Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

Analgesic efficacy of zoledronic acid and its effect on functional status of prostate cancer patients with metastasis

Objectives: A multi-centered observational study evaluated the efficacy of zoledronic acid for improving pain and mobility, and preventing skeletal-related events (SRE) (fracture, spinal compression, pain-relieving radiotherapy), in patients with prostate cancer and bone metastasis. Materials and Methods: Males (n = 218) with prostate cancer and bone metastasis undergoing oncologic therapy received zoledronic acid (4 mg iv/month) for 6 months. Parameters evaluated were: 1) pain and movement after 2 consecutive doses; 2) quality of life; 3) SRE incidence and time-to-appearance. Medication tolerance and treatment satisfaction were assessed using a questionnaire. Results: A total of 170 that matched all the inclusion criteria (78%) out of 218 were evaluable for efficacy. There was a measurable statistically significant reduction in pain at rest and on movement as well as an improvement in the quality of life compared with baseline. Best results were obtained with early treatment. Overall incidence of bone events was 11.2%. Of the 212 patients (97.2%) evaluable for safety, 16% suffered adverse events and 66% expressed satisfaction with the treatment Discussion: Zoledronic acid is effective for reducing pain, improving mobility, and increasing the quality of life in patients with prostate cancer with bone metastasis. Its easy administration and good tolerability make zoledronic acid one of the principal therapeutic tools in the management of patients with pain associated with bone metastasis from prostate cancer.

A two-stage approach for tonic identification in indian art music

In this paper we propose a new approach for tonic identification in Indian art music and present a proposal for acomplete iterative system for the same. Our method splits the task of tonic pitch identification into two stages. In the first stage, which is applicable to both vocal and instrumental music, we perform a multi-pitch analysis of the audio signal to identify the tonic pitch-class. Multi-pitch analysisallows us to take advantage of the drone sound, which constantlyreinforces the tonic. In the second stage we estimate the octave in which the tonic of the singer lies and is thusneeded only for the vocal performances. We analyse the predominant melody sung by the lead performer in order to establish the tonic octave. Both stages are individually evaluated on a sizable music collection and are shown toobtain a good accuracy. We also discuss the types of errors made by the method.Further, we present a proposal for a system that aims to incrementally utilize all the available data, both audio and metadata in order to identify the tonic pitch. It produces a tonic estimate and a confidence value, and is iterative in nature. At each iteration, more data is fed into the systemuntil the confidence value for the identified tonic is above a defined threshold. Rather than obtain high overall accuracy for our complete database, ultimately our goal is to develop a system which obtains very high accuracy on a subset of the database with maximum confidence.

Adaptations of two specialist herbivores to movement on the hairy leaf surface of their host, Solanum guaraniticum Hassl (Solanaceae)

Plant trichomes can difficult the attachment and movement of small insects. Here, we examine the hypothesis that the success on the use of densely haired hosts by two cassidine species is determined by differential morphology and behavior. Larvae of Gratiana graminea (Klug, 1829) and Gratiana conformis (Boheman, 1854) move on the leaf surface of their host, Solanum guaraniticum Hassl by anchoring their tarsungulus on the trichome rays or by inserting the tarsungulus tip directly into epidermis. This kind of movement is only possible due to a similar tarsungulus shape among the species. Tarsungulus growth pattern is also similar between species, being relatively small on the posterior aperture, matching the diameter of the host plant trichome rays. The tarsungulus shape associated with differences on ontogenetic growth and attachment pattern allow these two Cassidinae larvae to efficiently move on the pubescent leaf surface of their host.

New Genetic and Linguistic Analyses Show Ancient Human Influence on Baobab Evolution and Distribution in Australia

This study investigates the role of human agency in the gene flow and geographical distribution of the Australian baobab, Adansonia gregorii. The genus Adansonia is a charismatic tree endemic to Africa, Madagascar, and northwest Australia that has long been valued by humans for its multiple uses. The distribution of genetic variation in baobabs in Africa has been partially attributed to human-mediated dispersal over millennia, but this relationship has never been investigated for the Australian species. We combined genetic and linguistic data to analyse geographic patterns of gene flow and movement of word-forms for A. gregorii in the Aboriginal languages of northwest Australia. Comprehensive assessment of genetic diversity showed weak geographic structure and high gene flow. Of potential dispersal vectors, humans were identified as most likely to have enabled gene flow across biogeographic barriers in northwest Australia. Genetic-linguistic analysis demonstrated congruence of gene flow patterns and directional movement of Aboriginal loanwords for A. gregorii. These findings, along with previous archaeobotanical evidence from the Late Pleistocene and Holocene, suggest that ancient humans significantly influenced the geographic distribution of Adansonia in northwest Australia.

Differentially phased leaf growth and movements in Arabidopsis depend on coordinated circadian and light regulation.

