Disease-modifying treatments for neuromyelitis optica spectrum disorder in the context of a new generation of biotherapies.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices.

Clinical applications of deep learning in neuroinflammatory diseases: A scoping review.

BACKGROUND: Deep learning (DL) is an artificial intelligence technology that has aroused much excitement for predictive medicine due to its ability to process raw data modalities such as images, text, and time series of signals. OBJECTIVES: Here, we intend to give the clinical reader elements to understand this technology, taking neuroinflammatory diseases as an illustrative use case of clinical translation efforts. We reviewed the scope of this rapidly evolving field to get quantitative insights about which clinical applications concentrate the efforts and which data modalities are most commonly used. METHODS: We queried the PubMed database for articles reporting DL algorithms for clinical applications in neuroinflammatory diseases and the radiology.healthairegister.com website for commercial algorithms. RESULTS: The review included 148 articles published between 2018 and 2024 and five commercial algorithms. The clinical applications could be grouped as computer-aided diagnosis, individual prognosis, functional assessment, the segmentation of radiological structures, and the optimization of data acquisition. Our review highlighted important discrepancies in efforts. The segmentation of radiological structures and computer-aided diagnosis currently concentrate most efforts with an overrepresentation of imaging. Various model architectures have addressed different applications, relatively low volume of data, and diverse data modalities. We report the high-level technical characteristics of the algorithms and synthesize narratively the clinical applications. Predictive performances and some common a priori on this topic are finally discussed. CONCLUSION: The currently reported efforts position DL as an information processing technology, enhancing existing modalities of paraclinical investigations and bringing perspectives to make innovative ones actionable for healthcare.

Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Low sensitivity of SARS-CoV-2 rapid antigen self-tests under laboratory conditions.

SARS-CoV-2-antigen-testing has been proposed as a 'game-changing' tool to interrupt infection chains. Thereby European strategies focused on two pillars, namely rapid antigen tests conducted by health care experts and/or trained personal and so-called self-tests. Here, evidence is provided that these assays have a weak performance even under laboratory conditions.

Synergistic antitumor effects of topoisomerase inhibitors and natural cell-mediated cytotoxicity.

The mechanism of augmentation of tumor cell killing by immune effector cells and chemotherapeutic drugs was studied. The effect of treating tumor cells with various antineoplastic drugs on their sensitivity to murine natural cell-mediated cytotoxicity in vitro was investigated. Pretreatment with actinomycin D at nontoxic concentrations rendered L929 and WEHI-164 tumor cells more susceptible to killing by mouse spleen lymphocytes in a dose-dependent manner. Similarly, enhancement of L929 tumor cell killing by natural cell-mediated cytotoxicity was observed following treatment of the target cells with the topoisomerase II inhibitors, Adriamycin, amsacrine, bisantrene, etoposide, and teniposide, as well as with topoisomerase I inhibitor, camptothecin. In contrast, drugs which induce their cytotoxic effects by mechanisms that do not involve topoisomerase inhibition such as bleomycin, vinblastine, vincristine, and mitomycin C failed to exhibit synergism with natural cell-mediated cytotoxicity. However, moderate synergy was consistently observed with cis-platinum. The effector cells responsible for the cytotoxicity in the present system are natural cytotoxic cells since they kill WEHI-164 but not YAC cells, are resistant to treatment with anti-asialo-GM1 antibody, and their activity is abolished by anti-tumor necrosis factor antibodies. Indeed, tumor necrosis factor-mediated cytotoxicity of WEHI-164 or L929 was enhanced by treatment of the target cells with topoisomerase II inhibitors. Moreover, WEHI-164 cells selected for tumor necrosis factor resistance were resistant to natural cell-mediated cytotoxicity, and no synergy could be observed with topoisomerase inhibitors.

Effects of electrical stimulation on wound healing in patients with diabetic ulcers.

