Design of Si-rich nitride interposer waveguides for efficient light coupling from InP-based QD-emitters to Si3N4 waveguides on a silicon substrate.

In this paper, we present a systematic analysis for the design of Si-rich-nitride (SRN) based interposer waveguide layers interfacing InP-based devices and Si3N4 waveguides, towards monolithic co-integration of active and passive elements through a Back-End-Of-Line process. The investigation is performed via extensive 2D-eigenvalue and 3D-FDTD electromagnetic simulations and focuses on three different interposer designs, where performance in terms of coupling loss and back reflections is exchanged for fabrication complexity. In addition, a tolerance analysis is performed for the demonstration of the proposed coupling scheme's resilience to fabrication misalignments. The calculations use for the refractive index of the SRN interposer, real values extracted from ellipsometry measurements of a novel ultra-Si-rich-nitride material developed and engineered for this purpose. This new material provides tunability in the real part of the refractive index with low-stress crack free samples grown up to 500nm thickness. Test structures with cutbacks featuring waveguides of 500 × 500nm2 cross section formed via e-beam lithography reveal 15dB/cm propagation losses in line with similar amorphous silicon-rich nitride (aSi:N) materials. The proposed coupling concept although assumes an InP active medium, can be applied also with GaAs based lasers and dual facet devices such as Semiconductor Optical Amplifiers (SOAs) and electroabsorption modulators. In addition, all proposed designs are compatible in terms of critical dimensions with low cost 248nm DUV lithography targeting to maximize the low-cost advantage of the Si3N4 platform with very high coupling performance. Our results are expected to pave the way for the generation of a versatile, low cost, high performance monolithic InP-Quantum-Dot (QD)/Si3N4 platform on a common Si substrate.

[Type 3 Gaucher disease, also an adult disease?] / Maladie de Gaucher de type 3, une maladie également de l'adulte ?

INTRODUCTION: Gaucher disease is a genetic lysosomal storage disorder due to a glucocerebrosidase deficiency. Type 3, including neurological impairment, may have a specific phenotype in the context of the D409H mutation. OBSERVATION: We report the case of a 22-year-old woman who presented with Gaucher disease. Enzyme replacement therapy by imiglucerase was followed by rapid clinical and biological improvement. However, communication difficulties, which were initially attributed to the language barrier, revealed neurological impairment. After complementary assessment, the diagnosis of type 3 Gaucher disease was suspected. Gene analysis of the glucocerebrosidase showed a homozygous D409H mutation. CONCLUSION: This mutation results in calcified heart valves, corneal opacities, alteration of oculomotricity and hydrocephalus. The mild manifestation at onset and the late neurological involvement in the medical history make the diagnosis more difficult. This particular clinical phenotype deserves to be known in adult medicine departments.

Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease.

Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.

Moderate- and high-intensity exhaustive exercise in the heat induce a similar increase in monocyte Hsp72.

This study examined the relationship between exhaustive exercise in the heat at moderate and high intensities on the intracellular heat shock protein 72 (iHsp72) response. Twelve male subjects cycled to exhaustion at 60 and 75% of maximal oxygen uptake in hot conditions (40 °C, 50% RH). iHsp72 concentration was measured in monocytes before, at exhaustion and 24 h after exercise. Rectal temperature, heart rate and oxygen uptake were recorded during exercise. Volitional exhaustion occurred at 58.9 ± 12.1 and 27.3 ± 9.5 min (P < 0.001) and a rectal temperature of 39.8 ± 0.4 and 39.2 ± 0.6 °C (P = 0.002), respectively, for 60 and 75 %. The area under the curve above a rectal temperature of 38.5 °C was greater at 60 % (17.5 ± 6.6 °C min) than 75 % (3.4 ± 4.8 °C min; P < 0.001), whereas the rate of increase in rectal temperature was greater at 75 % (5.1 ± 1.7 vs. 2.2 ± 1.4 °C h(-1); P < 0.001). iHsp72 concentration increased similarly at exhaustion relative to pre-exercise (P = 0.044) and then increased further at 24 h (P < 0.001). Multiple regression analysis revealed no predictor variables associated with iHsp72 expression; however, a correlation was observed between exercise intensities for the increase in iHsp expression at exhaustion and 24 h (P < 0.05). These results suggest that iHsp72 expression increased in relation to the level of hyperthermia attained and sustained at 60 % and the higher metabolic rate and greater rate of increase in core temperature at 75 %, with the further increase in iHsp72 concentration 24 h after exercise reinforcing its role as a chaperone and cytoprotective agent.

