Peptide profiling by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry of the Lasiodora parahybana tarantula venom gland.

In order to establish a venom fingerprint and a peptide profile of the Lasiodora parahybana tarantula venom gland, we used conventional methods such as reversed phase liquid chromatography coupled to an electrospray-ionisation hybrid quadrupole time of flight mass spectrometer (LC/ESI-QqTOFMS), matrix-assisted laser desorption/ionization time-of-flight-MS (MALDI-TOFMS) and direct study of L. parahybana venom by nanospray-ionization QqTOFMS (nanoESI-QqTOFMS) and a new technology for the direct analysis of fresh tissues using MALDI-TOFMS. The analysis of the crude venom allowed the characterization of specific juvenile and adult biomarkers. In situ MALDI analysis of L. parahybana venom gland sections revealed different peptide expression levels all along the gland and non-processed peptide precursors, demonstrating the power of the method for the dynamic investigation of peptide evolution in the venom gland of spiders.     

Improvement in depressive illness is not associated with altered release of neurophysins over a course of ECT

The hypothesis that the release of vasopressin-associated neurophysin (hNpI) or oxytocin-associated neurophysin (hNpII) is modified by a course of electroconvulsive therapy (ECT) was tested by the measurement of serum neurophysins before and after the first and last ECTs given to 17 unipolar depressed patients. Neither basal nor ECT-induced neurophysin release changed between the first and last ECTs. Data from the present study were combined with data from a previous published study to provide a sample of 29 unipolar depressed patients. In this extended sample, the release of hNpII after the first ECT was significantly correlated with improvement in symptoms of depression over a course of ECT as measured by the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale.     

Blood lactate response to overtraining in male endurance athletes

Many physiological markers vary similarly during training and overtraining. This is the case for the blood lactate concentration ([La⁻]_b), since a right shift of the lactate curve is to be expected in both conditions. We examined the possibility of separating the changes in training from those of overtraining by dividing [La⁻]_b by the rating of perceived exertion ([La⁻]_b/RPE) or by converting [La⁻]_b into a percentage of the peak blood lactate concentration ([La⁻]_b,peak). Ten experienced endurance athletes increased their usual amount of training by 100% within 4 weeks. An incremental test and a time trial were performed before (baseline) and after this period of overtraining, and after 2 weeks of recovery (REC). The [La⁻]_b and RPE were measured during the recovery of each stage of the incremental test. We diagnosed overtraining in seven athletes, using both physiological and psychological criteria. We found a decrease in mean [La⁻]_b,peak from baseline to REC [9.64 (SD 1.17), 8.16 (SD 1.31) and 7.69 (SD 1.84) mmol · l⁻¹, for the three tests, respectively; P < 0.05] and a right shift of the lactate curve. Above 90% of maximal aerobic speed (MAS) there was a decrease of mean [La⁻]_b/RPE from baseline to REC [at 100% of MAS of 105.41 (SD 17.48), 84.61 (SD 12.56) and 81.03 (SD 22.64) arbitrary units, in the three tests, respectively; P < 0.05), but no difference in RPE, its variability accounting for less than 25% of the variability of [La⁻]_b/RPE (r=0.49). Consequently, [La⁻]_b/RPE provides little additional information compared to [La⁻]_b alone. Expressing [La⁻]_b as a %[La⁻]_b,peak resulted in a suppression of the right shift of the lactate curve, suggesting it was primarily the consequence of a decreased production of lactate by the muscle. Since the right shift of the curve induced by optimal training is a result of improved lactate utilization, the main difference between the two conditions is the decrease of [La⁻]_b,peak during overtraining. We propose retaining it as a marker of overtraining for long duration events, and repeating its measurement after a sufficient period of rest to make the distinction with overreaching. Accepted: 26 September 2000     

An international pilot study of an internet‐based platform to facilitate clinical research in epilepsy: The EpiNet project

