Dementia from the ABCD1 mutation c.1415-1416delAG in a female carrier

Objectives

Progressive dementia is a rare phenotypic feature of female X-ALD carriers. Even rarer is the additional presence of further risk factors for dementia, such as diabetes, hypothyroidism, and hepatopathy. We report a unique female X-ALD carrier presenting with severe, progressive dementia, paraspasticity, sphincteric dysfunction, and multisystem disease.

Case report

A 79 years-old female with a history of strumectomy, diabetes, hepatopathy, hypothyroidism, arterial hypertension, hiatal hernia, left retinal ablation, ovariectomy, hysterectomy, osteoporosis, bilateral hip endoprosthesis, and neurogenic bladder dysfunction developed slowly progressive cognitive decline since age of 77 years. She had been identified as a female carrier of X-ALD in 12/2010 upon a family screening. At age of 79 years she presented with severe dementia, anxiety, unsteadiness, helplessness, hypertelorism, exaggerated patella tendon reflexes, reduced Achilles tendon reflexes, club feet, contractures of the ankles, the knees, and the hips, and the inability to stay or walk. Cerebral CT showed diffuse atrophy, demyelination periventricularly, small lacunas in the basal ganglia, and small calcifications of the basal ganglia and the temporal lobe on the right side. Differential diagnoses of dementia were considered but were all excluded upon the clinical presentation, blood chemical investigations, imaging studies, and the pattern of neuropsychological deficits.

Conclusions

With progression of the disease manifesting X-ALD carriers may develop progressive severe dementia, severe paraspasticity, and sphincteric dysfunction. Female carriership of X-ALD can be a differential diagnosis of dementia.     

Identification of a novel IVD mutation in a consanguineous family with isovaleric acidemia

Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by a deficiency of isovaleryl-CoA dehydrogenase encoded by IVD gene. In this case study we report the first Saudi IVA patients from a consanguineous family with a novel transversion (p.G362V) and briefly discuss likely phenotype–genotype correlation of the disease in the Saudi population. We explored the functional consequences of the mutation by using various bioinformatics prediction algorithms and discussed the likely mechanism of the disease caused by the mutation.     

Neurologically normal development of a patient with severe methionine adenosyltransferase I/III deficiency after continuing dietary methionine restriction

Background

There is not much information on established standard therapy for patients with severe methionine adenosyltransferase (MAT) I/III deficiency.

Case presentation

We report a boy with MAT I/III deficiency, in whom plasma methionine and total homocysteine, and urinary homocystine were elevated. Molecular genetic studies showed him to have novel compound heterozygous mutations of the MAT1A gene: c.191T>A (p.M64K) and c.589delC (p.P197LfsX26). A low methionine milk diet was started at 31 days of age, and during continuing dietary methionine restriction plasma methionine levels have been maintained at less than 750 μmol/L. He is now 5 years old, and has had entirely normal physical growth and psychomotor development.

Conclusions

Although some severely MAT I/III deficient patients have developed neurologic abnormalities, we report here the case of a boy who has remained neurologically and otherwise normal for 5 years during methionine restriction, suggesting that perhaps such management, started in early infancy, may help prevent neurological complications.     

Real time monitoring of biofilm development under flow conditions in porous media

Biofilm growth can impact the effectiveness of industrial processes that involve porous media. To better understand and characterize how biofilms develop and affect hydraulic properties in porous media, both spatial and temporal development of biofilms under flow conditions was investigated in a translucent porous medium by using Pseudomonas fluorescens HK44, a bacterial strain genetically engineered to luminesce in the presence of an induction agent. Real-time visualization of luminescent biofilm growth patterns under constant pressure conditions was captured using a CCD camera. Images obtained over 8 days revealed that variations in bioluminescence intensity could be correlated to biofilm cell density and hydraulic conductivity. These results were used to develop a real-time imaging method to study the dynamic behavior of biofilm evolution in a porous medium, thereby providing a new tool to investigate the impact of biological fouling in porous media under flow conditions.     

