0.12 mmol/L]; 95% CI, 3.6 to 5.5 mg/dL [0.09 to 0.14 mmol/L]), and showed neutral effect on low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels. Rosiglitazone significantly increased HDL-C level (+2.7 mg/dL [+0.07 mmol/L]; 95% CI, 2.0 to 3.4 mg/dL [0.05 to 0.09 mmol/L]), but increased LDL-C level (+15 mg/dL [+0.39 mmol/L]; 95% CI, 13 to 17 mg/dL [0.34 to 0.44 mmol/L]), total cholesterol level (+21 mg/dL [+0.54 mmol/L]; 95% CI, 18 to 25 mg/dL [0.47 to 0.65 mmol/L]), and demonstrated neutral effect on triglyceride level (-1.1 mg/dL [-0.12 mmol/L]; 95% CI, -14 to 12 mg/dL [-0.16 to 0.14 mmol/L]). No data were available on pioglitazone and blood pressure. Rosiglitazone had a neutral effect on systolic (-0.7 mm Hg; 95% CI, -2.6 to 1.1 mm Hg) and diastolic (-0.8 mm Hg; 95% CI, -1.8 to 0.3) blood pressure. CONCLUSIONS: Thiazolidinediones have similar effects on glycemic control and body weight. Pioglitazone produced a more favorable lipid profile. Head-to-head comparative trials as well as longer-term cardiovascular outcome studies are needed to determine whether there are differences in efficacy between the 2 thiazolidinediones.     

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)‐parkinsonism (Brait‐Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)‐parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD‐parkinsonism‐ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor forparkinsonism. A prospective study may elucidate this possibility. © 2010 Movement Disorder Society.     

Effect of Blood Product Transfusion-Induced Tolerance on Incidence of Cardiac Allograft Rejection

Background

Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial.

Objective

To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection.

Patients and Methods

Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation.

Results

Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups.

Conclusions

Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.