Plasmodium falciparum rhoptry protein RSP2 triggers destruction of the erythroid lineage

The destruction of erythrocytes and defects in erythropoiesis are among the most frequently observed causes of morbidity in severe Plasmodium falciparum malaria. The molecular mechanisms involved remain unclear, despite extensive investigation. We show here, for the first time, that tagging with the parasite rhoptry protein ring surface protein 2 (RSP2) is not restricted to the surfaces of normal erythrocytes, as previously reported, but that it extends to erythroid precursor cells in the bone marrow of anemic malaria patients. Monoclonal mouse antibodies and human sera from patients with severe anemia, reacting with RSP2-tagged erythrocytes, induced cell destruction by phagocytosis and complement activation in vitro. Our observations reveal a new parasite mechanism implicated in the destruction of normal erythrocytes and probably dyserythropoiesis in malaria patients. These data suggest that the tagging of host cells with RSP2 may trigger anemia in falciparum malaria.     

A risk-benefit analysis approach to seafood intake to determine optimal consumption

Seafood provides n-3 long-chain PUFA (n-3 LC-PUFA), vitamins and minerals, which are essential to maintain good health. Moreover, seafood is a source of contaminants such as methylmercury, arsenic and persistent organic pollutants that may affect health. The aim of the present study was to determine in what quantities seafood consumption would provide nutritional benefits, while minimising the risks linked to food contaminants. Seafood was grouped into clusters using a hierarchical cluster analysis. Those nutrients and contaminants were selected for which it is known that seafood is a major source. The risk-benefit analysis consisted in using an optimisation model with constraints to calculate optimum seafood cluster consumption levels. The goal was to optimise nutrient intakes as well as to limit contaminant exposure with the condition being to attain recommended nutritional intakes without exceeding tolerable upper intakes for contaminants and nutrients, while taking into account background intakes. An optimum consumption level was calculated for adults that minimises inorganic arsenic exposure and increases vitamin D intake in the general population. This consumption level guarantees that the consumer reaches the recommended intake for n-3 LC-PUFA, Se and I, while remaining below the tolerable upper intakes for methylmercury, Cd, dioxins, polychlorobiphenyls, Zn, Ca and Cu. This consumption level, which is approximately 200 g/week of certain fatty fish species and approximately 50 g/week of lean fish, molluscs and crustaceans, has to be considered in order to determine food consumption recommendations in a public health perspective.     

Pharmacokinetics,hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children

Introduction

The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors.

Methods

Thirty-nine children with a high risk of low cardiac output syndrome were prospectively enrolled. Ep pharmacokinetics, hemodynamic and metabolic effects were analyzed using the non-linear mixed effects modeling software MONOLIX. According to the final model, an Ep dosing simulation was suggested.

Results

Ep dosing infusions ranged from 0.01 to 0.23 μg.kg^-1.min^-1 in children whose weight ranged from 2.5 to 58 kg. A one-compartment open model with linear elimination adequately described the Ep concentration-time courses. Bodyweight (BW) was the main covariate influencing clearance (CL) and endogenous Ep production rate (q0) via an allometric relationship: CL(BWi) = θ_CL x (BWi)^3/4 and q0(BWi) = θ_q0 x (BWi )^3/4. The increase in heart rate (HR) and mean arterial pressure (MAP) as a function of Ep concentration were well described using an Emax model. The effect of age was significant on HR and MAP basal level parameters. Assuming that Ep stimulated the production rate of plasma glucose, the increases in plasma glucose and lactate levels were well described by turnover models without any significant effect of age, BW or exogenous glucose supply.

Conclusions

According to this population analysis, the developmental effects of BW and age explained a part of the pharmacokinetic and pharmacodynamics between-subject variabilities of Ep administration in critically ill children. This approach ultimately leads to a valuable Ep dosing simulation which should help clinicians to determine an appropriate a priori dosing regimen.     