Liposomes and Micelles to Target the Blood Pool for Imaging Purposes

Abstract

The blood pool is among body compartments of a special interest for imaging using magnetic resonance (MR) and computed tomography (CT), since with the help of selective blood-pool contrast agents blood perfusion and various cardiac parameters as well as a status of the blood flow and vascular system in any organ can be evaluated. Blood pool-specific imaging agents can also provide minimally invasive angiography, image guidance of minimally invasive procedures, oncologic imaging of angiogenesis, ascertaining organ blood volume, and identifying hemorrhage. Particulate contrast agents (such as liposomes and micelles) whose distribution is limited to the blood pool, should have a size larger than fenestrated capillaries (> 10 nm), contain the reporter (paramagnetic or radiopaque) moiety structurally incorporated within the particulate, and be able to stay in the blood long enough to obtain clinically useful images. We describe here a new generation of long-circulating Gd-loaded liposomes and iodine-loaded micelles to provide an efficient blood pool MR and CT imaging, respectively. In this study, we developed the optimized protocol to prepare a liposomal MR contrast agent with high relaxivity and narrow size distribution. Liposomes were loaded with Gadolinium (Gd) via so called polychelating amphiphilic polymer (PAP) that represents a low-molecular-weight DTPA-polylysine linked via its N-terminus to a lipid anchor, NGPE-PE. Gd-containing liposomes were additionally modified with PEG to provide the longevity in vivo. We demonstrated also that upon the intravenous administration in rabbits and dogs, a new preparation causes prolonged decrease in the blood Tl value, permits to obtain sharp and clear MR images of the vasculature, and may be considered as a potential contrast agent for MRI of the blood pool. In addition, to prepare micellar contrast agents for CT blood-pool imaging, we synthesized an iodine-containing amphiphilic block-copolymer consisting of methoxypoly(ethyleneglycol) and polyl?,N-(triiodobenzoyl)]-L-lysine. In aqueous solutions, it forms stable micelles with an average diameter of 80 nm and an iodine content of 35–40% wt. Iodine-containing micelles were intravenously injected into rats and rabbits at a dose of 170 mg I/kg and produced significant and sustained enhancement of the blood pool (aorta and heart), liver and spleen for a period of at least 3 hours providing clear and informative CT images.     

Flow cytometry and live confocal analysis for the evaluation of the uptake and intracellular distribution of FITC-ODN into HaCaT cells

In this study, the mechanism of the internalization and the cellular distribution of 59 fluorescein conjugated PS-ODN (FITC-ODN) after transfection with different mixed lipidic vesicles/oligo complexes (lipoplexes) have been investigated. Mixed lipidic vesicles were prepared with one of the most used cationic lipid (DOTAP) and different amounts of a cholic acid (UDCA) to release the oligo into HaCaT cells. Using flow cytometry, the cellular uptake of the oligo was studied with and without different inhibitors able to block selectively the different pathways involved in the internalization mechanism. The intracellular distribution of the oligo was analyzed by confocal laser scanning microscopy (CLSM), treating the cells with the lipoplexes and directly observing without any fixing procedure. To better carry out the colocalization studies, fluorescent-labeled markers, specific for the different cellular compartments, were coincubated with 59 fluorescein-conjugated 29-mer phosphorotioate oligonucleotide (FITC-ODN). The different lipidic vesicles affect the internalization mechanism of FITC-ODN. After using the inhibitors, the uptake of complexes involved a different internalization mechanism. The live CLSM analysis demonstrated that, after 1 hour from the complex incubation, the oligo was transferred into cells and localized into the endosomes; after 24 hours, the oligo was intracellularly localized close to the nuclear structure in a punctuate pattern. However, the results from fusion experiments showed also a binding of a quite low amount of oligo with the cell membranes.     

Multifaceted applications of nanomaterials in cell engineering and therapy

Nanomaterials with superior physiochemical properties have been rapidly developed and integrated in every aspect of cell engineering and therapy for translating their great promise to clinical success. Here we demonstrate the multifaceted roles played by innovatively-designed nanomaterials in addressing key challenges in cell engineering and therapy such as cell isolation from heterogeneous cell population, cell instruction in vitro to enable desired functionalities, and targeted cell delivery to therapeutic sites for prompting tissue repair. The emerging trends in this interdisciplinary and dynamic field are also highlighted, where the nanomaterial-engineered cells constitute the basis for establishing in vitro disease model; and nanomaterial-based in situ cell engineering are accomplished directly within the native tissue in vivo. We will witness the increasing importance of nanomaterials in revolutionizing the concept and toolset of cell engineering and therapy which will enrich our scientific understanding of diseases and ultimately fulfill the therapeutic demand in clinical medicine.     

