Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT

Evaluating the Efficacy of Translaminar Epidural Injections for Pain Resulting From the Lumbar Spine Degenerative Disease

Background: Caused by the degenerative spine disease (DSD), the pain syndrome in the lumbosacral spine and lower extremities represents a socioeconomic problem. Nowadays, minimally invasive methods of treatment, in particular, epidural injections (EI), are commonly used.Objective: To do a literature review on translaminar EIs and their mechanism of action in treating patients with radicular and vertebrogenic pain symptoms arising from the DSD.Materials and methods: We analyzed the most recent literature data in which the efficacy of epidural corticosteroid injections for DSD was evaluated.Conclusions: Translaminar EIs with corticosteroids are effective in relieving symptoms in the short term (up to 6 months) and delaying the surgery, but the evidence of their long-term benefits is yet to be found

Role of the Kaiso gene in the development of inflammation in Mucin-2 defcient mice

The number of people with inflammatory bowel disease (IBD) is constantly increasing worldwide. The main factors that have effects on the etiology of the disease are genetic, environmental and immunological. However, the mechanism of disease development and effective treatment of IBD have not yet been found. Animal models help address these problems. The most popular model is considered to be transgenic models in which individual genes are knocked out. One of such models for the study of IBD are mice with a null mutation of the Muc2 gene encoding the Mucin-2 protein, which is involved in the formation of a protective mucin layer in the small and large intestine. Some of transcription factors that change the expression of intestinal genes are involved in the development of IBD and colorectal cancer. One of such transcription factors is “zinc fnger” domain-containing protein Kaiso which is able to bind to methylated DNA. In this study, we assessed the role of Kaiso in the development of intestinal inflammation using the experimental model of C57BL/6Muc2-/-Kaiso-/-. We have shown that mice with impaired intestinal barrier function that develop processes similar to human IBD also develop inflammatory responses, such as increased expression of Il1, Tnf and Il17a genes. The defciency of the Kaiso transcription factor in Mucin-2 knockout mice causes a decrease in the expression level of only the Cox2 and Tff3 genes. Perhaps a decline in the expression of the gene encoding cyclooxygenase-2 can lead to a decrease in the expression of the antibacterial factor Trefoil factor 3. However, in the experimental model of IBD, Kaiso protein did not play a signifcant role in the regulation of pro-inflammatory cytokines of tumor necrosis factor and interleukins 1 and 17

Anatomical and morphological features of Pinus sylvestris growing on the dumps of the mining industry in the middle urals

The results of the study of anatomical and morphological parameters of Pinus sylvestris L., growing on the serpentine dumps of Anatol'sko-Shilovsky Mining, are presented. Adaptive morphological and anatomical changes that contribute to the survival of the species in extreme environmental conditions have been identified. A significant decrease in P. sylvestris morphometic parameters (tree height, the annual growth of the tree, and the branches) under dump conditions were established. Under the influence of unfavorable factors on the dumps (lack of nutrients and water, high rockiness of the substrate), the length and the cross-sectional area of the needles decreased. Of the anatomical features, it is important to note a decrease in the number of resin ducts with a tendency to increase their diameter. © 2021 Author(s)

Diffuse-Charge Dynamics in Electrochemical Systems

The response of a model micro-electrochemical system to a time-dependent applied voltage is analyzed. The article begins with a fresh historical review including electrochemistry, colloidal science, and microfluidics. The model problem consists of a symmetric binary electrolyte between parallel-plate, blocking electrodes which suddenly apply a voltage. Compact Stern layers on the electrodes are also taken into account. The Nernst-Planck-Poisson equations are first linearized and solved by Laplace transforms for small voltages, and numerical solutions are obtained for large voltages. The ``weakly nonlinear'' limit of thin double layers is then analyzed by matched asymptotic expansions in the small parameter $\epsilon = \lambda_D/L$, where $\lambda_D$ is the screening length and $L$ the electrode separation. At leading order, the system initially behaves like an RC circuit with a response time of $\lambda_D L / D$ (not $\lambda_D^2/D$), where $D$ is the ionic diffusivity, but nonlinearity violates this common picture and introduce multiple time scales. The charging process slows down, and neutral-salt adsorption by the diffuse part of the double layer couples to bulk diffusion at the time scale, $L^2/D$. In the ``strongly nonlinear'' regime (controlled by a dimensionless parameter resembling the Dukhin number), this effect produces bulk concentration gradients, and, at very large voltages, transient space charge. The article concludes with an overview of more general situations involving surface conduction, multi-component electrolytes, and Faradaic processes.Comment: 10 figs, 26 pages (double-column), 141 reference

Возможности коррекции микробиоты ротоглотки и кишечника у детей природными средствами на основе экстрактов растений