Standardization and comparison of endogenous erythroid colony assays performed with bone marrow or blood progenitors for the diagnosis of polycythemia vera

The reliability of the assay of endogenous erythroid colony (EEC) formation in serum-free, cytokine-free collagen-based media was investigated in a multicentric study including 140 patients with polyglobuly (80 polycythemia vera (PV), 54 secondary erythrocytosis (SE), six idiopathic erythrocytosis (IE)) and 10 healthy donors. In each center, EEC assays were performed in parallel with progenitor cells from bone marrow (BM) and peripheral blood (PB); two commercialized media and 'low' and 'high' cell plating densities were tested. Negativity of EEC assays was considered certain only when sufficient BFU-E growth was obtained in control cultures with cytokines. In the two media, EEC formation was specific - never observed in cultures of healthy donors or SE patients - and comparable. BM EEC assays were positive (presence of eythroid colonies) for 75% ('low' plating) to 100% ('high' plating) of PV patients; PB EEC assays were positive for 83.3% ('low' plating) to 93.7% ('high' plating) of PV patients (differences not significant). Depending on the medium, 86.2-93.7% of patients with a positive BM EEC assay had a positive PB EEC assay. Hence, a standardized collagen-based EEC assay can be performed with either BM or PB progenitors; the EEC assay described here is positive for at least 75% of PV patients when a single EEC assay is performed, and for at least 94% of PV patients when both BM and PB EEC assays are performed.     

X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial

OBJECTIVES: We sought to compare, in a prospective randomized multicenter study, the effect of adjunctive thrombectomy using X-Sizer (eV3, White Bear Lake, Minnesota) before percutaneous coronary intervention (PCI) versus conventional PCI in patients with acute myocardial infarction (AMI) for <12 h and Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1. The primary end point was the magnitude of ST-segment resolution after PCI. BACKGROUND: Despite a high rate of TIMI flow grade 3 achieved by PCI in patients with AMI, myocardial reperfusion remains relatively low. Distal embolization of thrombotic materials may play a major role in this setting. METHODS: We conducted a prospective, randomized, multicenter study in patients with AMI <12 h and initial TIMI flow grade 0 to 1 who were treated with primary PCI. The magnitude of ST-segment resolution 1 h after PCI was the primary end point. RESULTS: A total of 201 patients were included. Treatment groups were comparable by age (61 +/- 13 years), diabetes (22%), previous MI (8%), anterior MI (52%), onset-to-angiogram (258 +/- 173 min), and glycoprotein IIb/IIIa inhibitor use (59%). The magnitude of ST-segment resolution was greater in the X-Sizer group compared with the conventional group (7.5 vs. 4.9 mm, respectively; p = 0.033) as ST-segment resolution >50% (68% vs. 53%; p = 0.037). The occurrence of distal embolization was reduced (2% vs. 10%; p = 0.033) and TIMI flow grade 3 was obtained in 96% vs. 89%, respectively (p = 0.105). Myocardial blush grade 3 was similar (30% vs. 31%; p = NS). Six-month clinical outcome was comparable (death, 6% vs. 4% and major adverse cardiac and cerebral events, 13% vs. 13%, respectively). By multivariate analysis, independent predictors of ST-segment resolution >50% were: younger age, non-anterior MI, use of the X-Sizer, and a short time interval from symptom onset. CONCLUSIONS: Reducing thrombus burden with X-Sizer before stenting leads to better myocardial reperfusion, as illustrated by a reduced risk of distal embolization and better ST-segment resolution.     

Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

OBJECTIVE:

To identify and characterize alterations seen on HRCT scans in nonsmoking females with COPD due to wood smoke exposure.

METHODS:

We evaluated 42 nonsmoking females diagnosed with wood smoke-related COPD and 31 nonsmoking controls with no history of wood smoke exposure or pulmonary disease. The participants completed a questionnaire regarding demographic data, symptoms, and environmental exposure. All of the participants underwent spirometry and HRCT of the chest. The COPD and control groups were adjusted for age (23 patients each).