Functional and anatomical variations in retinorecipient brain areas in Arvicanthis niloticus and Rattus norvegicus: implications for the circadian and masking systems

ABSTRACT

Daily rhythms in light exposure influence the expression of behavior by entraining circadian rhythms and through its acute effects on behavior (i.e., masking). Importantly, these effects of light are dependent on the temporal niche of the organism; for diurnal organisms, light increases activity, whereas for nocturnal organisms, the opposite is true. Here we examined the functional and morphological differences between diurnal and nocturnal rodents in retinorecipient brain regions using Nile grass rats (Arvicanthis niloticus) and Sprague-Dawley (SD) rats (Rattus norvegicus), respectively. We established the presence of circadian rhythmicity in cFOS activation in retinorecipient brain regions in nocturnal and diurnal rodents housed in constant dark conditions to highlight different patterns between the temporal niches. We then assessed masking effects by comparing cFOS activation in constant darkness (DD) to that in a 12:12 light/dark (LD) cycle, confirming light responsiveness of these regions during times when masking occurs in nature. The intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPN) exhibited significant variation among time points in DD of both species, but their expression profiles were not identical, as SD rats had very low expression levels for most timepoints. Light presentation in LD conditions induced clear rhythms in the IGL of SD rats but eliminated them in grass rats. Additionally, grass rats were the only species to demonstrate daily rhythms in LD for the habenula and showed a strong response to light in the superior colliculus. Structurally, we also analyzed the volumes of the visual brain regions using anatomical MRI, and we observed a significant increase in the relative size of several visual regions within diurnal grass rats, including the lateral geniculate nucleus, superior colliculus, and optic tract. Altogether, our results suggest that diurnal grass rats devote greater proportions of brain volume to visual regions than nocturnal rodents, and cFOS activation in these brain regions is dependent on temporal niche and lighting conditions.     

Non-identifiability of the Rayleigh damping material model in Magnetic Resonance Elastography

Magnetic Resonance Elastography (MRE) is an emerging imaging modality for quantifying soft tissue elasticity deduced from displacement measurements within the tissue obtained by phase sensitive Magnetic Resonance Imaging (MRI) techniques. MRE has potential to detect a range of pathologies, diseases and cancer formations, especially tumors. The mechanical model commonly used in MRE is linear viscoelasticity (VE). An alternative Rayleigh damping (RD) model for soft tissue attenuation is used with a subspace-based nonlinear inversion (SNLI) algorithm to reconstruct viscoelastic properties, energy attenuation mechanisms and concomitant damping behavior of the tissue-simulating phantoms. This research performs a thorough evaluation of the RD model in MRE focusing on unique identification of RD parameters, _μI${\mu }_I$ and _ρI${\rho }_I$.     

Peribacteroid space acidification: a marker of mature bacteroid functioning in Medicago truncatula nodules

Legumes form a symbiotic interaction with Rhizobiaceae bacteria, which differentiate into nitrogen‐fixing bacteroids within nodules. Here, we investigated in vivo the pH of the peribacteroid space (PBS) surrounding the bacteroid and pH variation throughout symbiosis. In vivo confocal microscopy investigations, using acidotropic probes, demonstrated the acidic state of the PBS. In planta analysis of nodule senescence induced by distinct biological processes drastically increased PBS pH in the N₂‐fixing zone (zone III). Therefore, the PBS acidification observed in mature bacteroids can be considered as a marker of bacteroid N₂ fixation. Using a pH‐sensitive ratiometric probe, PBS pH was measured in vivo during the whole symbiotic process. We showed a progressive acidification of the PBS from the bacteroid release up to the onset of N₂ fixation. Genetic and pharmacological approaches were conducted and led to disruption of the PBS acidification. Altogether, our findings shed light on the role of PBS pH of mature bacteroids in nodule functioning, providing new tools to monitor in vivo bacteroid physiology.