Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.     

Preoperative radio-chemotherapy in early breast cancer patients: Long-term results of a phase II trial

Purpose

This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS).

Patients and methods

From 2001 to 2003, 59 women were included. CT consisted of four cycles of 5-FU, 500 mg/m²/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m² (d1 and d6). Starting concurrently with the second cycle, RT delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular areas. Breast surgery and lymph node dissection were then performed. Adjuvant treatment consisted of a 16 Gy boost to the tumor bed after BCS, FEC (four cycles of fluorouracil 500 mg/m², cyclophosphamide 500 mg/m², and epirubicin 100 mg/m², d1; d21) for pN1-3 and hormone-therapy for positive hormone receptors BC.

Results

The in-breast pathological complete response rate was 27%. BCS was performed in 41 (69%) pts. Overall and distant-disease free survivals at 5 years were respectively 88% [95% CI 80-98] and 83% [95% CI 74-93] whereas locoregional and local controls were 90% [95% CI 82-97] and 97% [95% CI 92-100]. Late toxicity (CTCAE-V3) was assessed in 51 pts (86%) with a median follow-up of 7 years [5-8]. Four (8%) experienced at least one grade III toxicities (one telangectasia and three fibroses). Cosmetic results, assessed in 35 of the 41 pts (85%) who retained their breasts, were poor in four pts (11%).

Conclusion

Preoperative concurrent administration of RT and CT is an effective regimen. Long-term toxicity is moderate. This association deserves further evaluations in prospective trials.     

Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene

Plants maintain cytosine methylation at CG and non-CG residues to control gene expression and genome stability. In a screen for Arabidopsis mutants that alter methylation and silencing of a densely methylated endogenous reporter gene, we recovered 11 loss-of-function alleles in the CMT3 chromomethylase gene. The cmt3 mutants displayed enhanced expression and reduced methylation of the reporter, particularly at non-CG cytosines. CNG methylation was also reduced at repetitive centromeric sequences. Thus, CMT3 is a key determinant for non-CG methylation. The lack of CMT homologs in animal genomes could account for the observation that in contrast to plants, animals maintain primarily CG methylation.     

Epidural Administration of Neostigmine and Clonidine to Induce Labor Analgesia: Evaluation of Efficacy and Local Anesthetic-sparing Effect

Background: Epidural clonidine produces analgesia without motor impairment, and is associated with a local anesthetic-sparing effect during labor. The authors have recently demonstrated that epidural neostigmine initiates selective labor analgesia devoid of adverse effects. Both drugs possess common analgesic mechanisms mediated through spinal acetylcholine release. This study evaluates their epidural combination in parturients.

Methods: At the beginning of labor, parturients were randomly allocated to one of five groups to receive one of the following after a test dose: 150 [mu]g epidural clonidine, 750 [mu]g neostigmine, or 75 [mu]g clonidine combined with 250, 500, or 750 [mu]g neostigmine. A pain score (visual analog scale, 0-100) was recorded before administration and at regular intervals until request for a supplemental injection. Subsequent analgesia was provided by continuous epidural infusion of ropivacaine.

Results: Parturients did not differ regarding demographic data and initial pain score. Clonidine 150 [mu]g, neostigmine 750 [mu]g, and 75 [mu]g clonidine plus 250 [mu]g neostigmine produced ineffective and short-lasting effects. Clonidine 75 [mu]g plus 500 [mu]g neostigmine and 75 [mu]g clonidine plus 750 [mu]g neostigmine presented comparable durations of 90 +/- 32 and 108 +/- 38 min (mean +/- SD), respectively, and final analgesic efficacies, with 72.2% and 84%, respectively, of the parturients reporting a visual analog scale score of less than 30 out of 100 after 30 min. Ropivacaine use was significantly reduced in all clonidine groups (average, 9.5 mg/h) in comparison with neostigmine alone (17 +/- 3 mg/h). No adverse effects were observed for 75 [mu]g clonidine combined with any dose of neostigmine while maternal sedation (20%) and hypotension (33%) occurred with 150 [mu]g clonidine alone.     