Purpose: We created an epilepsy patient database that can be accessed via the Internet by neurologists from anywhere in the world. The database was designed to enroll and follow large cohorts of patients with specific epilepsy syndromes, and to facilitate recruitment of patients for investigator‐initiated clinical trials. Methods: The EpiNet database records physician‐derived information regarding seizure type and frequency, epilepsy syndrome, etiology, drug history, and investigations. It can be accessed from any country by approved investigators via a secure, password‐protected Website. All data are encrypted. The database is for both research and clinical purposes. Investigators were invited to register any patient with epilepsy, but were particularly encouraged to register patients when uncertain of the optimal management. Participation required approval from investigators’ ethics committees and institutional review boards, and all patients or their caregiver provided written informed consent. Patients were not enrolled in clinical trials in this pilot study. Key Findings: The international pilot study recruited patients from September 2010 to November 2011. Sixty‐four investigators or research assistants from 25 centers in 13 countries registered 1,050 patients. Patients with a wide range of epilepsy syndromes and etiologies were registered. Patients’ ages ranged from 2 weeks to 90 years. Significance: The Website was successfully used by doctors working in different health systems. The pilot study confirmed that this low‐cost, collaborative approach to research has great potential. Large, multicenter cohort studies will commence in 2012, and randomized clinical trials are being planned. All epileptologists are invited to join this project.     

Iron metabolism imbalance at the time of listing increases overall and infectious mortality after liver transplantation

BACKGROUND Liver transplantation(LT) is the best treatment for patients with liver cancer or end stage cirrhosis, but it is still associated with a significant mortality. Therefore identifying factors associated with mortality could help improve patient management. The impact of iron metabolism, which could be a relevant therapeutic target, yield discrepant results in this setting. Previous studies suggest that increased serum ferritin is associated with higher mortality.Surprisingly iron deficiency which is a well described risk factor in critically ill patients has not been considered.AIM To assess the impact of pre-transplant iron metabolism parameters on posttransplant survival.METHODS From 2001 to 2011, 553 patients who underwent LT with iron metabolism parameters available at LT evaluation were included. Data were prospectively recorded at the time of evaluation and at the time of LT regarding donor and recipient. Serum ferritin(SF) and transferrin saturation(TS) were studied as continuous and categorical variable. Cox regression analysis was used to determine mortality risks factors. Follow-up data were obtained from the local and national database regarding causes of death.RESULTS At the end of a 95-mo median follow-up, 196 patients were dead, 38 of them because of infections. In multivariate analysis, overall mortality was significantly associated with TS 75% [HR: 1.73(1.14; 2.63)], SF 100 μg/L [HR: 1.62(1.12;2.35)], hepatocellular carcinoma [HR: 1.58(1.15; 2.26)], estimated glomerular filtration rate(CKD EPI Cystatin C) [HR: 0.99(0.98; 0.99)], and packed red blood cell transfusion [HR: 1.05(1.03; 1.08)]. Kaplan Meier curves show that patients with low SF( 100 μg/L) or high SF( 400 μg/L) have lower survival rates at 36 mo than patients with normal SF(P = 0.008 and P = 0.016 respectively). Patients with TS higher than 75% had higher mortality at 12 mo(91.4% ± 1.4% vs 84.6% ±3.1%, P = 0.039). TS 75% was significantly associated with infection related death [HR: 3.06(1.13; 8.23)].CONCLUSION Our results show that iron metabolism imbalance(either deficiency or overload)is associated with post-transplant overall and infectious mortality. Impact of iron supplementation or depletion should be assessed in prospective study.     

Efficacité à moyen terme de l’autogreffe de cellules souches hématopoïétiques périphériques sur la polyneuropathie du syndrome POEMS : expérience chez 5 cas

Introduction

POEMS syndrome (polyneuropathy, organomegaly, endocrynopathy, M-protein, and skin changes) is a rare multisystem disease associated with plasma cell dyscrasia. The efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) reported in case series has been mainly based on hematologic criteria and clinical recovery of peripheral neuropathy dysfunctions but has not been specifically evaluated. This retrospective study aimed to analyze the efficacy of auto-PBSCT on disability and electrophysiological patterns in patients with POEMS syndrome.

