Mapping complex cell morphology in the grey matter with double diffusion encoding MR: A simulation study.

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter. To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (µA), a promising contrast derived from DDE measurements. The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived µA, for both water and metabolites. Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI.

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.

The γ-parameter of anomalous diffusion quantified in human brain by MRI depends on local magnetic susceptibility differences.

Motivated by previous results obtained in vitro, we investigated the dependence of the anomalous diffusion (AD) MRI technique on local magnetic susceptibility differences (Δχ) driven by magnetic field inhomogeneity in human brains. The AD-imaging contrast investigated here is quantified by the stretched-exponential parameter γ, extracted from diffusion weighted (DW) data collected by varying diffusion gradient strengths. We performed T2* and DW experiments in eight healthy subjects at 3.0T. T2*-weighted images at different TEs=(10,20,35,55)ms and DW-EPI images with fourteen b-values from 0 to 5000s/mm2 were acquired. AD-metrics and Diffusion Tensor Imaging (DTI) parameters were compared and correlated to R2* and to Δχ values taken from literature for the gray (GM) and the white (WM) matter. Pearson's correlation test and Analysis of Variance with Bonferroni post-hoc test were used. Significant strong linear correlations were found between AD γ-metrics and R2* in both GM and WM of the human brain, but not between DTI-metrics and R2*. Depending on Δχ driven magnetic field inhomogeneity, the new contrast provided by AD-γ imaging reflects Δχ due to differences in myelin orientation and iron content within selected regions in the WM and GM, respectively. This feature of the AD-γ imaging due to the fact that γ is quantified by using MRI, may be an alternative strategy to investigate, at high magnetic fields, microstructural changes in myelin, and alterations due to iron accumulation. Possible clinical applications might be in the field of neurodegenerative diseases.

Spatio-temporal anomalous diffusion in heterogeneous media by nuclear magnetic resonance.

In this paper, we describe nuclear magnetic resonance measurements of water diffusion in highly confined and heterogeneous colloidal systems using an anomalous diffusion model. For the first time, temporal and spatial fractional exponents, α and µ, introduced within the framework of continuous time random walk, are simultaneously measured by pulsed gradient spin-echo NMR technique in samples of micro-beads dispersed in aqueous solution. In order to mimic media with low and high level of disorder, mono-dispersed and poly-dispersed samples are used. We find that the exponent α depends on the disorder degree of the system. Conversely, the exponent µ depends on both bead sizes and magnetic susceptibility differences within samples. The new procedure proposed here may be a useful tool to probe porous materials and microstructural features of biological tissue.

Topical clindamycin 1% vs. linoleic acid-rich phosphatidylcholine and nicotinamide 4% in the treatment of acne: a multicentre-randomized trial.

It has been shown that topical linoleic acid rich-phosphatidylcholine seems to be effective in normalization of follicular hyperkeratinization, whereas nicotinamide has an interesting anti-inflammatory effect. However, little is known about their combined effect on acne. A multicentre, double-blind, 12-week randomized vehicle and parallel-active control study was conducted by clinical and biophysical non-invasive measurements to evaluate the efficacy, tolerability and safety of a 4% nicotinamide-phospholipidic (N-PHCL) emulsion vs. 1% topical clindamycin phosphate applied once daily. Four percentage N-PHCL cosmetic treatment resulted slightly superior to topical clindamycin with all the parameters studied for its better compliance and the global clinical improvement.

Analysis of tumour microstructure estimation from conventional diffusion MRI and application to skull-base chordoma.

Skull-base chordoma (SBC) is a rare tumour whose molecular and radiological characteristics are still being investigated. In neuro-oncology microstructural imaging techniques, like diffusion-weighted MRI (DW-MRI), have been widely investigated, with the apparent diffusion coefficient (ADC) being one of the most used DW-MRI parameters due to its ease of acquisition and computation. ADC is a potential biomarker without a clear link to microstructure. The aim of this work was to derive microstructural information from conventional ADC, showing its potential for the characterisation of skull-base chordomas. Sixteen patients affected by SBC, who underwent conventional DW-MRI were retrospectively selected. From mono-exponential fits of DW-MRI, ADC maps were estimated using different sets of b-values. DW-MRI signals were simulated from synthetic substrates , which mimic the cellular packing of a tumour tissue with well-defined microstructural features. Starting from a published method, an error-driven procedure was evaluated to improve the estimates of microstructural parameters obtained through the simulated signals. A quantitative description of the tumour microstructure was then obtained from the DW-MRI images. This allowed successfully differentiating patients according to histologically-verified cell proliferation information.Clinical Relevance - The impact on cancer management derives from the expected improvement of radiation treatment quality tailored to a patient-specific non-invasive description of tumour microstructure.

Prodrug and conjugate drug delivery strategies for improving HIV/AIDS therapy.