The widespread use of antibacterial drugs for the treatment of respiratory diseases causes antimicrobial resistance in opportunistic microorganisms, which leads to the chronic forms of respiratory diseases and contributes to the risk of repeated respiratory infections. One of the new therapeutic solutions is the use of multicomponent water-soluble plant extracts. The goal of this study was to evaluate the antibacterial efficacy of the extracts of multicomponent herbal remedies versus the synthetic antiseptic for the treatment of the oropharyngeal and gut opportunistic microflora in children with chronic tonsillitis.In a retrospective study, we compared the effectiveness of the plant extract Tonzinal (experimental group, 100 patients) versus the Miramistin antiseptic agent (control group, 40 patients) for the treatment of chronic tonsillitis in children 5 to 15 years old using various treatment regimens.The oropharyngeal microbiocenosis was investigated by the bacteriological analysis of smears from the posterior wall of the pharynx and tonsils. Bacterial strains were isolated by inoculation on liquid agar media with the subsequent identification of Staphylococcus aureus, Streptococcus pyogenes, Candida spp., Moraxela cataralis, and Mycoplasma pneumonie according to the morphological and biochemical characteristics. For the bacteriological analysis of gut microbiocenosis, Staphylococcus aureus, Streptococcus spp., Candida spp., Klebsiella spp., Clostridiums spp., and Proteus spp. were isolated from the fecal filtrate and then identified by the same methods. The occurrence rate of microorganisms in patients of the experimental and control groups was compared before and after the 10-day course of therapy.A statistically significant decrease in the occurrence rate of Staphylococcus aureus (from 25% to 0%, p<0.01) and Candida spp. (from 18% to 0%, p<0.01) in the oropharynx of patients in the experimental group and from 20% to 7.5% and from 5% to 0% (p<0.05), respectively, in the control group was observed. A statistically significant decrease in the occurrence rate of Streptococcus pyogenes was only observed in the experimental group (from 30% to 0%, p<0.01). Treatment with Tonzinal or Miramistin did not lead to the statistically significant changes in the occurrence rate of opportunistic microorganisms in the gut microflora of the patients in both groups. Therefore, we have shown a higher antimicrobial efficacy of Tonzinal versus the Miramistin antiseptic for the treatment of the oropharyngeal opportunistic microorganisms in children with chronic tonsillitis.Широкое применение антибактериальных препаратов для лечения респираторных заболеваний формирует резистентность к антибиотикам у условно-патогенных микроорганизмов, что влечет за собой хронические формы респираторных заболеваний и способствует риску повторных респираторных инфекций. Одним из новых терапевтических решений может быть применение многокомпонентных фитопрепаратов в виде водорастворимых экстрактов. Цель данного исследования – оценить эффективность антибактериального действия экстрактов многокомпонентных фитопрепаратов на условно-патогенную микрофлору ротоглотки и  кишечника у детей с диагнозом «хронический тонзиллит» по  сравнению с синтетическим антисептиком.В ретроспективном исследовании мы провели сравнение фитопрепарата «Тонзинал» (опытная группа, 100 человек) с антисептическим средством «Мирамистин» (группа контроля, 40 человек), определяя эффективность различных схем лечения хронического тонзиллита у детей в возрасте от 5 до 15 лет. Микробиоценоз ротоглотки исследовали с помощью бактериологического анализа мазков с задней стенки глотки и миндалин. Штаммы микроорганизмов выделяли методом посева на жидкие агаризованные среды с последующей идентификацией Staphylococcus aureus, Streptococcus pyogenes, Candida spp., Moraxela cataralis, Mycoplasma pneumonie по морфологическим и биохимическим признакам. Для проведения бактериологического анализа микробиоценоза кишечника штаммы условно-патогенных микроорганизмов выделяли из копрофильтрата аналогичным способом и идентифицировали Staphylococcus aureus, Streptococcus spp., Candida spp., Klebsiella spp., Clostridiums spp., Proteus spp. Сравнивали частоту встречаемости микроорганизмов, имеющих показатели интенсивности обсемененности более 104  КОЕ/г, в опытной группе и группе контроля до начала лечения и после 10‑дневного курса терапии.После 10‑дневного курса терапии в  ротоглотке наблюдали статистически значимое снижение частоты встречаемости Staphylococcus aureus и Candida spp. в опытной группе с 25% до 0% и с 18% до 0% соответственно (p<0.01) и в группе контроля с 20% до 7.5% и с 5% до 0% соответственно (p<0.01). Частота встречаемости Streptococcus pyogenes статистически значимо снизилась только в опытной группе (с 30% до 0%, p<0.01). При исследовании кишечной микрофлоры статистически значимых изменений частоты встречаемости исследуемых бактерий в опытной группе и группе контроля после применения препаратов не выявлено. Таким образом, мы показали более высокую антимикробную эффективность «Тонзинала» в отношении условно-патогенных микроорганизмов ротоглотки по сравнению с антисептиком «Мирамистин» при хроническом тонзиллите у детей