Methods

Five patients presenting with POEMS syndrome received auto-PBSCT. Disability was evaluated before treatment and at 6 and 12 months using the Overall Neuropathy Limitation Scale (ONLS) and MRC sumscore of 28 muscles. Nerve conduction studies were performed before and one year after treatment, on median, ulnar, fibular and tibial nerves.

Results

Mean age was 60.6 years (49–70). Disease duration between first symptoms and auto-PBSCT was 15.4 months (2–33). Before auto-PBSCT, mean ONLS score was 4.2 (1–10) and mean MRC sumscore 115.8/140 (74–140). At M6, mean ONLS score decreased and mean MRC sumscore increased; both were improved in all patients at M12: mean ONLS score 3 (range 0–8) at M6 and 2.2 (range 0–7) at M12; mean MRC sumscore 118/140 (77–140) at M6 and 122.4/140 (80–140) at M12. Significant recovery in electrophysiological patterns was observed in all patients on ulnar and median nerves: before-after treatment differences were observed for motor conduction velocities (34.41 vs. 45.47 m/s; P < 0.001), distal CMAP amplitudes (5.04 vs. 5.96 mV; P = 0.004), and sensory conduction velocities (43.20 vs. 49.20 m/s; P = 0.001). Distal CMAP amplitude remained low in fibular and tibial nerves (0.41 vs. 0.17 mV).

Conclusions

Clinical and electrophysiological improvement is obvious in POEMS syndrome peripheral neuropathy within one year after treatment with auto-PBSCT, undoubtedly resulting from extensive remyelinisation and axonal regeneration. Further studies are required to examine long-term outcome in patients with POEMS syndrome given auto-PBSCT.     

Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM

Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients (P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.     

Comparative pilot study of repeated large volume paracentesis vs the combination on clonidine-spironolactone in the treatment of cirrhosis-associated refractory ascites

OBJECTIVES: To study the usefulness of the combination of clonidine--spironolactone in refractory ascites. METHODS: Twenty cirrhotic patients with refractory ascites were randomly assigned to receive repeated large volume paracentesis plus intravenous albumin (group 1), or a combination of clonidine (0.075 mg twice daily) and spironolactone (200 to 400 mg daily) (group 2). RESULTS: During the first hospitalisation,, the mean weight loss in group 1 was higher than in group 2 (12.4 +/- 3.2 versus 4.3 +/- 1.1 kg, P < or = 0.01). Mean stay in hospital was shorter in group 2 (20 +/- 1.5 versus 10 +/- 2.8 days; P < or = 0.01). Paracentesis did not induce changes in neuro-hormonal measurements. Oppositely, clonidine induced a decreased sympathetic activity, an increased glomerular filtration rate and a delayed reduction of the renin-aldosterone levels. During the follow-up in group 1, the number of rehospitalisations for ascites was higher than in group 2 (37 versus 3; P < or = 0.01), and the mean time to the first readmission was shorter (10 +/- 2.7 versus 23.7 +/- 5.6 days; P < or = 0.01). The total duration spent in hospital were similar in both groups. CONCLUSION: Paracentesis is more effective for short-term treatment of ascites but clonidine-spironolactone association might provide better long-term control.     

A case of autochthonous Plasmodium vivax malaria, Corsica, August 2006

A case of Plasmodium vivax malaria was diagnosed in Corsica in summer 2006. This is the first case of autochthonous transmission of malaria to be reported in Corsica since 1972. Corsica is a well-known malaria endemic region characterised, for several years now by an anophelism situation without malaria disease, due to the presence of An. labranchiae and An. saccharovi able to transmit P. vivax. The occurring sequence of malaria signs in an imported case on 9 July and in an autochthonous case on 5 August, both in Porto, implies a transmission by local Anopheles. This suspicion is reinforced by the results of entomological investigations. However, from June to September 2006, no other P. vivax malaria case and no other autochthonous case were detected in Corsica. Therefore, it seems that no permanent malaria transmission occurs in this island. Mosquito eradication actions and anti-vectorial measures have been reinforced as well as individual prevention measures against imported diseases while travelling in tropical countries. Obviously, detection of one exceptional autochthonous transmission of one malaria case in Corsica does not justify proposing malaria protection to tourists.     

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase

In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.