Despite the wide variety of highly potent anti-HIV drugs that have been developed and made available in clinical practice over the years, eradication of HIV infection has not been achieved. Currently, HIV infection and AIDS are thought to be chronically treatable. HIV attacks host immune cells namely macrophages and CD4(+)T-cells and sequesters itself into sanctuary and reservoir sites such as the lymphoid tissues, testes, and brain. Initial drug delivery efforts with prodrugs and drug conjugates focused on improving the physicochemical (i.e. solubility), biopharmaceutic (i.e. absorption, metabolism), and pharmacokinetic (i.e. blood concentrations) properties of the parent drugs. Eradicating HIV, however, will require advanced drug delivery approaches in order to access and maintain effective drug concentrations for prolonged periods of time in sanctuary sites. The current review discusses prodrug/conjugate efforts, clinical successes and describes drug delivery challenges and approaches for eradicating HIV infection.

Multimodal-3D imaging based on µMRI and µCT techniques bridges the gap with histology in visualization of the bone regeneration process.

Bone repair/regeneration is usually investigated through X-ray computed microtomography (µCT) supported by histology of extracted samples, to analyse biomaterial structure and new bone formation processes. Magnetic resonance imaging (µMRI) shows a richer tissue contrast than µCT, despite at lower resolution, and could be combined with µCT in the perspective of conducting non-destructive 3D investigations of bone. A pipeline designed to combine µMRI and µCT images of bone samples is here described and applied on samples of extracted human jawbone core following bone graft. We optimized the coregistration procedure between µCT and µMRI images to avoid bias due to the different resolutions and contrasts. Furthermore, we used an Adaptive Multivariate Clustering, grouping homologous voxels in the coregistered images, to visualize different tissue types within a fused 3D metastructure. The tissue grouping matched the 2D histology applied only on 1 slice, thus extending the histology labelling in 3D. Specifically, in all samples, we could separate and map 2 types of regenerated bone, calcified tissue, soft tissues, and/or fat and marrow space. Remarkably, µMRI and µCT alone were not able to separate the 2 types of regenerated bone. Finally, we computed volumes of each tissue in the 3D metastructures, which might be exploited by quantitative simulation. The 3D metastructure obtained through our pipeline represents a first step to bridge the gap between the quality of information obtained from 2D optical microscopy and the 3D mapping of the bone tissue heterogeneity and could allow researchers and clinicians to non-destructively characterize and follow-up bone regeneration.

Structural disorder and anomalous diffusion in random packing of spheres.

Nowadays Nuclear Magnetic Resonance diffusion (dNMR) measurements of water molecules in heterogeneous systems have broad applications in material science, biophysics and medicine. Up to now, microstructural rearrangement in media has been experimentally investigated by studying the diffusion coefficient (D(t)) behavior in the tortuosity limit. However, this method is not able to describe structural disorder and transitions in complex systems. Here we show that, according to the continuous time random walk framework, the dNMR measurable parameter α, quantifying the anomalous regime of D(t), provides a quantitative characterization of structural disorder and structural transition in heterogeneous systems. To demonstrate this, we compare α measurements obtained in random packed monodisperse micro-spheres with Molecular Dynamics simulations of disordered porous media and 3D Monte Carlo simulation of particles diffusion in these kind of systems. Experimental results agree well with simulations that correlate the most used parameters and functions characterizing the disorder in porous media.

New chitin complexes and their anti-aging activity from inside out.

BACKGROUND: Nutritional and topical antioxidants and immuno-modulant compounds play a key role in maintaining healthy skin. However, little is known about the combined effects antioxidant cosmeceuticals and nutricosmetics can have on the appearance of aging skin. OBJECTIVE: The clinical trial was designed to study the combined effects on skin hydration, superficial lipids, elasticity, peroxidation and global clinical appearance, of melatonin, Vit. E and Betaglucan (MEB) complexed with chitin nano-crystals administered both topically and orally. Clinical examinations were conducted by dermatologists. DESIGN: By a randomized placebo-controlled, 12 week multicenter study on 70 healthy subjects, affected with skin photo-aging, the anti-aging efficacy and tolerability of the combined activity of topical emulsion and oral hard capsules, containing MEB complexed with chitin nano-crystals (CN) was evaluated clinically and by biophysical non-invasive measurements at week 4,8 and 12. RESULTS: The effects of MEB intake resulted significantly higher (p<0.005) than placebo for all the parameters evaluated by biophysical and clinical measurements. The values resulted higher when the active ingredients MEB were complexed with CN, whether used topically, orally or a combination of both (p<0.05). The positive results, observed since week 4, were accompanied by no side-effects throughout the entire study. CONCLUSION: The combined topical and oral use of MEB was associated with reduced wrinkling, better skin appearance and general overall wellness. When MEB were complexed with CN, the obtained results were statistically more positive (p<0.05) for all the biophysical and clinical parameters considered.

