Analyse par suivi de particule unique à la surface de lymphocytes vivants de l'organisation dynamique des récepteurs CD4 et CCR5 impliqués dans l'infection par le VIH

L'infection de lymphocytes T CD4+ par le virus de l'immunodéficience humaine (VIH) débute par l'interaction séquentielle de la protéine d'enveloppe du virus gp120 avec le récepteur primaire CD4 puis avec un corécepteur, CCR5 dans la majorité des cas de primo-infection. La nécessité de cette double interaction suggère que l'efficacité du mécanisme d'entrée du VIH pourrait dépendre de l'organisation membranaire dynamique de ces deux récepteurs. Pour étudier cette organisation à la surface de lymphocytes vivants, nous avons utilisé une technique non invasive de microscopie à haute résolution : le suivi de particule unique (SPT). Dans un premier temps, nous avons validé le choix des quantum dots (QD) pour nos expériences de SPT en réalisant une étude systématique de l'influence de la particule sur la mesure de coefficient de diffusion. Ensuite, notre travail a consisté à suivre et analyser le mouvement des récepteurs CD4 et CCR5 marqués avec des QD, à la surface de lymphocytes vivants. Nous avons montré qu'il existe, pour chaque récepteur, des sous-populations ayant des modes de diffusion distincts : aléatoire, confiné de manière permanente ou de manière transitoire. L'ajout de molécules déstabilisant l'interaction CD4-CCR5 (CD4 soluble, maraviroc) a ensuite révélé que celle-ci est partiellement à l'origine de leur confinement. L'ensemble de nos observations nous permet de poser les bases d'un modèle d'organisation membranaire dynamique de CD4 et CCR5 à la surface de lymphocytes vivants. Ces données constituent un point de départ vers la compréhension du lien présumé entre l'organisation dynamique des récepteurs et les premières étapes du processus d'infection par le VIH.Infection of CD4+ T lymphocytes by the human immunodeficiency virus (HIV) is initiated by the sequential interaction of the viral envelope protein gp120 with the primary receptor CD4 and then a coreceptor, CCR5 in most cases of primo-infection. The necessity of this double interaction suggests that the efficiency of the HIV entry process could depend on the dynamic membrane organization of these two receptors. To study this organization at the surface of living lymphocytes, we used single particle tracking (SPT), a high resolution and non-invasive microscopy approach. Firstly, we validated the choice of Quantum dots (QD) for SPT experiments based on the results of a systematic study that evaluated the influence of the particle on the measured diffusion coefficient. Secondly, we determined and analyzed the movement of CD4 and CCR5 receptors labeled with QD, at the surface of lymphocytes immobilized on glass coverslips. These experiments showed that both receptors exhibit three different diffusion modes: random, permanently or transiently confined diffusion. Addition of molecules that destabilize the CD4-CCR5 interaction (soluble CD4, maraviroc) revealed that it is partially responsible for their confinement. All these observations allow us to establish the basis for a model of the dynamic membrane organization of CD4 and CCR5 at the surface of living lymphocytes. These data represent a starting-point for the understanding of the presumed relationship between the dynamic organization of the receptors and the first steps of the HIV infection process

Primary Lumbo-sacral Spinal Epidural Non-Hodgkin's Lymphoma: A Case Report and Review of Literature

We present a case of 24-year-old male presented with low back pain radiating to the left lower limb, tingling numbness and weakness of 6 months duration. Magnetic resonance imaging scan with contrast reveals an extradural mass at lumbosacral region. Patient was operated with laminectomy and complete excision of the lesion was done. Patient's radicular pain relieved following the surgery and weakness also improved. Histopathology was suggestive of non-Hodgkin's lymphoma. Patient received chemotherapy which was followed by radiotherapy. Primary Non-Hodgkin's lymphoma of the lumbosacral spinal epidural tissue is an uncommon lesion. Lymphoma involves the central nervous system in 5-11% of cases either at presentation of the disease or during its course. The spinal epidural tissue is involved primarily in 0.1-3.3% of cases with spinal cord compression being the commonest presentation. Excision of the lesion followed by chemotherapy and radiotherapy is required to achieve cure

Fractal Analysis of MRI Data at 7 T: How Much Complex Is the Cerebral Cortex?

