Oral ribose supplementation in dystroglycanopathy: A single case study.

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.

[COVID-19 vaccines: the facts]. / COVID-19-vaccins: hoe zit het?

Not all physicians advocate for large-scale vaccination programmes against COVID-19. In this article, we respond on some of their reflections. Moreover, we explain that there are strong arguments for these large-scale vaccination programmes, aimed to prevent COVID-19 associated morbidity, mortality and overwhelmed health care systems, and to hinder the emergence of new strains of SARS-CoV-2 by reducing the virus transmission.

[Temporary suspension of AstraZeneca's vaccine; a reconstruction]. / Prikpauze AstraZeneca proportioneel?

In the middle of the worldwide COVID-19 crisis, the whole of Europe was alarmed about a possible side effect of the AstraZeneca vaccine against COVID-19. Consequently, the use of this AstraZeneca vaccine was temporarily suspended in many European nations including the Netherlands. In this article, we chronologically describe the decisions that were made about the use of this vaccine in the Netherlands and we discuss the risk-benefit ratios of these actions as well as possible non-medical reasons that may explain why these actions were taken.

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia.

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5-90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia.

Schizophrenia (SZ) is a neurodevelopmental disorder with a broad symptomatology, including cognitive symptoms that are thought to arise from the prefrontal cortex (PFC). The neurobiological aetiology of these symptoms remains elusive, yet both impaired redox control and PFC dysconnectivity have been recently implicated. PFC dysconnectivity has been linked to white matter, oligodendrocyte (OL) and myelin abnormalities in SZ patients. Myelin is produced by mature OLs, and OL precursor cells (OPCs) are exceptionally susceptible to oxidative stress. Here we propose a hypothesis for the aetiology of cognitive symptomatology in SZ: the redox-induced prefrontal OPC-dysfunctioning hypothesis. We pose that the combination of genetic and environmental factors causes oxidative stress marked by a build-up of reactive oxygen species that, during late adolescence, impair OPC signal transduction processes that are necessary for OPC proliferation and differentiation, and involve AMP-activated protein kinase, Akt-mTOR-P70S6K and peroxisome proliferator receptor alpha signalling. OPC dysfunctioning coincides with the relatively late onset of PFC myelination, causing hypomyelination and disruption of connectivity in this brain area. The resulting cognitive deficits arise in parallel with SZ onset. Hence, our hypothesis provides a novel neurobiological framework for the aetiology of SZ cognitive symptoms. Future research addressing our hypothesis could have important implications for the development of new (combined) antioxidant- and promyelination-based strategies to treat the cognitive symptoms in SZ.

Dual-comb spectroscopy of water vapor with a free-running semiconductor disk laser.

Dual-comb spectroscopy offers the potential for high accuracy combined with fast data acquisition. Applications are often limited, however, by the complexity of optical comb systems. Here we present dual-comb spectroscopy of water vapor using a substantially simplified single-laser system. Very good spectroscopy measurements with fast sampling rates are achieved with a free-running dual-comb mode-locked semiconductor disk laser. The absolute stability of the optical comb modes is characterized both for free-running operation and with simple microwave stabilization. This approach drastically reduces the complexity for dual-comb spectroscopy. Band-gap engineering to tune the center wavelength from the ultraviolet to the mid-infrared could optimize frequency combs for specific gas targets, further enabling dual-comb spectroscopy for a wider range of industrial applications.

Sub-50 nm metrology on extreme ultra violet chemically amplified resist--A systematic assessment.