[Principles of therapeutic approaches for mucopolysaccharidoses]. / Principes des approches thérapeutiques pour les mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are caused by a deficiency of enzymes involved in the catabolism of glycosaminoglycans (GAGs) and are multisystemic diseases, often including the central nervous system. Despite their rare prevalence, specific treatments for MPS are available. One of them is enzyme replacement therapy, which provides the missing enzyme in the form of a recombinant protein administered intravenously. The effectiveness of this treatment relies on the enzymes being taken up by the different tissues via mannose-6-phosphate receptors. Treatment is currently available for MPS I, II and VI, and may be available for other forms of the disease in the near future. An alternative in MPS I is hematopoietic stem cell transplantation, the indications for which must be very clearly defined, particularly given the inherent risks of the procedure. Other new treatment strategies are currently being investigated, including substrate reduction therapy which uses GAG biosynthesis inhibitors (genistein,...), which reduces the accumulation of pathological compounds and their repercussions on tissues. Other molecular therapies using molecular chaperones or read-through molecules for stop codon mutations are also being studied. Finally, gene therapy, by introducing a normal gene sequence through a viral vector, either directly or using genetically modified cells, is a potential future method (the first clinical trials are undergoing).

Large-mode-area infrared guiding in ultrafast laser written waveguides in sulfur-based chalcogenide glasses.

Current demands in astrophotonics impose advancing optical functions in infrared domains within embedded refractive index designs. We demonstrate concepts for large-mode-area guiding in ultrafast laser photowritten waveguides in bulk Sulfur-based chalcogenide glasses. If positive index contrasts are weak in As2S3, Ge doping increases the matrix rigidity and allows for high contrast (10(-3)) positive refractive index changes. Guiding with variable mode diameter and large-mode-area light transport is demonstrated up to 10 µm spectral domain using transverse slit-shaped and evanescently-coupled multicore traces.

[A retrospective study to evaluate a protocol aimed at reducing the number of unnecessary voiding cystourethrographies performed after a first episode of febrile urinary tract infection]. / Évaluation d'un protocole de limitation des indications de cystographie dans les infections urinaires fébriles.

AIM: Whether or not voiding cystourethrography (VCUG) should be performed after a first episode of urinary tract infection (UTI) remains a matter of debate. The role of VCUG is primarily to diagnose high-grade vesicoureteral reflux (≥grade III) (VUR) and hence prevent the development of renal scars and poor long-term outcome. We designed a protocol designed to reduce the indications for performing unnecessary VCUGs after a first episode of febrile UTI. In order to evaluate the efficacy of our protocol, we designed a retrospective study to verify whether high-grade VUR was subsequently being underdiagnosed. METHODS: This study compared the number of cases of VUR diagnosed over 2 1-year periods in children aged 1 month to 18 years. Data were collected from records held in the pediatric emergency department of the University Hospital of Reims. All cases included had presented to the department with a first episode of febrile UTI. During the first 1-year collection period, all patients underwent a VCUG. During the second collection period, the protocol was in place and VCUG was only performed in children with a serum procalcitonin level greater than 1 ng/L and/or an abnormal renal ultrasound scan. RESULTS: During the first year, 100 patients underwent routine VCUG and 7 cases of high-grade VUR were diagnosed. During the following year, VCUG was limited according to the new protocol: 102 patients were enrolled, 52 VCUGs were performed and 8 cases of high-grade VUR were diagnosed. Cases of low-grade VUR (I and II) were less frequently detected, without significant consequences for the patients. CONCLUSION: The protocol led to a 40% decrease in the number of VCUGs performed. No cases of high-grade VUR were missed; however, the number of VCUGs performed with a normal outcome remained significant.