What Can Animal Memory Study Bring to the Assessment of Memory and Cognitive Skills for Intellectual Disability?

Three case studies are presented to investigate the possibility of evaluating memory and cognitive capacities of severe intellectual disability with attention given to the ecological environment. Two 22-year-old male patients and a 27-year-old male patient, all three with severe intellectual disability with no verbal communication skills, were evaluated with a new and original paradigm adapted to study cognition in humans from experimental paradigms. We developed a test based on animal models to complement the “home” scale of the Adolescent and Adult Psychoeducational Profile (AAPEP), an assessment instrument designed for adolescents and adults with severe developmental disabilities. Results show that the new instrument is helpful, not only to staff members who can better understand the poor performances of their patients in daily life activities but also in the elaboration of individual acquisition plans. These preliminary results demonstrate the interest in developing a larger controlled study and in publishing our procedure.     

Enhanced visual processing contributes to matrix reasoning in autism

Recent behavioral investigations have revealed that autistics perform more proficiently on Raven's Standard Progressive Matrices (RSPM) than would be predicted by their Wechsler intelligence scores. A widely‐used test of fluid reasoning and intelligence, the RSPM assays abilities to flexibly infer rules, manage goal hierarchies, and perform high‐level abstractions. The neural substrates for these abilities are known to encompass a large frontoparietal network, with different processing models placing variable emphasis on the specific roles of the prefrontal or posterior regions. We used functional magnetic resonance imaging to explore the neural bases of autistics' RSPM problem solving. Fifteen autistic and eighteen non‐autistic participants, matched on age, sex, manual preference and Wechsler IQ, completed 60 self‐paced randomly‐ordered RSPM items along with a visually similar 60‐item pattern matching comparison task. Accuracy and response times did not differ between groups in the pattern matching task. In the RSPM task, autistics performed with similar accuracy, but with shorter response times, compared to their non‐autistic controls. In both the entire sample and a subsample of participants additionally matched on RSPM performance to control for potential response time confounds, neural activity was similar in both groups for the pattern matching task. However, for the RSPM task, autistics displayed relatively increased task‐related activity in extrastriate areas (BA18), and decreased activity in the lateral prefrontal cortex (BA9) and the medial posterior parietal cortex (BA7). Visual processing mechanisms may therefore play a more prominent role in reasoning in autistics. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Re-exposure to wild-type virus stabilizes measles-specific antibody levels in late convalescent patients.

BACKGROUND: Infection with wild-type (wt) measles virus strains induces high antibody levels believed to provide life-long protection against disease. OBJECTIVES: Humoral immunity was followed up in convalescent measles patients to assess the persistence of specific antibodies after measles disease in individuals without and with documented re-exposure to wt virus. STUDY DESIGN: Paired sera were collected from 43 late convalescents (LC) before re-exposure and 3.7-4.8 years after re-exposure to at least one measles patient (LC+ group). Antibody persistence in this group was compared to paired sera from 43 age- and sex-matched controls without documented exposure to wt virus (LC- group). Paired sera were also obtained from 26 measles patients 1.3-1.7 and 3.8-4.1 years after they had recovered from measles to observe the waning of antibodies in early convalescents (EC group). RESULTS: Antibody levels decreased by 12.1% (CI: 3.2-20.3%, p=0.01) within 6.3 years in the LC- group of late convalescent measles patients. In contrast, in the LC+ group GMT of first and second sera were virtually identical, indicating that exposure to wt virus stabilizes antibody levels even in absence of a detectable secondary immune response. In a subset of late convalescents of group LC+ with a secondary immune response, antibody waning after re-exposure was as high as 15.6%/year (CI: 13.0-17.7%/year), corresponding to a half-life of 4.1 years (CI: 3.5-5.0 years), but antibodies were still higher than before re-exposure. In the EC group GMT decreased by 6.5% (95% CI: -13.3% to +0.1%) during 2.5 years but significance was low (p=0.08). CONCLUSION: The maintenance of antibody levels in convalescent measles patients is at least partially dependant on recurrent exposure to circulating wt virus.