With lithographic patterning dimensions decreasing well below 50 nm, it is of high importance to understand metrology at such small scales. This paper presents results obtained from dense arrays of contact holes (CHs) with various Critical Dimension (CD) between 15 and 50 nm, as patterned in a chemically amplified resist using an ASML EUV scanner and measured at ASML and TNO. To determine the differences between various (local) CD metrology techniques, we conducted an experiment using optical scatterometry, CD-Scanning Electron Microscopy (CD-SEM), Helium ion Microscopy (HIM), and Atomic Force Microscopy (AFM). CD-SEM requires advanced beam scan strategies to mitigate sample charging; the other tools did not need that. We discuss the observed main similarities and differences between the various techniques. To this end, we assessed the spatial frequency content in the raw images for SEM, HIM, and AFM. HIM and AFM resolve the highest spatial frequencies, which are attributed to the more localized probe-sample interaction for these techniques. Furthermore, the SEM, HIM, and AFM waveforms are analyzed in detail. All techniques show good mutual correlation, albeit the reported CD values systematically differ significantly. HIM systematically reports a 25% higher CD uniformity number than CD-SEM for the same arrays of CHs, probably because HIM has a higher resolution than the CD-SEM used in this assessment. A significant speed boost for HIM and AFM is required before these techniques are to serve the demanding industrial metrology applications like optical critical dimension and CD-SEM do nowadays.

Screening of post-mortem tissue donors for Coxiella burnetii infection after large outbreaks of Q fever in The Netherlands.

BACKGROUND: After the largest outbreaks of Q fever ever recorded in history occurred in the Netherlands, concern arose that Coxiella may be transmitted via donated tissues of latent or chronically infected donors. The Dutch Health Council recently advised to screen tissue donors, donating high risk tissues, for Coxiella infection. METHODS: After validation of an enzyme immunoassay (EIA) test for IgG antibodies against phase 2 of C. burnetii for use on post-mortem samples, serum samples of 1033 consecutive Dutch post-mortem tissue donors were tested for IgG antibodies against phase 2 of C. burnetii. Confirmation of reactive results was done by immunofluorescence assay (IFA). All available tissues (corneas, heart valves, skin and bone marrow) from donors with IgG reactivity were tested for presence of Coxiella DNA by PCR. Risk factors for IgG reactivity were investigated. RESULTS: After validation of the tests for use on post-mortem samples, 50/1033 donors (4.8%) screened positive for phase 2 anti-Coxiella IgG by EIA, and 31 were confirmed by IFA (3.0%). One donor showed a serological profile compatible with chronic infection. All tested tissues (25 corneas, 6 heart valves, 4 skin and 3 bone marrow) from donors with IgG reactivity tested negative for the presence of Coxiella DNA. Except for living in a postal code area with a high number of Q fever notifications, no risk factors for IgG reactivity were found. CONCLUSIONS: The strong correlation between notifications and seroprevalence confirms that the used assays are sufficiently specific for use on post-mortem samples, although one has to be aware of differences between batches. Thus, this study provides a validated method for screening tissue donors for infection with Coxiella burnetii that can be used in future outbreaks.

A Q Fever Outbreak in the Netherlands: Consequences for Tissue Banking.

BACKGROUND: Emerging infectious diseases can compromise the safety of tissues for transplantations. A recent outbreak of Q fever, a zoonosis caused by the bacterium Coxiella burnetii, in the Netherlands compelled the Dutch tissue banks to assess the risk of Q fever transmission through tissue transplantation in order to maintain optimal safety. MATHODS: This article describes the systematic approach that was followed in the Netherlands. This approach included a review of the literature, a qualitative risk assessment, expert opinion gathering and investigations for specific strategies that can help to maintain the balance between tissue safety and availability. RESULTS: This resulted in a specific donor selection policy and in development of further research to fill in gaps in knowledge about Q fever in tissue transplantation. CONCLUSION: The strategy described in this article may be useful for tissue bankers facing similar outbreaks of emerging infections or may be useful for development of future guidelines or assessment strategies for tissue banking.

Design of an aberration corrected low-voltage SEM.

The low-voltage foil corrector is a novel type of foil aberration corrector that can correct for both the spherical and chromatic aberration simultaneously. In order to give a realistic example of the capabilities of this corrector, a design for a low-voltage scanning electron microscope with the low-voltage foil corrector is presented. A fully electrostatic column has been designed and characterised by using aberration integrals and ray tracing calculations. The amount of aberration correction can be adjusted relatively easy. The third order spherical and the first order chromatic aberration can be completely cancelled. In the zero current limit, a FW50 probe size of 1.0 nm at 1 kV can be obtained. This probe size is mainly limited by diffraction and by the fifth order spherical aberration.

High-power MIXSEL: an integrated ultrafast semiconductor laser with 6.4 W average power.