In contrast to vastly studied hypocotyl growth, little is known about diel regulation of leaf growth and its coordination with movements such as changes in leaf elevation angle (hyponasty). We developed a 3D live-leaf growth analysis system enabling simultaneous monitoring of growth and movements. Leaf growth is maximal several hours after dawn, requires light, and is regulated by daylength, suggesting coupling between growth and metabolism. We identify both blade and petiole positioning as important components of leaf movements in Arabidopsis thaliana and reveal a temporal delay between growth and movements. In hypocotyls, the combination of circadian expression of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 and their light-regulated protein stability drives rhythmic hypocotyl elongation with peak growth at dawn. We find that PIF4 and PIF5 are not essential to sustain rhythmic leaf growth but influence their amplitude. Furthermore, EARLY FLOWERING3, a member of the evening complex (EC), is required to maintain the correct phase between growth and movement. Our study shows that the mechanisms underlying rhythmic hypocotyl and leaf growth differ. Moreover, we reveal the temporal relationship between leaf elongation and movements and demonstrate the importance of the EC for the coordination of these phenotypic traits.

The relationship between virtual body ownership and temperature sensitivity.

In the rubber hand illusion tactile stimulation seen on a rubber hand, that is synchronous with tactile stimulation felt on the hidden real hand, can lead to an illusion of ownership over the rubber hand. This illusion has been shown to produce a temperature decrease in the hidden hand, suggesting that such illusory ownership produces disownership of the real hand. Here we apply immersive virtual reality (VR) to experimentally investigate this with respect to sensitivity to temperature change. Forty participants experienced immersion in a VR with a virtual body (VB) seen from a first person perspective. For half the participants the VB was consistent in posture and movement with their own body, and in the other half there was inconsistency. Temperature sensitivity on the palm of the hand was measured before and during the virtual experience. The results show that temperature sensitivity decreased in the consistent compared to the inconsistent condition. Moreover, the change in sensitivity was significantly correlated with the subjective illusion of virtual arm ownership but modulated by the illusion of ownership over the full virtual body. This suggests that a full body ownership illusion results in a unification of the virtual and real bodies into one overall entity - with proprioception and tactile sensations on the real body integrated with the visual presence of the virtual body. The results are interpreted in the framework of a"body matrix" recently introduced into the literature.

Using music as a signal for biofeedback

Studies on the potential benefits of conveying biofeedback stimulus using a musical signal have appeared in recent years with the intent of harnessing the strong effects that music listening may have on subjects. While results are encouraging, the fundamental question has yet to be addressed, of how combined music and biofeedback compares to the already established use of either of these elements separately. This experiment, involving young adults (N = 24), compared the effectiveness at modulating participants' states of physiological arousal of each of the following conditions: A) listening to pre-recorded music, B) sonification biofeedback of the heart rate, and C) an algorithmically modulated musical feedback signal conveying the subject's heart rate. Our hypothesis was that each of the conditions (A), (B) and (C) would differ from the other two in the extent to which it enables participants to increase and decrease their state of physiological arousal, with (C) being more effective than (B), and both more than (A). Several physiological measures and qualitative responses were recorded and analyzed. Results show that using musical biofeedback allowed participants to modulate their state of physiological arousal at least equally well as sonification biofeedback, and much better than just listening to music, as reflected in their heart rate measurements, controlling for respiration-rate. Our findings indicate that the known effects of music in modulating arousal can therefore be beneficially harnessed when designing a biofeedback protocol.

Morphological and molecular diversity among cassava genotypes

The objective of this work was to characterize morphologically and molecularly the genetic diversity of cassava accessions, collected from different regions in Brazil. A descriptive analysis was made for 12 morphological traits in 419 accessions. Data was transformed into binary data for cluster analysis and analysis of molecular variance. A higher proportion of white or cream (71%) root cortex color was found, while flesh colors were predominantly white (49%) and cream (42%). Four accession groups were classified by the cluster analysis, but they were not grouped according to their origin, which indicates that diversity is not structured in space. The variation was greater within regions (95.6%). Sixty genotypes were also evaluated using 14 polymorphic microsatellite markers. Molecular results corroborated the morphological ones, showing the same random distribution of genotypes, with no grouping according to origin. Diversity indices were high for each region, and a greater diversity was found within regions, with: a mean number of alleles per locus of 3.530; observed and expected heterozygosity of 0.499 and 0.642, respectively; and Shannon index of 1.03. The absence of spatial structure among cassava genotypes according to their origins shows the anthropic influence in the distribution and movement of germplasm, both within and among regions.

