Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option.     

A practice-based survey of familial age-related maculopathy

PURPOSE : We evaluated the efficacy of a practice-based survey of age-related maculopathy (ARM) to identify potential families for molecular genetic studies. Demographic and ophthalmic features of the eligible study population were compared with responders and with individuals who reported a positive family history of ARM. METHODS : Individuals seen within a three-year period in a comprehensive ophthalmic practice were identified through billing codes. Clinical records were reviewed, coded, and merged with questionnaire responses. Patient identifiers were removed prior to analyses. RESULTS : There were no significant differences between the respondents and the eligible cohort with respect to gender, age, or type of macular degeneration. Comparable percentages of younger and older individuals with ARM reported positive family histories. The distribution of atrophic macular degeneration, choroidal neovascular membranes, and milder forms of the disease among the individuals reporting positive family histories corresponded to the distribution of the entire eligible cohort of patients. CONCLUSIONS : This recruitment strategy for ARM families is cost-effective and confirmed a high prevalence of familial ARM. The respondents are representative of the general ARM population. This approach is applicable for other ophthalmic genetic conditions.     

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells

Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.     

Acetylcholine chloride as a potential source of variability in the study of cutaneous vascular function in man

Introduction

Laser-Doppler flowmetry (LDF) coupled with acetylcholine chloride (ACh) iontophoresis is increasingly recognized as a reliable non-invasive method to study the endothelial function. However, ACh-vasodilation measurement appears highly variable possibly due to the ACh pharmacological properties itself. These problems may be partially overcome by using methacholine chloride (MCh), a more stable synthetic agonist of muscarinic receptors, instead of ACh. Therefore, we first studied the correlation between the two drugs and then the effects of (1) spatial variability (inter-site measurements), (2) temporal variability (inter-day measurements), (3) intra-day variability (morning versus evening), and (4) age on the variability of both ACh-vasodilation and MCh-vasodilation.

Methods

The endothelium-dependent vasodilation response to simultaneous iontophoretic applications (4 doses of 10 s at 0.1 mA with 2 min of current-free interval) of ACh (11 mM) or MCh (10 mM) was studied on the forearm of 40 healthy subjects (36 males, median 28 yr, range 21-59 yr). The percent change in perfusion (CVCpeak) from baseline and the area under the curve (CVC_AUC) during iontophoresis were assessed. Inter-site, inter-day and intra-day coefficients of variation (CV) were studied for each drug as well as correlations between drugs and age.

Results

A linear relationship was found between ACh- and MCh-CVCpeak (r² = 0.75, p = 0.01) and between ACh- and MCh-CVC_AUC (r² = 0.55, p = 0.02). MCh inter-site CV for both CVCpeak (12.2%) and CVC_AUC (13.8%) was significantly lower than ACh inter-site CV for CVCpeak (15.5%) and CVC_AUC (15.3%), respectively. MCh inter-day CV for CVCpeak (17.2%) and CVC_AUC (14.6%) was significantly lower than ACh inter-day CV for CVCpeak (19.7%) and ACh CVC_AUC (21.2%). For ACh and MCh, the CVCpeak and CVC_AUC were higher at 16:00 pm than at 11:00 am (p < 0.05 for all). Finally, both ACh- and MCh-CVCpeak exhibited a logarithmic decrease with age (r² = 0.61, p < 0.01 and r² = 0.58, p < 0.01).

Conclusion

Although both drugs exhibited circadian and age variability, MCh exhibited less inter-site and interday variabilities than did ACh for the evaluation of cutaneous endothelium-dependent vasodilation. These findings should be taken into account in studies of cutaneous vascular function by iontophoresis coupled with laser Doppler flowmetry.     

Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency

Barth's syndrome (BTHS) is an X-linked mitochondrial disease that is due to a mutation in the Tafazzin (TAZ) gene. Based on sequence homology, TAZ has been characterized as an acyltransferase involved in the metabolism of cardiolipin (CL), a unique phospholipid almost exclusively located in the mitochondrial inner membrane. Yeast, Drosophila, and zebrafish models have been invaluable in elucidating the role of TAZ in BTHS, but until recently a mammalian model to study the disease has been lacking. Based on in vitro evidence of RNA-mediated TAZ depletion, an inducible short hairpin RNA (shRNA)-mediated TAZ knockdown (TAZKD) mouse model has been developed (TaconicArtemis GmbH, Cologne, Germany), and herein we describe the assessment of this mouse line as a model of BTHS. Upon induction of the TAZ-specific shRNA in vivo, transgenic mouse TAZ mRNA levels were reduced by >89% in cardiac and skeletal muscle. TAZ deficiency led to the absence of tetralineoyl-CL and accumulation of monolyso-CL in cardiac muscle. Furthermore, mitochondrial morphology from cardiac and skeletal muscle was altered. Skeletal muscle mitochondria demonstrated disrupted cristae, and cardiac mitochondria were significantly enlarged and displace neighboring myofibrils. Physiological measurements demonstrated a reduction in isometric contractile strength of the soleus and a reduction in cardiac left ventricular ejection fraction of TAZKD mice compared with control animals. Therefore, the inducible TAZ-deficient model exhibits some of the molecular and clinical characteristics of BTHS patients and may ultimately help to improve our understanding of BTHS-related cardioskeletal myopathy as well as serve as an important tool in developing therapeutic strategies for BTHS.     

Stage I non-seminomatous germ-cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse

There is no consensus about a reproducible prognostic model capable of distinguishing between clinical stage I non-seminomatous germ cell tumour (NSGCT) carrying a high and low risk of relapse. The aim of this study was to assess the prognostic value of histological parameters in patients with stage I NSGCT undergoing surveillance after orchiectomy. We retrospectively evaluated tumour specimens from 88 consecutive stage I NSGCT patients undergoing surveillance in our institution between 1984 and 1996. 24 patients relapsed (27%). Multivariate analysis singled out vessel invasion (VI) (relative risk (RR)=3.8; 95% confidence interval (CI) 1.4-10.4) and the presence of mature teratoma (RR= 0.2; 95% CI 0.1-0.6) as independently correlated with relapse-free survival (RFS). Patients can be classified accordingly into three prognostic groups with a low (27 patients with mature teratoma but without VI), intermediate (34 patients with both VI and mature teratoma or with neither VI or mature teratoma) and a high risk (23 patients with VI, but without mature teratoma) of relapse. Relapse rates in these three groups were 0%, 29% (95% CI: 23-35%) and 61% (95% CI: 55-67%), respectively. This prognostic index, based on two standard pathological parameters, identified a subgroup with a very low risk of relapse that represents approximately one third of stage I patients. Patients who belong to this subgroup should be managed by surveillance only, instead of retroperitoneal lymph node dissection (RPLND) or adjuvant chemotherapy.     

The caudal septum angle of deflection: an objective analysis for caudal septum deviation

ObjectivesThe purposes of the study were to describe an objective technique for the evaluation of caudal septum deviation (CSD) and to evaluate the effectiveness of an open septorhinoplasty technique for treatment of CSD.

Study design

A retrospective review of septorhinoplasty cases involving CSD was performed. For all patients, preoperative basal view photographs were analyzed. All patients underwent an external septorhinoplasty approach for treatment of their CSD. After a minimum of 4 months, postoperative basal view photographs were analyzed.

Results

Seventeen patients had significant CSD and airway obstruction. The mean change in their caudal septum angle of deflection was 22° (P < .05). All patients had subjective improvement in their nasal airway obstruction. There were no complications.

Conclusion

We describe a method to objectively analyze CSDs in septorhinoplasty candidates. An external approach using nasal base reconstruction techniques results in an improvement of CSD and subsequent nasal airway patency.