High-power ultrafast lasers are important for numerous industrial and scientific applications. Current multi-watt systems, however, are based on relatively complex laser concepts, for example using additional intracavity elements for pulse formation. Moving towards a higher level of integration would reduce complexity, packaging, and manufacturing cost, which are important requirements for mass production. Semiconductor lasers are well established for such applications, and optically-pumped vertical external cavity surface emitting lasers (VECSELs) are most promising for higher power applications, generating the highest power in fundamental transverse mode (>20 W) to date. Ultrashort pulses have been demonstrated using passive modelocking with a semiconductor saturable absorber mirror (SESAM), achieving for example 2.1-W average power, sub-100-fs pulse duration, and 50-GHz pulse repetition rate. Previously the integration of both the gain and absorber elements into a single wafer was demonstrated with the MIXSEL (modelocked integrated external-cavity surface emitting laser) but with limited average output power (<200 mW). We have demonstrated the power scaling concept of the MIXSEL using optimized quantum dot saturable absorbers in an antiresonant structure design combined with an improved thermal management by wafer removal and mounting of the 8-µm thick MIXSEL structure directly onto a CVD-diamond heat spreader. The simple straight cavity with only two components has generated 28-ps pulses at 2.5-GHz repetition rate and an average output power of 6.4 W, which is higher than for any other modelocked semiconductor laser.

Increased C-reactive protein is not associated with apathy: the Leiden 85-Plus Study.

BACKGROUND: Apathy has recently been recognized as a distinct clinical syndrome although it is difficult to differentiate from late life depression. In old age, apathy as a syndrome in itself and depression may have different etiologies. Inflammatory markers have been associated with depression in the elderly, but the relation with apathy is unknown. OBJECTIVE: To assess the relation between C-reactive protein (CRP) and apathy as a syndrome in itself, apart from depression, in subjects aged 85 and older. METHODS: All data come from the Leiden 85-Plus Study, a prospective, population-based study of 599 elderly subjects. CRP was measured at baseline. In all subjects with a Mini Mental State Examination (MMSE) > or = 19 points (n = 500), apathy and depression were assessed annually from age 85 to 90 using the three apathy and twelve depression questions of the 15-item Geriatric Depression Scale (GDS-15). The association between CRP and apathy or depressive symptoms was assessed both at baseline and longitudinally. RESULTS: At baseline, no association was found between CRP-concentration and apathy or depression. In subjects free of apathy and depression at baseline, subjects in the highest CRP-tertile at baseline had significantly more increase in depressive symptoms but not in apathy symptoms during follow-up. CONCLUSION: Higher CRP concentrations increased the risk of depression but not apathy in a community-based cohort of 85 years old subjects. This suggests that apathy and depression in old age have different etiologies.

Highly efficient optically pumped vertical-emitting semiconductor laser with more than 20 W average output power in a fundamental transverse mode.

We have demonstrated an optically pumped vertical-external-cavity surface-emitting laser (OP-VECSEL) generating more than 20 W of cw output power in a fundamental transverse mode (M2 approximately 1.1) at 960 nm. The laser is highly efficient with a slope efficiency of 49%, a pump threshold of 4.4 W, and an overall optical-to-optical efficiency of 43%.

[Immune activation and depression in the elderly]. / Immuunactivatie en depressie bij ouderen.

Besides the monoamine hypothesis, the stress hypothesis and the vascular hypothesis, the inflammatory hypothesis might be an etiological explanation for late-life depression. There is a growing amount of evidence to support this hypothesis. In animal studies, injection with cytokines was shown to cause behavioural changes ('sickness behaviour') similar to depressive symptoms in humans. Cytokine treatment of certain tumours and chronic hepatitis can also cause depressive symptoms. The prevalence of depression in patients with autoimmune diseases is higher than in the general population. Etanercept had a favourable effect on the depressive symptoms in patients with psoriasis, independent of improvement of physical symptoms. Cytokines affect the hypothalamus-pituitary-adrenal axis and cerebral neurotransmitter systems, both of which are thought to be involved in depression. Immune activation has been associated with depression, and several anti-depressive treatments affect immune parameters, although inconsistently. Since the aging process is associated with a dysregulation of the immune system, the inflammation hypothesis might be particularly true in late-life depression.

