Increased Intracranial Arterial Pulsatility and Microvascular Brain Damage in Pseudoxanthoma Elasticum.

BACKGROUND AND PURPOSE: Carotid siphon calcification might contribute to the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum through increased arterial flow pulsatility. This study aimed to compare intracranial artery flow pulsatility, brain volumes, and small-vessel disease markers between patients with pseudoxanthoma elasticum and controls and the association between arterial calcification and pulsatility in pseudoxanthoma elasticum. MATERIALS AND METHODS: Fifty patients with pseudoxanthoma elasticum and 40 age- and sex-matched controls underwent 3T MR imaging, including 2D phase-contrast acquisitions for flow pulsatility in the assessment of ICA and MCA and FLAIR acquisitions for brain volumes, white matter lesions, and infarctions. All patients with pseudoxanthoma elasticum underwent CT scanning to measure siphon calcification. Flow pulsatility (2D phase-contrast), brain volumes, white matter lesions, and infarctions (3D T1 and 3D T2 FLAIR) were compared between patients and controls. The association between siphon calcification and pulsatility in pseudoxanthoma elasticum was tested with linear regression models. RESULTS: Patients with pseudoxanthoma elasticum (mean age, 57 [SD, 12] years; 24 men) had significantly higher pulsatility indexes (1.05; range, 0.94-1.21 versus 0.94; range, 0.82-1.04; P = .02), lower mean GM volumes (597 [SD, 53] mL versus 632 [SD, 53] mL; P < .01), more white matter lesions (2.6; range, 0.5-7.5 versus 1.1; range, 0.5-2.4) mL; P = .05), and more lacunar infarctions (64 versus 8, P = .04) than controls (mean age, 58 [SD, 11] years; 20 men). Carotid siphon calcification was associated with higher pulsatility indexes in patients with pseudoxanthoma elasticum (ß = 0.10; 95% CI, 0.01-0.18). CONCLUSIONS: Patients with pseudoxanthoma elasticum have increased intracranial artery flow pulsatility and measures of small-vessel disease. Carotid siphon calcification might underlie the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum.

Assessment of blood flow velocity and pulsatility in cerebral perforating arteries with 7-T quantitative flow MRI.

Thus far, blood flow velocity measurements with MRI have only been feasible in large cerebral blood vessels. High-field-strength MRI may now permit velocity measurements in much smaller arteries. The aim of this proof of principle study was to measure the blood flow velocity and pulsatility of cerebral perforating arteries with 7-T MRI. A two-dimensional (2D), single-slice quantitative flow (Qflow) sequence was used to measure blood flow velocities during the cardiac cycle in perforating arteries in the basal ganglia (BG) and semioval centre (CSO), from which a mean normalised pulsatility index (PI) per region was calculated (n = 6 human subjects, aged 23-29 years). The precision of the measurements was determined by repeated imaging and performance of a Bland-Altman analysis, and confounding effects of partial volume and noise on the measurements were simulated. The median number of arteries included was 14 in CSO and 19 in BG. In CSO, the average velocity per volunteer was in the range 0.5-1.0 cm/s and PI was 0.24-0.39. In BG, the average velocity was in the range 3.9-5.1 cm/s and PI was 0.51-0.62. Between repeated scans, the precision of the average, maximum and minimum velocity per vessel decreased with the size of the arteries, and was relatively low in CSO and BG compared with the M1 segment of the middle cerebral artery. The precision of PI per region was comparable with that of M1. The simulations proved that velocities can be measured in vessels with a diameter of more than 80 µm, but are underestimated as a result of partial volume effects, whilst pulsatility is overestimated. Blood flow velocity and pulsatility in cerebral perforating arteries have been measured directly in vivo for the first time, with moderate to good precision. This may be an interesting metric for the study of haemodynamic changes in aging and cerebral small vessel disease. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.

Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.

The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D.

Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics.

Crosstalk between organs is crucial for controlling numerous homeostatic systems (e.g. energy balance, glucose metabolism and immunity). Several pathological conditions, such as obesity and type 2 diabetes, are characterised by a loss of or excessive inter-organ communication that contributes to the development of disease. Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis). Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance. Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia. Recently, we hypothesised that specific metabolic dysregulations occurring at the level of numerous organs (e.g. gut, adipose tissue, muscles, liver and brain) rely from gut microbiota modifications. In this review, we discuss the mechanisms linking gut permeability, adipose tissue metabolism, and glucose homeostasis, and recent findings that show interactions between the gut microbiota, the endocannabinoid system and the apelinergic system. These specific systems are discussed in the context of the gut-to-peripheral organ axis (intestine, adipose tissue and brain) and impacts on metabolic regulation. In the present review, we also briefly describe the impact of a variety of non-digestible nutrients (i.e. inulin-type fructans, arabinoxylans, chitin glucans and polyphenols). Their effects on the composition of the gut microbiota and activity are discussed in the context of obesity and type 2 diabetes.

