On the calculation and interpretation of signal intensity in echo-shifted sequences.

Echo-shifted sequences have been shown to be useful in applications where strong T*2-weighting and short repetition times are wanted, such as BOLD-contrast fMRI, MR thermometry, and perfusion studies. However, a full understanding of signal formation with such methods, which is mandatory to optimize sequence parameters for particular applications, has still not been achieved. Here, two methods are proposed to calculate the steady-state signal intensity in coherent TR-periodic and TR-shifted gradient-echo sequences. The integration method, which consists of averaging the steady-state magnetization over all isochromats in a voxel, is shown to be a particularly efficient way of obtaining the analytical expression of the measurable signal. The partition method, based on a physical decomposition of the steady-state magnetization into a sum of contributions from past excitation pulses, reveals that the net transverse magnetization results from a destructive interference between the wanted component and a series of stimulated echoes. The analysis includes off-resonance effects and is illustrated by phantom measurements. Relationships with previous publications on this subject are discussed.     

Development of an in vitro screening model for the biosynthesis of acyl glucuronide metabolites and the assessment of their reactivity toward human serum albumin.

An in vitro screening model was developed to determine the reactivity of acyl glucuronide metabolites from carboxylic drugs. This assay is composed of two phases. The first is a phase of biosynthesis of acyl glucuronides by human liver microsomes (HLM). The second, during which acyl glucuronides are incubated with human serum albumin (HSA), consists of assessing the reactivity of acyl glucuronides toward HSA. Both phases are performed successively in the same experiment. This model was validated using eight carboxylic drugs that were well known for their reactivity, their extent of covalent binding, and their immunological potential. These products were representative of the scale of reactivity. Each compound was incubated with HLM at 400 microM and metabolized into acyl glucuronide to different extents, ranging from 5.6% (tolmetin) to 89.4% (diclofenac). The first-order aglycone appearance rate constant and the extent of covalent binding to proteins were assayed during the incubation of acyl glucuronides formed with HSA for 24 h. Extensive isomerization phenomenon was observed for each acyl glucuronide between the two phases. An excellent correlation was observed (r(2), 0.94) between the extent of drug covalent binding to albumin and the aglycone appearance constant weighted by the percentage of isomerization. This correlation represents an in vitro reactivity scale, which will be helpful in drug discovery support programs to predict the covalent binding potential of new chemical entities. This screening model will also allow the comparison of acyl glucuronide reactivity for related structure compounds.     

Compte-rendu de la première journée de réflexion sur l’endoscopie digestive en France organisée par la SFED — Le 16 janvier 1999

Acta Endoscopica - En préambule, Jean-Marc Canard, organisateur de cette première journée de réflexion sur l’endoscopie digestive, en expose les objectifs. Il s’agit...     

Evolutionary lability of odour-mediated host preference by the malaria vector Anopheles gambiae

Many species of disease‐vector mosquitoes display vertebrate host specificity. Despite considerable progress in recent years in understanding the proximate and ultimate factors related to non‐random host selection at the interspecific level, the basis of this selection remains only partially understood. Anopheles gambiae sensu stricto, the main malaria vector in Africa, is considered a highly anthropophilic mosquito, and host odours have been shown to play a major role in the host‐seeking process of this species. Studies on host preference of An. gambiae have been either conducted in controlled conditions using laboratory reared mosquitoes and worn stockings as host‐related stimuli, or have been done in the field with methods that do not account for internal (e.g. age of sampled mosquitoes) and/or environmental effects. We explored differential behavioural responses to host odours between two populations of the same sibling species, An. gambiae in semi‐field conditions in Burkina Faso. The behavioural responses (i.e. degree of activation and strength of anemotaxis) were investigated using a Y‐olfactometer designed to accommodate whole hosts as a source of odour stimuli. Two strains of An. gambiae (3 to 4‐day‐old female) from laboratory Kisumu strain, and from field‐collected individuals were confronted to combinations of stimuli comprising calf odour, human odour and outdoor air. In dual‐choice tests, field mosquitoes chose human odour over calf odour, outdoor air over calf odour and responded equally to human and outdoor air, while laboratory mosquitoes responded equally to human and calf odour, human odour over outdoor air and calf odour over outdoor air. Overall, no effect of CO₂ exhaled by humans and calves neither on the proportion of activated mosquitoes nor on the relative attractiveness to odour stimuli was found. We report for the first time an intraspecific variation in host‐odour responses. This study clearly suggests that there may be genetic polymorphism underlying host preference and emphasizes that the highly anthropophilic label given to An. gambiae s.s. must be carefully interpreted and refer to populations rather than the whole sibling species.     