OBJECTIVE: To evaluate the effects of two stimulation waveforms on healing rates in patients with diabetes and open ulcers. The hypothesis was that stimulus waveforms with minimal polar characteristics would provide significant healing for this patient sample. RESEARCH DESIGN AND METHODS: This was a prospective study that enrolled 80 patients with open ulcers. Patients received stimulation with either an asymmetric biphasic (A) or symmetric biphasic (B) square-wave pulse. Amplitudes were set to activate intact peripheral nerves in the skin. Two other groups received either very low levels of stimulation current (MC), or no electrical stimulation (C). When combined these groups were referred to as the control group. Treatment was carried out daily until the wound healed, the patient withdrew from the study, or the physician changed the overall wound management program. Average healing rates were calculated from weekly measures of the wound perimeter and were used for statistical comparison through a one-way analysis of variance. RESULTS: Stimulation with the A protocol significantly increased the healing rate, enhancing healing by nearly 60% over the control rate of healing. Stimulation with the B protocol did not increase the healing rate when compared with control subjects. CONCLUSIONS: Electrical stimulation, given daily with a short pulsed, asymmetric biphasic waveform, was effective for enhancement of healing rates for patients with diabetes and open ulcers.

A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect.

The clinical features of Angelman syndrome (AS) comprise severe mental retardation, postnatal microcephaly, macrostomia and prognathia, absence of speech, ataxia, and a happy disposition. We report on seven patients who lack most of these features, but presented with obesity, muscular hypotonia and mild mental retardation. Based on the latter findings, the patients were initially suspected of having Prader-Willi syndrome. DNA methylation analysis of SNRPN and D15S63, however, revealed an AS pattern, ie the maternal band was faint or absent. Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental inheritance. We conclude that these patients have an imprinting defect and a previously unrecognised form of AS. The mild phenotype may be explained by an incomplete imprinting defect or by cellular mosaicism.

Maternal UPD 20 in a hyperactive child with severe growth retardation.

Maternal uniparental disomy was observed in a 4-year-old boy with severe pre- and postnatal growth retardation (body height: 85 cm = 12 cm < third percentile, head circumference: 48 cm = 10 cm < third percentile), a few minor facial findings, and with apparent hyperactivity. His intelligence is within the normal range for his age. Karyotype analysis revealed two cell lines, one apparently normal with 46,XY, the other with a tiny marker (47,XY, + mar). Microdissection and reverse chromosome painting using the marker DNA library as a probe, as well as PCR analysis revealed that the marker is from chromosome 20 and contains only the centromere and pericentromeric segments, but none of the pericentromeric loci for microsatellites. Microsatellite analysis of 25 chromosome 20 loci disclosed maternal uniparental disomy for all 16 informative markers. Maternal heterodisomy was evident for seven loci of the short arm segment 20p11.2-pter. Maternal isodisomy was found at five loci, three of them map to the proximal 20p11.2 segment and two to 20q. To our knowledge, this is the first case of maternal disomy 20 in humans.

Neurogenesis in the central olfactory pathway of adult decapod crustaceans.

Based on the previous findings that the number of olfactory projection neurons increases continuously in adult shore crabs, Carcinus maenas, and that this increase is associated with the presence of 5-bromo-2-deoxyuridine (BrdU)-positive, proliferating cells in the appropriate soma clusters (lateral soma clusters), we studied the further fate of these proliferating cells and the presence of apparent adult neurogenesis throughout the central olfactory pathway of diverse species of decapod crustaceans. Double labeling experiments combining biocytin-backfills and in vivo BrdU labeling as well as BrdU labeling with extended survival times (1 month) indicate that the cells proliferating in the lateral soma clusters of adult Carcinus undergo neuronal differentiation in about 3-4 weeks. In vivo BrdU labeling of different species representing important taxa of decapod crustaceans (shrimps, spiny lobsters, clawed lobsters, crayfish) revealed that neurogenesis among olfactory projection neurons is a constitutive feature of the adult decapod brain. In contrast, adult neurogenesis of the other neuron types present in the central olfactory pathway occurs in a taxon-specific manner and appears to be related to the development and reduction of accessory lobes throughout decapod phylogeny.

Effect of dantrolene sodium on [3H]nitrendipine binding to rat cardiac plasma membranes.

Dantrolene sodium (Dantrium) has antiarrhythmic activity in addition to its direct-acting skeletal muscle relaxant activity. Dantrolene sodium exerts its skeletal muscle relaxant action by reducing Ca2+ release for sarcoplasmic reticulum. The mechanism by which dantrolene sodium produces its antiarrhythmic effects is not well defined. The effects of dantrolene sodium on [3H]nitrendipine binding to rat cardiac plasma membranes were, therefore, investigated to determine whether the antiarrhythmic action involves an interaction with calcium channels. Whereas 1,4-dihydropyridines maximally inhibited [3H]nitrendipine binding with IC50 values less than 1 nM, verapamil and gallopamil (D 600) inhibited the binding not more than 70% with IC50 values at microM concentrations. Dantrolene sodium caused only minimal inhibition at concentrations up to 100 microM. Thus, the antiarrhythmic action of the drug probably involves a mechanism(s) other than an interaction with the nitrendipine binding site of the slow inward calcium channel.

