Objective
Changes in the normal‐appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular ...characteristics of the axon–myelin unit in MS NAWM and determined how this correlates with low‐grade inflammation.
Methods
Human brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics. In this study, we performed high‐resolution immunohis tochemistry and quantitative transmission electron microscopy to study inflammation and ultrastructural characteristics of the axon–myelin unit in MS NAWM (n = 8) and control white matter (WM) in the optic nerve.
Results
In the MS NAWM, there were more activated and phagocytic microglia cells (HLA+P2RY12− and Iba1+CD68+) and more T cells (CD3+) compared to control WM, mainly located in the perivascular space. In MS NAWM compared to control WM, there were, as expected, longer paranodes and juxtaparanodes and larger overlap between paranodes and juxtaparanodes. There was less compact myelin wrapping, a lower g‐ratio, and a higher frequency of axonal mitochondria. Changes in myelin and axonal mitochondrial frequency correlated positively with the number of active and phagocytic microglia and lymphocytes in the optic nerve.
Interpretation
These data suggest that in MS NAWM myelin detachment and uncompact myelin wrapping occurs, potassium channels are unmasked at the nodes of Ranvier, and axonal energy demand is increased, or mitochondrial transport is stagnated, accompanied by increased presence of activated and phagocytic microglia and T cells. These subclinical alterations to the axon–myelin unit in MS NAWM may contribute to disease progression. ANN NEUROL 2023;93:856–870
Music and language are two fundamental forms of human communication. Many studies examine the development of music‐ and language‐specific knowledge, but few studies compare how listeners know they ...are listening to music or language. Although we readily differentiate these domains, how we distinguish music and language—and especially speech and song— is not obvious. In two studies, we asked how listeners categorize speech and song. Study 1 used online survey data to illustrate that 4‐ to 17‐year‐olds and adults have verbalizable distinctions for speech and song. At all ages, listeners described speech and song differences based on acoustic features, but compared with older children, 4‐ to 7‐year‐olds more often used volume to describe differences, suggesting that they are still learning to identify the features most useful for differentiating speech from song. Study 2 used a perceptual categorization task to demonstrate that 4–8‐year‐olds and adults readily categorize speech and song, but this ability improves with age especially for identifying song. Despite generally rating song as more speech‐like, 4‐ and 6‐year‐olds rated ambiguous speech–song stimuli as more song‐like than 8‐year‐olds and adults. Four acoustic features predicted song ratings: F0 instability, utterance duration, harmonicity, and spectral flux. However, 4‐ and 6‐year‐olds’ song ratings were better predicted by F0 instability than by harmonicity and utterance duration. These studies characterize how children develop conceptual and perceptual understandings of speech and song and suggest that children under age 8 are still learning what features are important for categorizing utterances as speech or song.
Research Highlights
Children and adults conceptually and perceptually categorize speech and song from age 4.
Listeners use F0 instability, harmonicity, spectral flux, and utterance duration to determine whether vocal stimuli sound like song.
Acoustic cue weighting changes with age, becoming adult‐like at age 8 for perceptual categorization and at age 12 for conceptual differentiation.
Young children are still learning to categorize speech and song, which leaves open the possibility that music‐ and language‐specific skills are not so domain‐specific.
Speech and song are two important modes of humun communication, but how do we distinguish between them? Children and adults use temporal and spectral features to categorize speach and song from as early as age 4. However, this ability increases with age in parallel with changes in acoustic feature weighting and conceptual representations. These findings open the door for asking how much of music‐ and language‐specific processing is really domain‐specific.
Image-guided focussed ultrasound (FUS) ablation is a non-invasive procedure that has been used for treatment of benign or malignant breast tumours. Image-guidance during ablation is achieved either ...by using real-time ultrasound (US) or magnetic resonance imaging (MRI). The past decade phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. We provide an overview of studies assessing the efficacy of FUS for breast tumour ablation as measured by percentages of complete tumour necrosis. Successful ablation ranged from 20% to 100%, depending on FUS system type, imaging technique, ablation protocol, and patient selection. Specific issues related to FUS ablation of breast cancer, such as increased treatment time for larger tumours, size of ablation margins, methods used for margin assessment and residual tumour detection after FUS ablation, and impact of FUS ablation on sentinel node procedure are presented. Finally, potential future applications of FUS for breast cancer treatment such as FUS-induced anti-tumour immune response, FUS-mediated gene transfer, and enhanced drug delivery are discussed. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment.
Classical galactosaemia revisited Bosch, Annet M.
Journal of inherited metabolic disease,
August 2006, Letnik:
29, Številka:
4
Journal Article
Recenzirano
Summary
Classical galactosaemia (McKusick 230400) is an: autosomal recessive disorder of galactose metabolism, caused by a deficiency of the enzyme galactose‐1‐phosphate uridyltransferase (GALT; EC ...2.7.712). Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycaemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. The gold standard for diagnosis of classical galactosaemia is measurement of GALT activity in erythrocytes. Gas‐chromatographic determination of urinary sugars and sugar alcohols demonstrates elevated concentrations of galactose and galactitol. The only therapy for patients with classical galactosaemia is a galactose‐restricted diet, and initially all galactose must be removed from the diet as soon as the diagnosis is suspected. After the neonatal period, a lactose‐free diet is advised in most countries, without restriction of galactose‐containing fruit and vegetables. In spite of the strict diet, long‐term complications such as retarded mental development, verbal dyspraxia, motor abnormalities and hypergonadotrophic hypogonadism are frequently seen in patients with classical galactosaemia. It has been suggested that these complications may result from endogenous galactose synthesis or from abnormal galactosylation. Novel therapeutic strategies, aiming at the prevention of galactose 1‐phosphate production, should be developed. In the meantime, the follow‐up protocol for patients with GALT deficiency should focus on early detection, evaluation and, if possible, early intervention in problems of motor, speech and cognitive development.
Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal ...timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1. SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression. SIRT1 interacts with the Polycomb silencing complex to decrease Kiss1 promoter activity. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive switch in chromatin landscape. Early-onset overnutrition accelerates these changes, enhances Kiss1 expression and advances puberty. In contrast, undernutrition raises SIRT1 levels, protracts Kiss1 repression and delays puberty. This delay is mimicked by central pharmacological activation of SIRT1 or SIRT1 overexpression, achieved via transgenesis or virogenetic targeting to the ARC. Our results identify SIRT1-mediated inhibition of Kiss1 as key epigenetic mechanism by which nutritional cues and obesity influence mammalian puberty.
Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus ...(ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.
The techniques used in oral implantology to remove bacterial biofilm from the surface of implants by machining the titanium surface (implantoplasty) or by placing rough dental implants through ...friction with the cortical bone generate a large release of particles. In this work, we performed a simulation of particle generation following clinical protocols. The particles were characterized for commercially pure titanium with particle sizes of 5, 10, 15, and 30 μm. The aim was to determine the effect of particle size and chemical composition of the implant on the immune response. For this purpose, their morphology and possible contamination were characterized by scanning electron microscopy and X-ray microanalysis. In addition, the granulometry, specific surface area, release of metal ions into the medium, and studies of cytocompatibility, gene expression, and cytokine release linked to the inflammatory process were studied. The release of ions for titanium particles showed levels below 800 ppb for all sizes. Smaller particle sizes showed less cytotoxicity, although particles of 15 μm presented higher levels of cytocompatibility. In addition, inflammatory markers (TNFα and Il-1β) were higher compared to larger titanium. Specifically, particles of 15 μm presented a lower proinflammatory and higher anti-inflammatory response as characterized by gene expression and cytokine release, compared to control or smaller particles. Therefore, in general, there is a greater tendency for smaller particles to produce greater toxicity and a greater proinflammatory response.
Background. An important requirement for an effective antibiotic stewardship program is the ability to measure appropriateness of antibiotic use. The aim of this study was to develop quality ...indicators (QIs) that can be used to measure appropriateness of antibiotic use in the treatment of all bacterial infections in hospitalized adult patients. Methods. A RAND-modified Delphi procedure was used to develop a set of QIs. Potential QIs were retrieved from the literature. In 2 questionnaire mailings with an in-between face-to-face consensus meeting, an international multidisciplinary expert panel of 17 experts appraised and prioritized these potential QIs. Results. The literature search resulted in a list of 24 potential QIs. Nine QIs describing recommended care at patient level were selected: (1) take 2 blood cultures, (2) take cultures from suspected sites of infection, (3) prescribe empirical antibiotic therapy according to local guideline, (4) change empirical to pathogen-directed therapy, (5) adapt antibiotic dosage to renal function, (6) switch from intravenous to oral, (7) document antibiotic plan, (8) perform therapeutic drug monitoring, and (9) discontinue antibiotic therapy if infection is not confirmed. Two QIs describing recommended care at the hospital level were also selected: (1) a local antibiotic guideline should be present, and (2) these local guidelines should correspond to the national antibiotic guidelines. Conclusions. The selected QIs can be used in antibiotic stewardship programs to determine for which aspects of antibiotic use there is room for improvement. At this moment we are testing the clinimetric properties of these QIs in 1800 hospitalized patients, in 22 Dutch hospitals.
Radioembolization with yttrium-90 microspheres (
90
Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but ...overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent
90
Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for
90
Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC,
90
Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC,
90
Y-RE with resin microspheres is significantly more effective than
90
Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.
Introduction
Cerebral visual impairment (CVI) is an important cause of visual impairment in western countries. Perinatal hypoxic-ischemic damage is the most frequent cause of CVI but CVI can also be ...the result of a genetic disorder. The majority of children with CVI have cerebral palsy and/or developmental delay. Early diagnosis is crucial; however, there is a need for consensus on evidence based diagnostic tools and referral criteria. The aim of this study is to develop guidelines for diagnosis and referral in CVI according to the grade method.
Patients and Methods
We developed the guidelines according to the GRADE method 5 searches on CVI (children, developmental age ≤ 18 years) were performed in the databases Medline, Embase, and Psychinfo, each with a distinct topic.
Results
Based on evidence articles were selected on five topics: 1. Medical history and CVI-questionnaires 23 (out of 1,007). 2. Ophthalmological and orthoptic assessment 37 (out of 816). 3. Neuropsychological assessment 5 (out of 716). 4. Neuroradiological evaluation and magnetic resonance imaging (MRI) 9 (out of 723). 5. Genetic assessment 5 (out of 458).
Conclusion
In medical history taking, prematurity low birth weight and APGAR (Appearance, Pulse, Grimace, Activity, Respiration) Scores (<5) are important. Different questionnaires are advised for children under the age of 3 years, older children and for specific risk groups (extremely preterm). In ophthalmological examination, eye movements, specially saccades, accommodation, crowding, contrast sensitivity and visual fields should be evaluated. OCT can show objective signs of
trans
-synaptic degeneration and abnormalities in fixation and saccades can be measured with eye tracking. Screening of visual perceptive functioning is recommended and can be directive for further assessment. MRI findings in CVI in Cerebral Palsy can be structured in five groups: Brain maldevelopment, white and gray matter lesions, postnatal lesions and a normal MRI. In children with CVI and periventricular leukomalacia, brain lesion severity correlates with visual function impairment. A differentiation can be made between cortical and subcortical damage and related visual function impairment. Additional assessments (neurological or genetic) can be necessary to complete the diagnosis of CVI and/or to reveal the etiology.
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