The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are ...only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.
X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in
COL4A5
primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from ...microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in
COL4A5
compared to healthy controls. A total of 56 females with a heterozygous disease-causing
COL4A5
variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort (
rho
= 0.403,
p
= 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the
COL4A5
variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the
COL4A5
variant carrying allele in female individuals with AS.
Background
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of ...established biomarkers or risk factors for the development of CIDP and patients’ treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy.
Methods
In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy.
Results
In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence.
Conclusion
Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a “hit hard and early” treatment paradigm.
Abstract
The use of growth estimation methods that depend on unreliable age data has previously hindered the quantification of perceived differences in growth rates between the two cod stocks ...inhabiting the Baltic Sea. Data from cod tagged in different regions of the Baltic Sea during 2007–2019 were combined, and general linear models were fit to investigate inter-regional (defined as area of release) and inter-stock (assigned to a subset of recaptures using genetic and otolith shape analyses) differences in individual growth. An average-sized cod (364 mm) caught in the western Baltic Sea and assigned to the western Baltic cod stock grew at more than double the rate (145 mm year−1) on average than a cod of the same size caught in the eastern Baltic Sea and assigned to the eastern Baltic cod stock (58 mm year−1), highlighting the current poor conditions for the growth of cod in the eastern Baltic Sea. The regional differences in growth rate were more than twice as large (63 mm year−1) as the stock differences (24 mm year−1). Although the relative importance of environmental and genetic factors cannot be fully resolved through this study, these results suggest that environmental experience may contribute to growth differences between Baltic cod stocks.
Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to ...prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.
The potassium channel KIR4.1 (KCNJ10) and the glutamate catalyzing enzyme glutamine synthetase (GS) are highly expressed in glial cells of the central nervous system. Both glial proteins play ...important roles in the maintenance of neuronal activity and neurotransmission. Dysfunction of both proteins can result in altered neuronal excitability and may lead to excitotoxicity. We analyzed 35 snap frozen tissue blocks (glioblastoma GBM, n=22; low grade astrocytoma (LGA), n=8; oligodendroglioma (OG), n=3; oligoastrocytoma, n=2). All glioma samples had a matching tissue specimen from both the tumor core and the adjacent normal-appearing infiltration zone. Molecular subtyping (MGMT, IDH1/2, 1p/19q) was available from tumor specimens. We combined conventional histology and immunohistochemistry with gene expression analysis and western blot. In preliminary analysis, we found downregulation of KIR4.1 and GS in the tumor core of GBM samples as compared to matching infiltration zone tissue of the same patients. In addition, KIR4.1 transcript levels were reduced in GBM core tissue as compared to LGA tumor core. The pan-astroglial protein AQP4 was not different between tumor core and infiltration zone. We observed a tendency that reduced GS transcript levels were associated with increased epileptic activity in GBM patients. In summary, we found that both KIR4.1 and GS were downregulated in tumor core versus infiltration zone tissue. Enhanced neuronal excitability and increased risk for epileptic activity might be associated with lack of KIR4.1 and GS activity.
Antibiotic-associated diarrhea is an important clinical problem, associated with morbidity, mortality and healthcare costs. Our randomized, placebo controlled multicenter trial do not support the ...efficacy of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea.
Background.
Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients.
Methods.
We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks.
Results.
Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 ± 16.5 years and 231 patients aged 56.5 ± 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55–1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation.
Conclusions.
We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment.
ClinicalTrials.gov Identifier.
NCT01143272.
Structural information on electronically excited neutral molecules can be indirectly retrieved, largely through pump-probe and rotational spectroscopy measurements with the aid of calculations. Here, ...we demonstrate the direct structural retrieval of neutral carbonyl disulfide (CS\(_2\)) in the B\(^1\)B\(_2\) excited electronic state using laser-induced electron diffraction (LIED). We unambiguously identify the ultrafast symmetric stretching and bending of the field-dressed neutral CS\(_2\) molecule with combined picometer and attosecond resolution using intrapulse pump-probe excitation and measurement. We invoke the Renner-Teller effect to populate the B\(^1\)B\(_2\) excited state in neutral CS\(_2\), leading to bending and stretching of the molecule. Our results demonstrate the sensitivity of LIED in retrieving the geometric structure of CS\(_2\), which is known to appear as a two-center scatterer.
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