[Familial juvenile nephronophthisis--a genetically-caused kidney disease]. / Die familiäre juvenile Nephronophthise--eine genetisch bedingte Nierenerkrankung.

It is reported on the course of the autosomal recessive transmitted familiar juvenile nephronophthisis in 3 siblings. Direct symptoms are polydipsia and polyuria with terminal course of chronic renal failure which could treated by dialysis and transplantation. Examination of the safe (parents) and possible (healthy siblings) heterozygotes was without particularities.

[Familial juvenile nephronophthisis. Pathohistology of a rare genetic disease in three siblings]. / Die familiäre juvenile Nephronophthise. Zur Pathohistologie einer seltenen, genetisch bedingten Erkrankung dreier Geschwister.

Reported in this paper are clinical and morphological findings recorded from two sisters and one brother with familial juvenile nephronophthisis. Coherency in the basic course of the disease was not detectable by histological examinations, in the first place, though infancy developments had been almost identical, and clinical patterns were very similar to each other, with the characteristics including polyuria, polydipsia, hyposthenuria, anaemia, retarded growth, azotaemia, and progressing renal insufficiency. Some of the morphological findings were masked by secondary alterations and organ shrinkage. They were incoherently interpreted following preliminary investigations by different examiners. The pathogenesis of the disease has continued to be obscure. A disorder with tubular basal membranes as primary points of attack is discussed. Autosomal-recessive inheritance seems to be beyond any doubt, following genetic analysis of the family.

Suppressed IL-2 production and response in AA rats: role of suppressor cells and the effect of auranofin treatment.

The marked suppression of mitogenic responses to concanavalin A observed in adjuvant arthritic (AA) rats during the development and progression of the clinical disease is mediated primarily by splenic adherent cell population. The suppressed mitogenic response of spleen cells from AA rats was in part due to suppressed production of and response to interleukin 2 (IL-2). Unfractionated spleen cells from AA rats did not produce or respond to IL-2. However, IL-2 production and response were normalized after removal of adherent cells. Reconstitution experiments demonstrated that adherent cells from AA rats suppressed both the mitogenic response and IL-2 production by normal spleen cells. The low IL-2 levels was not a result of degradation or consumption of endogenously produced interleukin. In vitro treatment of suppressor adherent cells from AA rats with micromolar concentrations of auranofin (AF), but not gold sodium thiomalate, totally abolished the suppression of both mitogenesis and IL-2 production. Our studies demonstrate that the suppressed lymphocyte mitogenic responses, IL-2 response and IL-2 production of AA rat spleen cells are due to the presence of suppressor adherent cells, and that treatment with AF inhibited suppressor cell activity and restored to normal levels lymphocyte mitogenic responses and IL-2 production.

Alternative splicing of dystrophin mRNA complicates carrier determination: report of a DMD family.

Carrier determination is important for genetic counselling in DMD/BMD families. The detection of altered PCR amplified dystrophin mRNA fragments owing to deletions, insertions, or point mutations has increased the possibilities of carrier determination. However, problems may occur because of alternative splicing events. Here we present a family with a DMD patient characterised by a deletion of exons 45 to 54. At the mRNA level we detected a corresponding altered fragment which served for carrier determination. The mother and the sister of the patient showed the same altered dystrophin mRNA fragment as the patient and are therefore carriers. In the mother two additional altered dystrophin mRNA fragments were detectable, obviously resulting from alternative splicing in the normal allele. The grandmother and two other related females of the patient possess only the normal mRNA fragment. In a further female we detected an altered fragment owing to an mRNA deletion of exon 44. This fragment is created either by alternative splicing or a new mutation. Therefore, the carrier status of this female is still ambiguous indicating problems in carrier determination by the method of dystrophin mRNA analysis.

Effect of electrical stimulation waveform on healing of ulcers in human beings with spinal cord injury.