Femtosecond thin disk laser oscillator with pulse energy beyond the 10-microjoule level.

We report on a passively mode-locked Yb:YAG thin disk laser oscillator that generates 11.3-microJ pulses without the use of any additional external amplification. A repetition rate of 4 MHz is obtained using a 23.4-m-long multiple-pass cavity that extends the resonator length to a total of 37 m. The nearly transform-limited pulses at 45 W of average output power have a duration of 791 fs with a 1.56-nm-broad spectrum centered at 1030 nm. The laser is operated in a helium atmosphere to eliminate the air nonlinearity inside the resonator that previously limited the pulse energy.

High precision optical characterization of semiconductor saturable absorber mirrors.

Semiconductor saturable absorber mirrors (SESAMs) have become a key element of many ultrafast laser sources, enabling passively modelocked lasers with >100 GHz repetition rate or with >10 microJ pulse energy. Precise knowledge of the nonlinear optical reflectivity is required to optimize the SESAMs for self-starting passive modelocking at record high repetition rates or pulse energies. In this article, we discuss a new method for wide dynamic range nonlinear reflectivity measurements. We achieve a higher accuracy (<0.05%) with a simpler and more cost-efficient measurement scheme compared with previous measurement systems. The method can easily be implemented for arbitrary wavelength regions and fluence ranges.

Growth parameter optimization for fast quantum dot SESAMs.

Semiconductor saturable absorber mirrors (SESAMs) using quantum dot (QD) absorbers exhibit a larger design freedom than standard quantum well absorbers. The additional parameter of the dot density in combination with the field enhancement allows for an independent control of saturation fluence and modulation depth. We present the first detailed study of the effect of QD growth parameters and post growth annealing on the macroscopic optical SESAM parameters, measuring both nonlinear reflectivity and recombination dynamics. We studied a set of self-assembled InAs QD-SESAMs optimized for an operation wavelength around 960 nm with varying dot density and growth temperature. We confirm that the modulation depth is controlled by the dot density. We present design guidelines for QD-SESAMs with low saturation fluence and fast recovery, which are for example important for modelocking of vertical external cavity surface emitting lasers (VECSELs).

Efficient femtosecond high power Yb:Lu(2)O(3) thin disk laser.

We demonstrate the first passively mode-locked thin disk laser based on Yb:Lu(2)O(3). The laser generates 370-fs pulses with 20.5 W of average power in a diffraction-limited beam (M(2) < 1.1). The nearly transform-limited pulses have a spectral bandwidth of 3.4 nm centered near 1034 nm. With slightly longer pulses (523 fs) we obtained 24 W of average power at a pump power of 56 W, resulting in an optical-to-optical efficiency of 43%, which is higher than for any previously mode-locked thin disk laser.

Plasma leptin concentrations during extended fasting and graded glucose infusions: relationships with changes in glucose, insulin, and FFA.

Despite numerous studies, the in vivo regulation of plasma leptin levels in response to nutritional factors continues to remain unclear. We investigated temporal and dose-response relationships of plasma leptin in response to physiological changes in insulin/glucose. After an overnight fast of 10 h, lean, healthy subjects were investigated for an additional 16 h of either extended fasting or one of three levels of glycemia/insulinemia induced by stepwise increasing iv glucose infusions. During extended fasting, plasma leptin values declined steadily and significantly. Plasma leptin levels remained constant at glucose concentrations between 5.8-6.5 mmol/liter, which maintained normoinsulinemia at 41.5-45.4 pmol/liter and FFA at 106-123 mg/liter, but leptin concentrations were increased at higher rates of glucose infusion (with plasma glucose rising to 8.7 mmol/liter). Concentrations of serum leptin were inversely related to FFA levels during extended fasting and at all levels of glycemia. Our data indicate that in lean healthy subjects, physiological changes in glycemia and insulinemia significantly alter plasma FFA and leptin concentrations. The increases in leptin concentrations demonstrate dose-dependent relationships that appear to relate to changes in FFA levels as well as to changes in glycemia/insulinemia.