The human brain is a highly complex structure, which can be only partially described by conventional metrics derived from magnetic resonance imaging (MRI), such as volume, cortical thickness, and gyrification index. In the last years, the fractal dimension (FD) - a useful quantitative index of fractal geometry - has proven to well express the morphological complexity of the cerebral cortex. However, this complexity is likely higher than that we can observe using MRI scanners with 1.5 T or 3 T field strength. Ultrahigh-field MRI (UHF-MRI) improves imaging of smaller anatomical brain structures by exploring down to a submillimetric spatial resolution with higher signal-to-noise and contrast-to-noise ratios. Accordingly, we hypothesized that UHF-MRI might reveal a higher level of the structural complexity of the cerebral cortex. In this study, using an improved box-counting algorithm, we estimated the FD of the cerebral cortex in six public or private T1-weighted MRI datasets of young healthy subjects (for a total of 87 subjects), acquired at different field strengths (1.5 T, 3 T, and 7 T). Our results showed, for the first time, that MRI-derived FD values of the cerebral cortex imaged at 7 T were significantly higher than those observed at lower field strengths. UHF-MRI provides an anatomical definition not achievable at lower field strengths and can improve unveiling the real structural complexity of the human brain

The "Peeking" Effect in Supervised Feature Selection on Diffusion Tensor Imaging Data

We read with great interest the article by Haller et al[1][1] in the February 2013 issue of the American Journal of Neuroradiology . The authors used whole-brain diffusion tensor imaging–derived fractional anisotropy (FA) data, skeletonized through use of the standard tract-based spatia

Central Precocious Puberty in a Child With Metachromatic Leukodystrophy

Metachromatic leucodystrophy (MLD) is a rare inherited lysosomal disorder caused by reduced activity of the enzyme arylsulfatase A with accumulation of sulfatides in the nervous system. We report a female child affected by MLD who developed central precocious puberty (CPP). This association has not been described so far. The proposita, after normal growth and psychomotor development, at age of 30 months presented with a rapidly progressive gait disturbance with frequent falls and with loss of acquired language skills. Magnetic resonance imaging showed leukoencephalopathy. Biochemical blood essays showed a 91% reduction in the arylsulfatase A activity and genetic analysis revealed compound heterozygous mutations of the Arylsulfatase A gene, enabling diagnosis of MLD. Subsequently, the patient had further rapid deterioration of motor and cognitive functions and developed drug-resistant epilepsy. At 4 years and 7 months of age bilateral thelarche occurred. Magnetic resonance imaging showed a small pituitary gland, extensive signal changes of the brain white matter, increased choline, decreased N-acetyl-aspartate and presence of lactate on 1HMR spectroscopy. Pelvic ultrasound demonstrated a slightly augmented uterine longitudinal diameter (42 mm). The gonadotropin-releasing hormone stimulation test revealed a pubertal LH peak of 12.9 UI/l. A diagnosis of CPP was made and treatment with gonadotropin-releasing hormone agonists was initiated, with good response. In conclusion, a CPP may occur in MLD as in other metabolic diseases with white matter involvement. We hypothesize that brain accumulation of sulfatides could have interfered with the complex network regulating with the hypothalamic-pituitary axis and thus triggering CPP in our patient

Efficacy of MRI data harmonization in the age of machine learning. A multicenter study across 36 datasets

Pooling publicly-available MRI data from multiple sites allows to assemble extensive groups of subjects, increase statistical power, and promote data reuse with machine learning techniques. The harmonization of multicenter data is necessary to reduce the confounding effect associated with non-biological sources of variability in the data. However, when applied to the entire dataset before machine learning, the harmonization leads to data leakage, because information outside the training set may affect model building, and potentially falsely overestimate performance. We propose a 1) measurement of the efficacy of data harmonization; 2) harmonizer transformer, i.e., an implementation of the ComBat harmonization allowing its encapsulation among the preprocessing steps of a machine learning pipeline, avoiding data leakage. We tested these tools using brain T1-weighted MRI data from 1740 healthy subjects acquired at 36 sites. After harmonization, the site effect was removed or reduced, and we measured the data leakage effect in predicting individual age from MRI data, highlighting that introducing the harmonizer transformer into a machine learning pipeline allows for avoiding data leakage