Lepra Dimorfa Lepromatosa (Borderline Lepromatosa, BL) / Dimorphous Lepromatous Leprosy (Borderline Lepromatous, BL

Presentamos un caso de lepra dimorfa lepromatosa, en un hombre austríaco radicado en la Argentina desde hace 40 años, que presentaba placas infiltradas monomorfas y asintomáticas en tronco y miembros, sin alteraciones neurológicas periféricas evidentes. La biopsia de una de las lesiones demostró áreas de hiperplasia fibroblástica perineural "en catafilas de cebolla", granulomas en contacto focal con la epidermis, con transgresión del muro de contención y abundantes bacilos ácido-alcohol resistentes, agrupados en la tinción para micobacterias. El paciente respondió adecuadamente a la terapia con dapsona, rifampicina y clofazimina; sin embargo presentó episodio reacciónal tipo 1 o "reversal", que requirió terapia con prednisona por seis meses.

A case of Dimorphous Lepromatous Leprosy in an Austrian man, who had been living in Argentina for the past 40 years is reported. He presented asymptomatic, infiltrated, monomorphous plaques in his trunk and limbs, without peripheral neurologic manifestations. A skin biopsy specimen obtained from an infiltrated lesion on the back, demonstrated areas of perineural fibroblastic hyperplasia "onion-cataphylls like", granulomas contacting epidermis with violation of the Grenz zone and numerous grouped acid-fast bacilli demonstrated with the Ziehl-Neelsen stain. The patient responded well to therapy with dapsone, rifampicine, and clofazamine, but presented a type 1 reaction (reversal reaction) which required a six-months prednisone therapy.

¿cuál es su dignnóstico? / What i your diaggnosis?

Se presenta el caso de un varón de 45 años, que consultó por una lesión presente en dorso de la nariz, de aproximadamente dos meses de evolución. ¿Cuál es su diagnóstico?.

A 45 years old- man presented a firm, erythematous, indolent lesion on his nose from two months. What is your diagnosis?.

Enfermedad de Fabry: Comunicación de ocho casos / Fabry disease: Report of eight cases

La Enfermedad de Fabry (EF) constituye una alteración hereditaria del metabolismo de los glicoesfingolípidos, debida a la deficiencia parcial o completa de la enzima alfa-galactosidasa A. Es una enfermedad de transmisión genética ligada a X, que afecta universalmente a todas las etnias humanas con una incidencia comunicada de 1 cada 100.000 nacimientos, aunque es probable que esta cifra subestime la real prevalencia de la enfermedad, especialmente por el gran número de casos no diagnosticados. La EF se manifiesta en su forma más florida, en varones homocigotas que carecen completamente de actividad alfa-galactosidasa A, provocando una miríada de alteraciones, incluyendo anomalías renales (proteinuria progresiva e insuficiencia renal), cardiovasculares (cardiopatías, arritmias, accidentes cerebrovasculares), neurológicas (dolor acral y abdominal), y cocleo-vestibulares, entre las más importantes. Sin embargo, la afectación cutánea constituye la alteración más específica de la enfermedad y es en general, la que conduce a la sospecha diagnóstica. La EF no tratada reduce francamente la expectativa de vida de acuerdo a la severidad de la afectación renal y cardiovascular, si bien la terapia con reemplazo enzimático puede modificar e incluso detener el curso de la enfermedad. En 2010, una paciente de 28 años oriunda de la Provincia de Santa Fe, consultó porangioqueratomas, que condujeron al diagnóstico de enfermedad de Fabry. Desde entonces hemos estudiado y tratado a toda la familia, con ocho casos confirmados a la fecha y otros tantos en evaluación.

Fabry disease (Online Mendelian Inheritance in Man No. 301500) is an X-linked inherited condition due to absence or reduction of ɑ galactosidase activity in lysosomes that results in accumulation of globotriaosylceramide and related neutral glycosphingolipids (storage disorder). It is estimated to occur in 1 in 40.000 to 117.000 live male births, although a more recent screening study in newborns suggests a much higher incidence. The main clinical traits include cutaneous lesions (angiokeratomas), progressive renal damage with proteinuria, painful neuropathy predominantly affecting the hands and feet (acroparesthesias), myocardial hypertrophy, gastrointestinal manifestations, corneal dystrophy and hypohidrosis. This entails severe progressive multi-system involvement leading to premature death. More than 600 mutations have been described worldwide most of which are private or particular mutations of a single family. We report a 28 years-old woman who consulted to one of us and since 2010 eight cases of the same family were studied and treated with support and enzyme replacement therapy in order to delay the damage to the end organ.

Síndrome de Werner: Dos nuevos casos / Werner´S Syndrome: Two New Cases

Se comunican dos casos del síndrome de Werner, el primero es un hombre con canicie desde la tercera década de la vida y diabetes mellitus diagnosticada el año pasado. El segundo caso es un hombre con alopecia masculina desde los 30 años y cataratas. Ambos nos consultaron por úlceras muy dolorosas en piernas y tobillos. Se efectúa una revisión del síndrome de Werner.

Two cases of Werner´s syndrome are reported. The first case is a man with grey hair since his 30s and diabetes mellitus diagnosed last year. The second case is a man with male alopecia since his 30s and cataracts, both consulted us for extremely painful ulcers in their legs and ankles. A review of the Werner´s syndrome is made.