Various electrical stimulation waveforms have been used to enhance wound healing, with little consideration for potential differences in their physiologic effect. The present study evaluated the effect of stimulation waveform and electrode placement on wound healing. Eighty patients with spinal cord injury and one or more pressure ulcers were treated. A total of 185 ulcers received 45 minutes of stimulation daily. Each ulcer was subjected to one of four treatment protocols: asymmetric biphasic waveform, symmetric biphasic waveform, microcurrent stim-ulation, or a sham control protocol. Electrodes were placed outside the wounds, over intact skin and surrounding the area of the ulcer. Data were categorized by ulcers which healed during the protocol and those which did not. Analysis of the "good response" ulcers (n = 104) showed significantly better healing rates for those receiving stimulation with the asymmetric biphasic waveform, compared with the control and microcurrent groups. Mean healing rates from the present study were similar to previously reported measures. The waveforms studied possessed minimal polar capabilities, and the electrodes were placed outside the wound. These data show that electrical stimulation clearly enhanced healing of pressure ulcers in a significant number of individuals with spinal cord injury; the physiologic implications of these findings relative to the mechanism(s) by which electrical stimulation enhances wound healing are discussed. However, extrapolation of these results to patients with other types of wounds must await further study.

The effect of ethanol on the fate of mercury vapor inhaled by man.

Three human subjects ingested 1065 ml of beer equivalent to 65 ml of ethanol 30 min before exposure (12-20 min) to mercury vapor. An additional two subjects were exposed to mercury vapor without ethanol pretreatment. The results show that alcohol brings about: 1) reduced mercury retention, 2) an increase in the rapid phase of vapor loss by expiration, 3) an increased mercury storage in the liver, 4) a marked reduction in mercury uptake by the red blood cells and 5) the abolition of vapor exposure experiments were performed by using control and ethanol-pretreated mice and rats. Sacrifice occurred at 1 hr and 3 days. The results support and extend the human data.

Prediction of human analgesic dosages of nonsteroidal anti-inflammatory drugs (NSAIDs) from analgesic ED50 values in mice.

The oral analgesic activities (ED50's) of 15 NSAIDs were determined in the phenylquinone-induced writhing test in mice. ED50 values (mg/kg) were: acetylsalicylic acid (182), fenclofenac (168), phenylbutazone (129), ibuprofen (82.2), diflunisal (55.6), benoxaprofen (25.4), naproxen (24.1), mefenamic acid (20.7), indomethacin (19.0), meclofenamate sodium (9.60), sulindac (7.20), fenoprofen calcium (3.70), tolmetin (1.30), zomepirac sodium (0.70), and piroxicam (0.44). Significant linear correlations were found between mouse ED50 values and the various recommended human analgesic or anti-inflammatory dosages. Thus, analgesic ED50 values (mg/kg p.o.) in mice (X) may be used to predict human dosages (Y) of NSAIDs according to the equation Y = 8.26X + 535, where Y is the projected human daily dosage (mg).

Influenza A subtype cross-protection after immunization of outbred mice with a purified chimeric NS1/HA2 influenza virus protein.

Influenza A/PR/8/34-derived chimeric (D) protein (SK&F 106160) composed of the first 81 amino acids (aa) of NS1 fused to the conserved 157 C-terminal aa of HA2 (NS1 1-81-HA2 65-222) was previously shown to induce H-2d-restricted protective cytotoxic T-lymphocyte (CTL) immunity in inbred mice. However, D protein, like other small peptides, exhibited haplotype dependence and was not immunogenic in H-2b and H-2K mice. A potential use of this antigen in humans and the role of T cells in any protection were evaluated in outbred Swiss and inbred CBF6F1 (H-2d/b) mice. Mice immunized with D protein and challenged by small-particle aerosol with a lethal dose of influenza virus were significantly protected against mortality from influenza A/H1N1 and A/H2N2 (p < 0.05-< 0.0000001), but not from A/H3N2 and influenza B viruses when compared with control mice. D protein did not induce serum virus-neutralizing antibody but caused virus to be cleared faster in immunized mice. Protection was long-lasting. In vivo depletion of either Lyt2 (CD8+) or L3T4 (CD4+) T cells with monoclonal antibodies led to abrogation of in vitro-generated CTL activity in CF6F1 mice and significant reduction in the protective efficacy of D protein against virus challenge in both Swiss and CF6F1 mice. These results suggest that protection was mediated by CD8+ and/or CD4+ cells and not antibody. Thus D protein, via a conserved sequence on the HA2 polypeptide, has the potential to induce partially cross-reactive CTL that may protect against influenza virus disease in humans.