Niemann–Pick disease type C (NP-C) is an inherited neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Different clinical forms have been defined ...based on patient age at onset: perinatal, early-infantile (EI), late-infantile (Li), juvenile and adult. We evaluated the efficacy and tolerability of miglustat in 16 symptomatic NP-C patients, with comparative reference to one neurologically asymptomatic, untreated patient. All patients were categorized according to age at neurological disease onset, and were assessed using a standardized clinical assessment protocol: disability and cognitive function scales, positron emission tomography (PET), and biochemical markers. PET and disability scale evaluations indicated that cerebral hypometabolism and neurological symptoms were stabilized during treatment in juvenile-onset NP-C patients. EI and Li NP-C patients, who had higher disease severity at baseline (treatment start), showed increased disability scores and progressive cerebral hypometabolism during follow up. Similarly, while cognitive scale scores remained relatively stable in patients with juvenile NP-C, cognition deteriorated in EI and Li patients. Plasma chitotriosidase (ChT) activity was lower in the juvenile NP-C subgroup than in EI and Li patients, and generally increased in patients who discontinued treatment. Plasma CCL18/PARC and ChT activities indicated greater macrophagic activity in EI and Li patients
versus juveniles. Miglustat was generally well tolerated; frequent adverse events included diarrhea and flatulence, which were managed effectively by dietary modification and loperamide. Overall, miglustat appeared to stabilize neurological status in juvenile-onset NP-C patients, but therapeutic benefits appeared smaller among younger patients who were at a more advanced stage of disease at baseline.
Nonlinear silicon photonics offers unique abilities to generate, manipulate and detect optical signals in nano-devices, with applications based on field localization and large third order ...nonlinearity. However, at the nanoscale, inefficient nonlinear processes, absorption, and the lack of realistic models limit the nano-engineering of silicon. Here we report measurements of second and third harmonic generation from undoped silicon membranes. Using experimental results and simulations we identify the effective mass of valence electrons, which determines second harmonic generation efficiency, and oscillator parameters that control third order processes. We can then accurately predict the nonlinear optical properties of complex structures, without introducing and artificially separating the effective χ
into surface and volume contributions, and by simultaneously including effects of linear and nonlinear dispersions. Our results suggest that judicious exploitation of the nonlinear dispersion of ordinary semiconductors can provide reasonable nonlinear efficiencies and transformational device physics well into the UV range.
The combined effect of enzymatic treatment (biobeating) and NFC addition on the mechanical and physical properties of a papermaking pulp suspension was investigated. The influence of pH, consistency ...of pulp and reaction time of the enzyme on the pulp strength was evaluated by measuring the breaking length of paper sheets made thereof. The results showed that the enzymatic treatment improved mechanical properties of fibres without modifying drainability. After biobeating, NFC was added to the enzyme-treated pulps. Mechanical properties were enhanced, obtaining length at break values similar to those observed in commercial printing/writing paper. Opacity remained constant, whereas porosity was gradually reduced as more amount of NFC was added. The presence of NFC also reduced drainability, although it remained at suitable levels for the papermaking industry. The results suggest that the combination of biobeating and NFC addition can be considered as an alternative to mechanical beating.
Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, ...genotype and phenotype--genotype correlation has been lacking.
We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8).
Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
Quintana E, Gort L, Busquets C, Navarro‐Sastre A, Lissens W, Moliner S, Lluch M, Vilaseca MA, De Meirleir L, Ribes A, Briones P, PDH Working Group. Mutational study in the PDHA1 gene of 40 patients ...suspected of pyruvate dehydrogenase complex deficiency.
We screened for PDHA1 mutations in 40 patients with biochemically demonstrated PDHc deficiency or strong clinical suspicion, and found changes with probable pathological significance in 20. Five patients presented new mutations: p.A169V, c.932_938del, c.1143_1144 ins24, c.1146_1159dup and c.510‐30G> A, this latter is a new undescribed cause of exon 6 skipping. Another four mutations have been found, and previously reported, in our patients: p.H113D, p.P172L, p.Y243del and p.Y369Q. Eleven patients presented seven known mutations: p.R127Q, p.I166I, p.A198T, p.R263G, p.R302C, p.R378C and c.1142_1145dup. The latter three were found in more than one unrelated patient: p.R302C was detected in a heterozygous girl and a mosaic male, p.R378C in two males and finally, c.1142_1145dup in three females; only one in 20 mothers was found to be a carrier (p.R263G).