[Molecular diagnosis of Gaucher disease in Tunisia]. / Diagnostic moléculaire de la maladie de Gaucher en Tunisie.

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid ß-glucosidase. In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in 30 Tunisian patients with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing had shown that N370S was the most frequent mutation (22/50 mutant alleles, 44%), followed by L444P mutation, which is found in 16% (8/50 mutant alleles). The recombinant allele (RecNciI) represented 14%. Our findings revealed that the genotype N370S/RecNciI was mosst frequent in patients with childhood onset and it was associated with severe visceral involvement. The screening of these three mutations provided a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allowed also genetic counselling for their family members.

Effect of an 8-weeks aerobic training program in elderly on oxidative stress and HSP72 expression in leukocytes during antioxidant supplementation.

OBJECTIVE: To investigate the effect of aerobic training in the context of antioxidant supplementation on systemic oxidative stress and leukocytes heat shock protein (Hsp)72 expression in the elderly. DESIGN: Sixteen septuagenarians (8 males and 8 females, mean age 74.6) were supplemented with Vitamin C and E (respectively 500 and 100mg per day) and randomly assigned either to sedentary (AS) or individualized aerobically trained (AT) group for 8 weeks. METHODS: Plasma Vitamin C and E concentrations and aerobic fitness, as well as resting and post graded exercise (GXT) Hsp72 expression in leukocytes, plasma levels of thiobarbituric acid reactive substances (TBARS) and advanced oxidation protein product (AOPP) were measured pre and post training / supplementation. RESULTS: At the end of the intervention, the two groups showed a significant increase in resting plasma vitamin C and E (approximately 50 and 20% increase respectively) and a significant decrease in both resting and post GXT plasma TBARS and AOPP (approximately 25 and 20% decrease respectively). These changes were of similar magnitude in the two groups. The reduced oxidative stress was concomitant with a 15% decreased expression of Hsp72 in monocytes and granulocytes in both groups. CONCLUSION: This study provides evidence that in elderly, increased concentration of antioxidant vitamins C and E is associated with a reduction in oxidative stress and leukocytes Hsp72. In this context, 8 weeks of aerobic training has no impact on oxidative stress or leukocytes Hsp72 expression in elderly people.

The effect of ageing and fitness on thermoregulatory response to high-intensity exercise.

There are conflicting reports as to whether ageing causes a decreased thermoregulatory response, or if observed differences in previous studies are related to maximal aerobic capacity or training status. This study hypothesized that thermoregulatory response to severe exercise-heat stress is maintained with ageing when both young and older subjects are well trained. Seven older highly trained (OHT = 51-63 years) cyclists were matched with two groups of young cyclists (19-35 years); one group matched for training status [young highly trained (YHT) participants, n = 7] and another for V ˙ O 2 max [young moderately trained (YMT), n = 7]. Each participant exercised at 70% V ˙ O 2 max in hot (35°C, 40% relative humidity) and thermoneutral (20°C, 40% relative humidity) conditions for 60 min. Final rectal temperature in the thermoneutral and heat (YHT = 39.13 ± 0.33°C, YMT = 39.11 ± 0.38°C, OHT = 39.11 ± 0.51°C) tests were similar between all three groups. %HR(max) (heat test: YHT = 92.5 ± 6.0%, YMT = 91.6 ± 4.4%, OHT = 88.6 ± 5.1%), skin temperature, and cutaneous vascular conductance during cycling in both environments were similar between groups. Lower sweat loss and evaporative heat loss in the heat test in the OHT and YMT groups when compared with the YHT group reflected lower metabolic heat production. The findings of the present study suggest that thermoregulatory response is maintained with age among highly trained subjects.

[Enzyme replacement therapy for lysosomal storage disorders]. / Le traitement par enzymothérapie des maladies lysosomales.