Harnessing the beneficial properties of adipogenic microbes for improving human health.

Obesity is associated with numerous metabolic comorbidities. Weight loss is an effective measure for alleviating many of these metabolic abnormalities. However, considering the limited success of most medical weight-management approaches in producing a sustained weight loss, approaches that improve obesity-related metabolic abnormalities independent of weight loss would be extremely attractive and of practical benefit. Metabolically healthy obesity supports the notion that a better metabolic profile is possible despite obesity. Moreover, adequate expansion of adipose tissue appears to confer protection from obesity-induced metabolic comorbidities. To this end, the 10th Stock conference examined new approaches to improve metabolic comorbidities independent of weight loss. In particular, human adenovirus 36 (Ad36) and specific gut microbes were examined for their potential to influence lipid and glucose homeostasis in animals and humans. While these microbes possess some undesirable properties, research has identified attributes of adenovirus Ad36 and gut microbes that may be selectively harnessed to improve metabolic profile without the obligatory weight loss. Furthermore, identifying the host signalling pathways that these microbes recruit to improve the metabolic profile may offer new templates and targets, which may facilitate the development of novel treatment strategies for obesity-related metabolic conditions.

Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.

BACKGROUND AND AIMS: Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. METHODS: Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. RESULTS: Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. CONCLUSION: We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.

Digital hearing aids and future directions for hearing aids.

In recent years many technical evolutions have been applied in hearing aids. In this paper differences between analog, programmable and fully digital hearing aids, the basic and supplementary functions of a hearing aid, and some important issues and future directions for digital hearing aids will be mentioned.

Coding of the fundamental frequency in continuous interleaved sampling processors for cochlear implants.

In this study the perception of the fundamental frequency (F0) of periodic stimuli by cochlear implant users is investigated. A widely used speech processor is the Continuous Interleaved Sampling (CIS) processor, for which the fundamental frequency appears as temporal fluctuations in the envelopes at the output. Three experiments with four users of the LAURA (Registered trade mark of Philips Hearing Implants, now Cochlear Technology Centre Europe) cochlear implant were carried out to examine the influence of the modulation depth of these envelope fluctuations on pitch discrimination. In the first experiment, the subjects were asked to discriminate between two SAM (sinusoidally amplitude modulated) pulse trains on a single electrode channel differing in modulation frequency ( deltaf = 20%). As expected, the results showed a decrease in the performance for smaller modulation depths. Optimal performance was reached for modulation depths between 20% and 99%, depending on subject, electrode channel, and modulation frequency. In the second experiment, the smallest noticeable difference in F0 of synthetic vowels was measured for three algorithms that differed in the obtained modulation depth at the output: the default CIS strategy, the CIS strategy in which the F0 fluctuations in the envelope were removed (FLAT CIS), and a third CIS strategy, which was especially designed to control and increase the depth of these fluctuations (F0 CIS). In general, performance was poorest for the FLAT CIS strategy, where changes in F0 are only apparent as changes of the average amplitude in the channel outputs. This emphasizes the importance of temporal coding of F0 in the speech envelope for pitch perception. No significantly better results were obtained for the F0 CIS strategy compared to the default CIS strategy, although the latter results in envelope modulation depths at which sub-optimal scores were obtained in some cases of the first experiment. This indicates that less modulation is needed if all channels are stimulated with synchronous F0 fluctuations. This hypothesis is confirmed in a third experiment where subjects performed significantly better in a pitch discrimination task with SAM pulse trains, if three channels were stimulated concurrently, as opposed to only one.

Detection of small across-channel timing differences by cochlear implantees.

Five post-lingually deafened users of the LAURA cochlear implant were presented with two trains of biphasic pulses applied concurrently to two widely separated channels. They could all discriminate between stimuli where pulses on the two channels were nearly synchronous (inter-channel delay=0.1 ms) and those where there was a longer delay applied to one channel. All showed an asymmetry, being more sensitive when the longer delay was on either the more basal or, depending on the listener, the more apical channel. For four out of the five listeners this asymmetry could be at least partly attributed to one stimulus, with a 0.1-ms delay in either the apical (three listeners) or basal (one listener) channel, sounding markedly different from all other stimuli used in the experiment. Both the overall sensitivity of listeners and the general pattern of results survived the presentation of maskers on intermediate channels, and did not vary markedly with changes in the polarity of the pulses applied to one channel. Although the results varied substantially across listeners, it is concluded that they demonstrate a genuine sensitivity to the relative timing of stimulation applied to discrete populations of auditory nerve fibers.