Apart from those 20 patients, the only alteration detected in one girl with clear PDHc and PDH‐E1 deficiency was the silent change c.396A> C (p.R132R), and other eight PDHc deficient patients carry combinations of known infrequent polymorphisms that are overrepresented among our 20 unsolved patients. The importance of these changes on PDH activity is unclear.
Investigations in the other PDHc genes are in course in order to elucidate the genetic defect in the unresolved patients.
The use of coupling agents based on polyolefins is an interesting strategy for the preparation of composites with marked different chemical structure between their components. That is the case of ...polypropylene-based composites reinforced with lignocellulose fibers. In this work a deep study of the influence of the intrinsic parameters of maleated polypropylene (MAH-PP) has been carried out in order to determine the effect of its acid number as well as molecular weight in mechanical properties of composites reinforced with low cost reinforcements, under tensile, flexural and impact stresses, flow capacity, water absorption behavior and surface morphology. The use of high functionalized MAH-PP coupling leaded to important improvements in mechanical stresses and also a lower capacity of water absorption due to the formation of thinner interfaces. In the case high molecular weight MAH-PP agents, even higher than plain polymer matrix, conducted to an interesting increase in unnotched Charpy Impact Strength attributed to a low dispersion of the coupling agent in the matrix during mixing process keeping microdomains that help to avoid crack propagation.
Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which ...account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.
This research focuses on the behavior of the tensile and flexural modulus of polypropylene/hemps strands composites. The intrinsic tensile modulus of the hemp strands was computed using Hirsch model ...and experimental data of the tensile modulus of the polypropylene composites at the 20–50 wt.% hemp strands content. The modified rule of mixtures was used to evaluate the efficiency factor. Square packing distribution was assumed and the length factor was fixed by Cox–Krenchel’s model. The mean value of the orientation efficiency factor was found to be 0.55. Tensile and flexural modulus were compared concluding that its value was independent of the manner the composite was loaded. Finally the Tsai–Pagano model was applied to predict the behavior of the composite’s tensile modulus.
In this work, a starch-based biopolymer was reinforced with flax strands. Composite materials at different fiber content were obtained by means of high-shearing mixing followed by injection molding ...processing. The evaluation of the mechanical properties gave a significant increase of the strength and stiffness of composites with the percentage of flax strands. The enhancement was analyzed in terms of compatibility and extension of the adhesion at fiber–matrix interface. The intrinsic mechanical properties of the reinforcement were measured and the behavior of the obtained composites was studied in terms of the modified rule of mixtures and the modified Halpin–Tsai equations.
Background Treatment with oral creatine monohydrate has not shown efficacy in patients with creatine transporter deficiency (CRTR-D). Another therapeutic option proposed is l-arginine, the substrate ...for the enzyme l-arginine:glycine amidinotransferase (AGAT). We evaluate clinical characteristics and cerebral creatine replenishment after l-arginine therapy in four patients with CRTR-D. Patients and methods Four boys with genetically confirmed diagnosis of CRTR-D (ages 9-16 years) were supplemented with l-arginine (0.4 g/kg per day) for a period of 9 months. Treatment efficacy was evaluated by clinical and neuropsychological assessment and determination of creatine signals by brain proton magnetic resonance spectroscopy (¹H-MRS). Results Epileptic seizures remained well controlled with antiepileptic drugs in three cases, both before and after l-arginine supplementation. Vineland Adaptive Behaviour Scale did not show any change in communication, daily living skills, socialization or motor skills, and a lack of improvement in brain ¹H-MRS follow-up was observed. l-Arginine was discontinued at the end of the observation period. Conclusions Nine months of l-arginine supplementation did not show effectiveness in the four patients affected with CRTR-D in this protocol.
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