WSPM: wavelet-based statistical parametric mapping

Recently, we have introduced an integrated framework that combines wavelet-based processing with statistical testing in the spatial domain. In this paper, we propose two important enhancements of the framework. First, we revisit the underlying paradigm; i.e., that the effect of the wavelet processing can be considered as an adaptive denoising step to "improve" the parameter map, followed by a statistical detection procedure that takes into account the non-linear processing of the data. With an appropriate modification of the framework, we show that it is possible to reduce the spatial bias of the method with respect to the best linear estimate, providing conservative results that are closer to the original data. Second, we propose an extension of our earlier technique that compensates for the lack of shift-invariance of the wavelet transform. We demonstrate experimentally that both enhancements have a positive effect on performance. In particular, we present a reproducibility study for multi-session data that compares WSPM against SPM with different amounts of smoothing. The full approach is available as a toolbox, named WSPM, for the SPM2 software; it takes advantage of multiple options and features of SPM such as the general linear model.     

Modern plasma fractionation

Protein products fractionated from human plasma are an essential class of therapeutics used, often as the only available option, in the prevention, management, and treatment of life-threatening conditions resulting from trauma, congenital deficiencies, immunologic disorders, or infections. Modern plasma product production technology remains largely based on the ethanol fractionation process, but much has evolved in the last few years to improve product purity, to enhance the recovery of immunoglobulin G, and to isolate new plasma proteins, such as alpha1-protease inhibitor, von Willebrand factor, and protein C. Because of the human origin of the starting material and the pooling of 10,000 to 50,000 donations required for industrial processing, the major risk associated to plasma products is the transmission of blood-borne infectious agents. A complete set of measures--and, most particularly, the use of dedicated viral inactivation and removal treatments--has been implemented throughout the production chain of fractionated plasma products over the last 20 years to ensure optimal safety, in particular, and not exclusively, against HIV, hepatitis B virus, and hepatitis C virus. In this review, we summarize the practices of the modern plasma fractionation industry from the collection of the raw plasma material to the industrial manufacture of fractionated products. We describe the quality requirements of plasma for fractionation and the various treatments applied for the inactivation and removal of blood-borne infectious agents and provide examples of methods used for the purification of the various classes of plasma protein therapies. We also highlight aspects of the good manufacturing practices and the regulatory environment that govern the whole chain of production. In a regulated and professional environment, fractionated plasma products manufactured by modern processes are certainly among the lowest-risk therapeutic biological products in use today.     

Effects of knee surgery on cardiac function in soccer players

OBJECTIVE: To evaluate the effects of knee surgery on hematocrit and hemoglobin concentration and on resting cardiac parameters as measured by echocardiography. DESIGN: Ten soccer players who underwent knee surgery were evaluated before (T1) and after (T2) hospitalization within a 7-day interval. RESULTS: After hospitalization, end diastolic volume and stroke volume were significantly reduced (P < 0.05) by 14 and 22%, respectively. Despite a significant increase in resting heart rate (T1: 68 +/- 3.3 beats/ min, T2: 72 +/- 3.1 beats/min, P < 0.05), cardiac output was significantly decreased (T1: 4.89 +/- 0.56 liters/min; 3.95 +/- 0.62 liters/min, P < 0.05). The ejection fraction was 65% at T1 and fell to 58% at T2 (P < 0.05). After hospitalization, significant decreases in hemoglobin concentration and hematocrit were observed, suggesting a fall in blood volume. CONCLUSION: In soccer players, knee surgery leads to resting cardiac deconditioning, which is characterized by a significant reduction in stroke volume.     

Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome.     

Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A)

We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippocampus. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H; c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process.