Leptomeningitis in a person with radiologically isolated syndrome and latent tuberculosis. A case report with implications for clinical research

A 39-year-old man, followed with serial MRI of CNS for a radiologically isolate syndrome (RIS, a recently described condition considered a subclinical form of MS), was hospitalized for the occurrence of a leptomeningitis. Routine blood tests and contrast enhanced total body CT scan were unremarkable. Cerebrospinal fluid (CSF) examination showed increase of cells (22 mononuclear cells/mm3), albumin (294 mg/L), immunoglobilins G (161 mg/L) and Link Index (1.9), with 17 oligoclonal bands. Microbiological examinations of CSF (including those for Koch’s Bacillus) were negative. The Mantoux reaction and the QuantiFERON test were positive, featuring a latent tuberculosis (TB). The patient started prophylaxis with rifampicin and isoniazid for four months, until a new MRI showed the disappearance of the leptomeningeal enhancement, and the stability of white matter brain and spinal cord lesions. Two other MRI scans showed a new brain Gd-enhancing lesion nine month after anti-tubercular therapy and, after additional six months, new cerebral and spinal cord areas. This case provides the following suggestions about the effects of TB infection and related therapies on the underlying autoimmune status: the infection, while actively present, did not exacerbate the RIS condition; the worsening nine months after the prophylaxis discontinuation might have been the ‘natural’ evolution of RIS condition. Alternative speculative hypotheses include a remote effect of the infection, of isoniazid (that was reported in some cases to trigger MS), or the result of the clearance of the infection itself. Irrespective of the existence of any interaction between RIS and TB infection, It seems important to collect cases with MS-related diseases and concomitant infections, that may provide clues about disease pathogenesis and treatment

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan

Genome-Wide Multiple Sclerosis Association Data and Coagulation

The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; z-score = 17.39; p-value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets

Spatial abilities and the gender gap in mathematics (Matabì)

Learning mathematics is a general problem in Italy, but it is more relevant for females. Male students typically outperform their female classmates in maths test scores from the earliest years of schooling, and the gap worsens as school grades progress. The different experiences and expectations about potential abilities of boys and girls are key to understanding the possible causes of the observed relative differences in education performance. Early life experiences are essential for developing a child’s cognitive capacities, and environmentally induced gender differences may arise when children are exposed to heterogeneous sources of development opportunities. One of the sources of gender inequalities in mathematics is related to differences in the acquisition of visuospatial abilities between girls and boys from a very young age. Existing works find that playing with specific toys facilitates learning in maths and science. Boys usually gain more experience than girls because of different parental and educators’ beliefs and behaviour regarding the gender-specific suitability of toys. Moreover, self-confidence and anxiety are not gender-neutral and can affect educational outcomes. The Matabì project aims to enhance spatial abilities and reduce the gender gap via construction play (i.e., by using building toys and Lego Duplo brick sets). Using the bricks should help students process abstract concepts, while the playful approach should reduce maths anxiety. Girls should benefit more from Matabì than males, who are (on average) able to develop these skills early on in life. The project started in October 2022, so we would present the overall structure and what has been accomplished so far. This should be engaging in three respects: the teachers' reinforcement of their spatial abilities, the instruments used to collect the outcomes, and the impact evaluation design conducted with Randomized Control Trial (RCT). Teachers’ training includes a pre- and post-standardised test, the mental rotation section of the Revised Purdue Spatial Visualization Test. The RCT involves around 60 classes in five schools in Torino (60 teachers and 1200 third and fourth grade pupils). Within each school, we randomly assigned a third of the teachers to the control group and two-thirds to the treatment group. The study will provide evidence of the effects of teaching methods exploiting construction play. The primary research questions are: 1- What is the impact on the spatial abilities of teachers? 2- What is the impact on the spatial abilities of pupils? 3- How does the impact differ by gender? 4- How does the treatment affect the gender gap in mathematics

Analysis of the flows and of the factors that impact the accessibility and identity of public spaces

The territory and the contemporary city require a dynamic approach capable of embracing the life cycles of the different functions and their relationships. The article discusses tools developed in three case studies in which some factors that determine the evolution of tourist and healthcare functions in a historical centre and recreational functions in a protected natural park can be observed and interpreted. The research presented aims to provide the territorial conservation, transformation and enhancement project with tools capable of interacting with new social demands for inclusiveness, identity, accessibility and sharing, favouring new forms of administration as well as participation and collaboration between different knowledge and skill sets

CO2 capture from natural gas combined cycles by CO2 selective membranes

This paper performs a techno-economic analysis of natural gas-fired combined cycle (NGCC) power plants integrated with CO2 selective membranes for post-combustion CO2 capture. The configuration assessed is based on a two-membrane system: a CO2 capture membrane that separates the CO2 for final sequestration and a CO2 recycle membrane that selectively recycles CO2 to the gas turbine compressor inlet in order to increase the CO2 concentration in the gas turbine flue gas. Three different membrane technologies with different permeability and selectivity have been investigated. The mass and energy balances are calculated by integrating a power plant model, a membrane model and a CO2 purification unit model. An economic model is then used to estimate the cost of electricity and of CO2 avoided. A sensitivity analysis on the main process parameters and economic assumptions is also performed. It was found that a combination of a high permeability membrane with moderate selectivity as a recycle membrane and a very high selectivity membrane with high permeability used for the capture membrane resulted in the lowest CO2 avoided cost of 75 US$/tCO2. This plant features a feed pressure of 1.5 bar and a permeate pressure of 0.2 bar for the capture membrane. This result suggests that membrane systems can be competitive for CO2 capture from NGCC power plants when compared with MEA absorption. However, to achieve significant advantages with respect to benchmark MEA capture, better membrane permeability and lower costs are needed with respect to the state of the art technology. In addition, due to the selective recycle, the gas turbine operates with a working fluid highly enriched with CO2. This requires redesigning gas turbine components, which may represent a major challenge for commercial deployment

Peripheral Biomarkers in Manifest and Premanifest Huntington’s Disease

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades

CADASIL or MS? Consider “Red Flags” but Avoid a Misdiagnosis: Case Series of a Concomitant Diagnosis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic autosome-dominant disease with chronic clinical course. Rarely, CADASIL may present with atypical relapsing-remitting manifestations, cerebral and spinal white matter lesions, mimicking inflammatory CNS disease as multiple sclerosis (MS). The rarely co-occurrence of MS and CADASIL may represent a hard challenging diagnosis even for an expert neurologist. Here, we present a case series of two patients with CADASIL showing MRI pattern overlapping MS. They were the only case of co-occurrence of CADASIL and MS in their own family. Both patients were treated with anti-inflammatory and anti-platelet drugs, mostly with good response. Pathogenic hypothesis highlights that genetic events, related to monogenic disease, may expose CNS antigens with a consequent self-immune attack. In CADASIL, the function of Notch3 receptor showed a consistent interplay with immune system activity. Indeed, certain mutations of Notch3 receptor show abnormal upregulation of specific pro-inflammatory patterns. However, even if it is not possible to determinate if the proinflammatory activity may be promoted by pathogenic mutations in Notch3, the "apparent" difference between MS and “inflammatory CADASIL” could be considered more semantic than etiologic