Gas Accretion and Giant Lyman-alpha Nebulae

Several decades of observations and discoveries have shown that high-redshift AGN and massive galaxies are often surrounded by giant Lyman-alpha nebulae extending in some cases up to 500 kpc in size. In this review, I discuss the properties of the such nebulae discovered at z>2 and their connection with gas flows in and around the galaxies and their halos. In particular, I show how current observations are used to constrain the physical properties and origin of the emitting gas in terms of the Lyman-alpha photon production processes and kinematical signatures. These studies suggest that recombination radiation is the most viable scenario to explain the observed Lyman-alpha luminosities and Surface Brightness for the large majority of the nebulae and imply that a significant amount of dense, ionized and cold clumps should be present within and around the halos of massive galaxies. Spectroscopic studies suggest that, among the giant Lyman-alpha nebulae, the one associated with radio-loud AGN should have kinematics dominated by strong, ionized outflows within at least the inner 30-50 kpc. Radio-quiet nebulae instead present more quiescent kinematics compatible with stationary situation and, in some cases, suggestive of rotating structures. However, definitive evidences for accretion onto galaxies of the gas associated with the giant Lyman-alpha emission are not unambiguously detected yet. Deep surveys currently ongoing using other bright, non-resonant lines such as Hydrogen H-alpha and HeII1640 will be crucial to search for clearer signatures of cosmological gas accretion onto galaxies and AGN.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics and Space Science Library, eds. A. J. Fox & R. Dave', to be published by Springe

Gas Accretion and Star Formation Rates

Cosmological numerical simulations of galaxy evolution show that accretion of metal-poor gas from the cosmic web drives the star formation in galaxy disks. Unfortunately, the observational support for this theoretical prediction is still indirect, and modeling and analysis are required to identify hints as actual signs of star-formation feeding from metal-poor gas accretion. Thus, a meticulous interpretation of the observations is crucial, and this observational review begins with a simple theoretical description of the physical process and the key ingredients it involves, including the properties of the accreted gas and of the star-formation that it induces. A number of observations pointing out the connection between metal-poor gas accretion and star-formation are analyzed, specifically, the short gas consumption time-scale compared to the age of the stellar populations, the fundamental metallicity relationship, the relationship between disk morphology and gas metallicity, the existence of metallicity drops in starbursts of star-forming galaxies, the so-called G dwarf problem, the existence of a minimum metallicity for the star-forming gas in the local universe, the origin of the alpha-enhanced gas forming stars in the local universe, the metallicity of the quiescent BCDs, and the direct measurements of gas accretion onto galaxies. A final section discusses intrinsic difficulties to obtain direct observational evidence, and points out alternative observational pathways to further consolidate the current ideas.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics and Space Science Library, eds. A. J. Fox & R. Dav\'e, to be published by Springe

Observational Diagnostics of Gas Flows: Insights from Cosmological Simulations

Galactic accretion interacts in complex ways with gaseous halos, including galactic winds. As a result, observational diagnostics typically probe a range of intertwined physical phenomena. Because of this complexity, cosmological hydrodynamic simulations have played a key role in developing observational diagnostics of galactic accretion. In this chapter, we review the status of different observational diagnostics of circumgalactic gas flows, in both absorption (galaxy pair and down-the-barrel observations in neutral hydrogen and metals; kinematic and azimuthal angle diagnostics; the cosmological column density distribution; and metallicity) and emission (Lya; UV metal lines; and diffuse X-rays). We conclude that there is no simple and robust way to identify galactic accretion in individual measurements. Rather, progress in testing galactic accretion models is likely to come from systematic, statistical comparisons of simulation predictions with observations. We discuss specific areas where progress is likely to be particularly fruitful over the next few years.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics and Space Science Library, eds. A. J. Fox & R. Dave, to be published by Springer. Typos correcte

Terrestrial biosphere changes over the last 120 kyr

A new global synthesis and biomization of long (> 40 kyr) pollen-data records is presented and used with simulations from the HadCM3 and FAMOUS climate models and the BIOME4 vegetation model to analyse the dynamics of the global terrestrial biosphere and carbon storage over the last glacial–interglacial cycle. Simulated biome distributions using BIOME4 driven by HadCM3 and FAMOUS at the global scale over time generally agree well with those inferred from pollen data. Global average areas of grassland and dry shrubland, desert, and tundra biomes show large-scale increases during the Last Glacial Maximum, between ca. 64 and 74 ka BP and cool substages of Marine Isotope Stage 5, at the expense of the tropical forest, warm-temperate forest, and temperate forest biomes. These changes are reflected in BIOME4 simulations of global net primary productivity, showing good agreement between the two models. Such changes are likely to affect terrestrial carbon storage, which in turn influences the stable carbon isotopic composition of seawater as terrestrial carbon is depleted in 13C