Using music as a signal for biofeedback

Studies on the potential benefits of conveying biofeedback stimulus using a musical signal have appeared in recent years with the intent of harnessing the strong effects that music listening may have on subjects. While results are encouraging, the fundamental question has yet to be addressed, of how combined music and biofeedback compares to the already established use of either of these elements separately. This experiment, involving young adults (N = 24), compared the effectiveness at modulating participants' states of physiological arousal of each of the following conditions: A) listening to pre-recorded music, B) sonification biofeedback of the heart rate, and C) an algorithmically modulated musical feedback signal conveying the subject's heart rate. Our hypothesis was that each of the conditions (A), (B) and (C) would differ from the other two in the extent to which it enables participants to increase and decrease their state of physiological arousal, with (C) being more effective than (B), and both more than (A). Several physiological measures and qualitative responses were recorded and analyzed. Results show that using musical biofeedback allowed participants to modulate their state of physiological arousal at least equally well as sonification biofeedback, and much better than just listening to music, as reflected in their heart rate measurements, controlling for respiration-rate. Our findings indicate that the known effects of music in modulating arousal can therefore be beneficially harnessed when designing a biofeedback protocol.

The relationship between virtual body ownership and temperature sensitivity.

In the rubber hand illusion tactile stimulation seen on a rubber hand, that is synchronous with tactile stimulation felt on the hidden real hand, can lead to an illusion of ownership over the rubber hand. This illusion has been shown to produce a temperature decrease in the hidden hand, suggesting that such illusory ownership produces disownership of the real hand. Here we apply immersive virtual reality (VR) to experimentally investigate this with respect to sensitivity to temperature change. Forty participants experienced immersion in a VR with a virtual body (VB) seen from a first person perspective. For half the participants the VB was consistent in posture and movement with their own body, and in the other half there was inconsistency. Temperature sensitivity on the palm of the hand was measured before and during the virtual experience. The results show that temperature sensitivity decreased in the consistent compared to the inconsistent condition. Moreover, the change in sensitivity was significantly correlated with the subjective illusion of virtual arm ownership but modulated by the illusion of ownership over the full virtual body. This suggests that a full body ownership illusion results in a unification of the virtual and real bodies into one overall entity - with proprioception and tactile sensations on the real body integrated with the visual presence of the virtual body. The results are interpreted in the framework of a"body matrix" recently introduced into the literature.

The Connectivity of Musical Aptitude and Foreign Language Learning Skills: Neural and Behavioural Evidence

Given the structural and acoustical similarities between speech and music, and possible overlapping cerebral structures in speech and music processing, a possible relationship between musical aptitude and linguistic abilities, especially in terms of second language pronunciation skills, was investigated. Moreover, the laterality effect of the mother tongue was examined with both adults and children by means of dichotic listening scores. Finally, two event-related potential studies sought to reveal whether children with advanced second language pronunciation skills and higher general musical aptitude differed from children with less-advanced pronunciation skills and less musical aptitude in accuracy when preattentively processing mistuned triads and music / speech sound durations. The results showed a significant relationship between musical aptitude, English language pronunciation skills, chord discrimination ability, and sound-change-evoked brain activation in response to musical stimuli (durational differences and triad contrasts). Regular music practice may also have a modulatory effect on the brain’s linguistic organization and cause altered hemispheric functioning in those who have regularly practised music for years. Based on the present results, it is proposed that language skills, both in production and discrimination, are interconnected with perceptual musical skills.

The regulation and function of collagenase-3 (MMP-13) in cutaneous wound healing and squamous cell carcinoma

Matrix metalloproteinase-13 (MMP-13) is a potent proteolytic enzyme, whose expression has been previously associated with fetal bone development and postnatal bone remodeling and with adult gingival wound healing. MMP-13 is also known to be involved in the growth and invasion of various cancers including squamous cell carcinoma (SCC) of the skin. The aim of this study was to further elucidate the function and regulation of MMP-13 in wound repair and cancer. In this study, it was shown that fetal skin fibroblasts express MMP-13 in response to transforming growth factor-β in a p38 MAP kinase dependent manner. In addition, MMP-13 was found to be expressed in vivo by wound fibroblasts in human fetal skin grafted on SCID mice. Adenovirally delivered expression of MMP-13 enhanced collagen matrix contraction by fibroblasts in vitro in association with altered cytoskeletal structure, enhanced proliferation and survival. These results indicate that MMP-13 is involved in cell-mediated collagen matrix remodeling and suggest a role for MMP-13 in superior matrix remodeling and scarless healing of fetal skin wounds. Using an MMP-13 deficient mouse strain, it was shown that MMP-13 is essential for the normal development of experimental granulation tissue in mice. MMP-13 was implicated in the regulation of myofibroblast function and angiogenesis and the expression of genes involved in cellular proliferation and movement, immune response, angiogenesis and proteolysis. Finally, epidermal mitogen, keratinocyte growth factor (KGF) was shown to suppress the malignant properties of skin SCC cells by downregulating the expression of several target genes with potential cancer promoting properties, including MMP-13, and by reducing SCC cell invasion. These results provide evidence that MMP-13 potently regulates cell viability, myofibroblast function and angiogenesis associated with wound healing and cancer. In addition, fibroblasts expressing MMP-13 show high collagen reorganization capacity. Moreover, the results suggest that KGF mediates the anti-cancer effects on skin SCC