RESULTS:

Most of the patients in the study group were diagnosed with mild to moderate COPD (83.3%). The most common findings on HRCT scans in the COPD group were bronchial wall thickening, bronchiectasis, mosaic perfusion pattern, parenchymal bands, tree-in-bud pattern, and laminar atelectasis (p < 0.001 vs. the control group for all). The alterations were generally mild and not extensive. There was a positive association between bronchial wall thickening and hour-years of wood smoke exposure. Centrilobular emphysema was uncommon, and its occurrence did not differ between the groups (p = 0.232).

CONCLUSIONS:

Wood smoke exposure causes predominantly bronchial changes, which can be detected by HRCT, even in patients with mild COPD.     

Modelling selective activation of small myelinated nerve fibres using a monopolar point electrode

The aim of this study is to investigate theoretically the possibility for activation of small myelinated nerve fibres without activating larger ones when stimulating a nerve fibre bundle using a monopolar point electrode. Therefore, the sensitivity of excitation and blocking threshold currents of nerve fibres to fibre diameter, electrode-fibre distance and pulse duration has been simulated by a computer model. A simple infinite, homogeneous volume conductor and a cathodal point source were used in combination with a model representing the electrical properties of a myelinated nerve fibre. The results show that selective activation of small myelinated fibres may be possible in a region at some distance from the electrode.     

Prediction of the neurophysiological diagnosis of carpal tunnel syndrome from the demographic and clinical data.

OBJECTIVE: To use demographic and clinical data to identify the clinical pattern that best predicts the diagnosis of carpal tunnel syndrome (CTS), as defined by neurophysiologic studies. METHODS: A diagnostic cross-sectional study in 2535 consecutive patients (3907 upper limbs) older than 12 years old who were referred for nerve conduction studies in the upper limbs between August 2001 and January 2003 in 3 university hospitals and 2 private neurophysiology services in the state of Rio Grande do Sul, Brazil. RESULTS: A neurophysiologic diagnosis of CTS was established in 39.1% of these upper limbs. The presence of paresthesias or pain at least 2 of the first 4 digits in association with one of the following: female gender, symptoms worsening at night or on awakening, an BMI > or =30, thenar atrophy, or other sign (Tinel's, Phalen's, or Reversed Phalen's signs); were the best pattern associated with the diagnosis. CONCLUSIONS: We have found that the clinical picture alone does not seem sufficient, in majority of the population, to correctly predict the diagnosis of CTS, as defined by median nerve neuropathy at the carpal tunnel. We believe that a compressive lesion of the median nerve at the carpal tunnel can be present both in patients with no typical symptoms of CTS (including asymptomatic individuals) and in patients in which neurophysiologic studies are negative. SIGNIFICANCE: Further studies separating patients into these groups will allow us to identify the long-term prognosis as well as the ideal therapeutic approach for each of these clinical situations.     

Intrinsic laryngeal muscle reinnervation with nerve-muscle pedicle.

OBJECTIVE: To test the application of the nerve-muscle pedicle (NMP) technique for selective reinnervation of previously denervated posterior cricoarytenoid (PCA) muscle. METHODS: The left recurrent laryngeal nerve (RLN) was severed in 5 mongrel dogs, and an ansa cervicalis-sternohyoid muscle pedicle was sutured to the left PCA muscle. Three dogs underwent a sham operation. Videolaryngoscopy was performed, and electromyographic data were collected after 1 year on average. Finally, histologic analysis of the NMP was performed. RESULTS: The video records showed the return of mobility of the PCA muscle reinnervated by the NMP. EMG data as to show evoked polyphasic potentials showed also evidence of reinnervation of the PCA muscle. With immunohistochemical reaction (antineurofilament antibody+biotin) we could show neurofilaments and motor endplates in both sides in all 5 animals. CONCLUSIONS: The NMP technique could eliminate the need for arytenoidectomy and laterofixation in patients with unilateral or bilateral vocal fold paralysis. The quality of life and voice may be improved.