A concept for a research tool for experiments with cochlear implant users.

APEX, an acronym for computer Application for Psycho-Electrical eXperiments, is a user friendly tool used to conduct psychophysical experiments and to investigate new speech coding algorithms with cochlear implant users. Most common psychophysical experiments can be easily programmed and all stimuli can be easily created without any knowledge of computer programing. The pulsatile stimuli are composed off-line using custom-made MATLAB (Registered trademark of The Mathworks, Inc., http://www.mathworks.com) functions and are stored on hard disk or CD ROM. These functions convert either a speech signal into a pulse sequence or generate any sequence of pulses based on the parameters specified by the experimenter. The APEX personal computer (PC) software reads a text file which specifies the experiment and the stimuli, controls the experiment, delivers the stimuli to the subject through a digital signal processor (DSP) board, collects the responses via a computer mouse or a graphics tablet, and writes the results to the same file. At present, the APEX system is implemented for the LAURA (Registered trademark of Philips Hearing Implants) cochlear implant. However, the concept-and many parts of the system-is portable to any other device. Also, psycho-acoustical experiments can be conducted by presenting the stimuli acoustically through a sound card.

Enhancing the speech envelope of continuous interleaved sampling processors for cochlear implants.

A new method to code the speech envelope in continuous interleaved sampling (CIS) processors for cochlear implants is proposed. In this enhanced envelope, the rapid adaptation seen in the response of auditory nerves to sound stimuli is incorporated. Two strategies, one using the standard envelope (CIS) and one using the enhanced envelope (EECIS), were tested perceptually with six postlingually deafened users of the LAURA cochlear implant. The tests included identification of stop consonants in three different vowel contexts and monosyllabic consonant-vowel-consonant (CVC) words. Significant improvements in correct identification scores were observed for stop consonants in intervocalic /a/ context (p = 0.026): average results varied from 46% correct for CIS to 55% for EECIS. This improvement was mainly due to the better transmission of place of articulation. The differences in identification scores for stop consonants in /i/ and /u/ context were not significant. The identification scores for the medial vowels of the CVC words were significantly higher when the EECIS strategy was used: average results increased from 39% correct to 46% correct (p = 0.018). No significant differences were observed between the results for initial and final consonants of the CVC words. The present results demonstrate that the inclusion of the rapid adaptation in the speech processing for cochlear implants can improve speech intelligibility.

Developments in speech processing for cochlear implants.

The status of speech processing for cochlear implants is reviewed. Points of interest to enhance further speech intelligibility based on improved signal processing, are discussed.

Urinary 3 alpha,17 beta-androstanediol glucuronide is a measure of androgenic status in Eld's deer stags (Cervus eldi thamin).

To determine the primary excretory by-products of testosterone (T), 85 microCi [3H]T was administered i.v. to two adult Eld's deer stags. Blood (10 ml) was collected by jugular venipuncture at 0, 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 240, and 480 min after isotope infusion, and all urine and feces were collected for 96 h after injection. Seventy percent of labeled circulating steroid was conjugated by 30 min postinfusion. The majority (80.4 +/- 3.2%) of T metabolites were excreted into urine, and 95.0 +/- 0.9% of these were conjugated, 95.8 +/- 0.2% being hydrolyzable with glucuronidase. Seven urinary androgen metabolites, including androstanediol (5 alpha-androstan-3 alpha-17 beta-diol and 5 beta-androstan-3 alpha-17 beta-diol), were identified in glucoronidase-hydrolyzed, ether-extracted Eld's deer urine pools after gas chromatography/mass spectrometry. A double-antibody 125I RIA for 5 alpha-androstanediol-3 alpha, 17 beta-diol,17-glucuronide (3 alpha-diol-G) was validated for unprocessed urine. Longitudinal assessments of urine samples collected from 13 stages for 3 yr revealed biological concordance between fluctuations in urinary 3 alpha-diol-G and serum T, as well as seasonal changes in secondary sexual characteristics. Overall correlation between "same-day" matched serum T and urinary 3 alpha-diol-G was 0.58, (n = 6; p < 0.001). Thus, monitoring urinary 3 alpha-diol-G provides a noninvasive, alternative method for characterizing male endocrine interrelationships in an endangered ungulate species.