In the last years, much progress has been achieved in the treatment of lysosomal storage disorders. Until recently only symptomatic treatment was available for the affected patients. Progressively enzyme replacement treatments have been developed for several diseases, namely Gaucher disease, Fabry disease, mucopolysaccharidoses type I, II and VI and Pompe disease. In this review we will summarize the efficacy and safety of these treatments and describe new therapeutic trials for other lysosomal storage disorders or perspectives in the use of currently available treatments.

Heat exposure does not alter eccentric exercise-induced increases in mitochondrial calcium and respiratory dysfunction.

Eccentric exercise can lead to muscle damage including dramatic changes to mitochondrial calcium content (MCC) and impaired respiratory function. Heat acclimation can create a cross-tolerance to a number of stresses including eccentric exercise but little is known about any protection to mitochondria. We hypothesised that intermittent heat exposure will lead to improved control of MCC and to preserved mitochondrial function following eccentric exercise. Sprague-Dawley rats were exposed to 3 weeks of intermittent heat exposure (36°C, 40% relative humidity, 6 h/day, 5 days a week) or kept in cool conditions (20°C). Animals were then assigned to a control or exercise group (-14°C decline treadmill exercise for 90 min). MCC, mitochondrial respiration and mitochondrial permeability transition pore opening (mPTP) were measured in mitochondria isolated from the red quadriceps in animals killed immediately, 2 h and 48 h post-exercise. Results showed that heat exposure was associated with lower plasma creatine kinase levels (p < 0.05) post-exercise suggesting lower levels of muscle damage. There was a significant (~500%) rise in MCC (p < 0.001) and a reduction in mitochondrial respiratory control ratio (p < 0.001) 48 h post-exercise. mPTP displayed increased (p < 0.05) sensitivity to calcium immediately and 48 h post-exercise. Thus, decline running led to significant impairment of mitochondria respiration and calcium loading which was more pronounced 48 h post-exercise compared with earlier time points. MCC levels and mitochondrial function were not altered by heat exposure. In conclusion, intermittent heat exposure does not appear to provide protection against mitochondrial dysfunction resulting from eccentric exercise.

Basal plasma leptin levels in healthy elderly males are related to physical fitness without impact on bone metabolism.

AIM: Investigated the relationship between leptin levels or bone remodelling and physical fitness level in healthy elderly participants. METHODS: Twenty women and 18 men (mean age 72.7 years, range 59-90) performed a maximal incremental exercise test to evaluate their maximal oxygen uptake (VOmax). Basal blood concentrations of bone biochemical markers (BM) and leptin were analysed. RESULTS: Women presented higher values of leptin than men (+34.7%, P=0.024), but no difference related to gender was observed for the other biological parameters. Leptin levels were positively correlated with Body Mass Index (BMI) in both genders. Whether adjusted or not for BMI, leptin was negatively correlated with VOmax only in men (r=-0.55, P=0.02 and r=-0.57, P=0.01, respectively). No relationship between VOmax or leptin and BM was observed, except for leptin and osteocalcin in men (r=-0.66, P=0.015). CONCLUSION: Our data suggest that neither physical fitness nor leptin level seems to have a noticeable effect in the regulation of bone cell activity in healthy elderly participants. In this specific population, physical fitness plays a crucial role on leptin secretion, independently of BMI variation, and this action appears to be sex-dependent.

Progress in the development of new drugs in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease with a global prevalence estimated at 26.55 million in 2006. During the past decades, several agents have been approved that enhance cognition of AD patients. However, the effectiveness of these treatments are limited or controversial and they do not modify disease progression. Recent advances in understanding AD pathogenesis have led to the development of numerous compounds that might modify the disease process. AD is mainly characterized neuropathologically by the presence of two kinds of protein aggregates: extracellular plaques of Abeta-peptide and intracellular neurofibrillary tangles. Abeta and tau could interfere in an original way contributing to a cascade of events leading to neuronal death and transmitter deficits. Investigation for novel therapeutic approaches targeting the presumed underlying pathogenic mechanisms is major focus of research. Antiamyloid agents targeting production, accumulation, clearance, or toxicity associated with Abeta peptide, are some approaches under investigation to limit extracellular plaques of Abeta-peptide accumulation. We can state as an example: Abeta passive and active immunization, secretases modulation, Abeta degradation enhancement, or antiaggregation and antifibrillization agents. Tau-related therapies are also under clinical investigation but few compounds are available. Another alternative approach under development is neuroprotective agents such as antioxidants, anti-inflammatory drugs, compounds acting against glutamate mediated neurotoxicity. Neurorestorative approaches through neurotrophin or cell therapy also represent a minor avenue in AD research. Finally, statins, receptor for advanced glycation end products inhibitors, thiazolidinediones, insulin, and hormonal therapies are some other ways of research for a therapeutic approach of Alzheimer's disease. Taking into account AD complexity, it becomes clear that polypharmacology with drugs targeting different sites could be the future treatment approach and a majority of the recent drugs under evaluation seems to act on multiple targets. This article exposes general classes of disease-modifying therapies under investigation.

Cognitive and neuroradiological improvement in three patients with attenuated MPS I treated by laronidase.

Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.

Bone and joint involvement in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by deficient activity of the enzyme alpha-galactosidase A. Although the disease has progressive effects on most organ systems in the body, data is limited regarding skeletal involvement in this rare disorder. We describe four family-related patients, three men and one premenopausal female, sharing a classic phenotype of FD. Dual-energy X-ray was performed in all cases and osteoporosis or osteopenia were found in all patients and osteoporotic fractures in one. One patient also showed both neuropathic joint disease and osteonecrosis. Several mechanisms that may explain osteoporosis and osteoarthropathy in the setting of FD are emphasized.

Aseptic meningitis and ischaemic stroke in Fabry disease.

BACKGROUND: Fabry disease (OMIM 301 500) is an X-linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients. METHODS: Clinical analysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analysed in three cases of meningitis associated with Fabry disease. FINDINGS: Mean age at meningitis onset was 26.6 (24-28) years. Headache was present in all cases and fever in two cases. Meningitis was always diagnosed before Fabry disease. A familial history of Fabry disease was present in two cases. Non-neurological symptoms caused by Fabry disease were present in all cases. All patients also suffered stroke and sensorineural hearing loss. Cerebrospinal fluid (CSF) analysis showed pleocytosis (mean, 36; range: 8-76 cells/mm(3)) and a high protein level (mean, 63; range, 47-70 mg/dl). C-reactive protein blood levels and erythrocyte sedimentation rate were raised. Diagnosis was assessed by low alpha-galactosidase A dosage and/or gene mutation analysis in all cases. All patients were treated with enzyme replacement therapy (ERT). In two cases, lumbar puncture was repeatedly performed and there was no normalisation of CSF under ERT alone, at 9 and 24 months of follow-up, respectively. One patient who suffered intracranial hypertension was treated efficiently with steroids, associated with azathioprine. The fact that Fabry disease could be an auto-inflammatory disorder is discussed. INTERPRETATION: Fabry disease may cause aseptic meningitis.

Phenotypic continuum of type 2 Gaucher's disease: an intermediate phenotype between perinatal-lethal and classic type 2 Gaucher's disease.

The natural history and clinical presentation of the perinatal-lethal Gaucher's disease, a severe variant of acute type 2 Gaucher's disease, is quite different from classic type 2 Gaucher's disease. Rare reported patients had an overlapping phenotype between these two forms confirming that phenotyping may be difficult. Here we report three patients with an intermediate phenotype. The first two patients showed at birth cholestatic jaundice, hepatosplenomegaly and hematological involvement consistent with hemophagocytosis in one patient, the death occurred from a severe liver involvement in one and lung disease in the second in the absence of neurological symptoms. The third patient displayed ichthyosis and facial dysmorphism but with neurological degeneration course and survival consistent with classic type 2 Gaucher's disease.