Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy.

Anti-MAG demyelinating neuropathy is difficult to treat. All immunotherapies have failed except for rituximab, a chimeric B-cell–depleting monoclonal antibody against CD20, that helps up to 40% of patients based on 2 controlled and several uncontrolled series.1,–,3 Because the majority of these patients are left disabled, stronger anti–B-cell agents might be promising. We describe clinical response and autoantibody changes after treatment with obinutuzumab (Gazyva), a new generation of humanized anti-CD20 monoclonal antibodies, in 2 patients with anti-MAG neuropathy who continued to worsen despite multiple courses of rituximab. Obinutuzumab, approved for chronic lymphocytic leukemia (CLL), exerts greater peripheral and lymphoid B-cell depletion4 and might be more effective in rituximab-refractory patients. © Rakocevic et al

Molecular treatment effects of alemtuzumab in skeletal muscles of patients with IBM.

BACKGROUND: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. METHODS: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. RESULTS: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-β, TNF-α, and IL-1β. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1β and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and β-amyloid. CONCLUSIONS: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM

Agrohemijske osobine mladog karbonatnog fluvisola u slivu reke Ljig

Morphological study of several open profiles different depths and their analysis showed that land in the Ljig River belongs to the type of young alluvial soil (fluvisol) and subtype young carbonate alluvial soil. Based on the agrochemical analysis, can be concluded that this land is mostly poor and poorly supplied with humus, weakly to moderately alkaline, poor available phosphorus and mostly medium provided available potassium. The total content of Cu, Zn, Pb and Cd within the maximum allowable concentration, while the content of Ni and Cr above these values.Morfološkim proučavanjem nekoliko otvorenih profila i poluprofila različite dubine i njihovom analizom utvrđeno je da zemljište u slivu reke Ljig pripada tipu mladog aluvijalnog zemljišta (fluvisola) i to podtipu mladog karbonatnog aluvijalnog zemljišta. Na osnovu urađenih agrohemijskih analiza može se zaključiti da je ovo zemljište uglavnom siromašno do slabo obezbeđeno humusom, slabo do srednje alkalne reakcije, siromašno lakopristupačnim fosforom i uglavnom srednje obezbeđeno lakopristupačnim kalijumom. Ukupni sadržaj Cu, Zn, Pb i Cd je u okviru maksimalno dozvoljenih koncentracija, dok je sadržaj Ni i Cr iznad ovih vrednosti

Prinos i kvalitet krtola krompira u zavisnosti od đubrenja

Research on the effect of different rates and methods of application of mineral NPK fertilizers on the yield and quality of potato variety ‘Carrera’ was conducted on a luvisol of the Radočelo Mountain massif. Treatments included an unfertilized control, NPK 16:16:16 (1500 kg ha) applied in-furrow at planting, NPK 16:16:16 (1200kg ha-1) applied in-furrow at planting, and NPK 16:16:16 applied at 700 kg ha-1 during seedbed preparation and 500 kg ha-1 in-furrow at planting. Mineral fertilizers led to a very significant increase in tuber yield compared to the control, giving the highest total yield under 1500 kg ha-1 NPK treatment. Results on the nutritional value of potato tubers showed that the levels of tested nutrients were higher in the skin than in the flesh. The concentrations of tested nutrients in potato tubers were highest at the highest NPK fertilizer rate.Ispitivanje uticaja različitih doza i načina primene mineralnog đubriva NPK 16:16:16 (1500 kg ha-1, primenjenog u brazde zavreme sadnje, 1200 kg ha-1, primenjenog u brazde za vreme sadnje i 700 kg ha-1 za vreme predsetvene pripreme uz 500 kg ha-1 u brazde za vreme sadnje) na prinos i kvalitet krompira sorte Karera izvedeno je na lesiviranom zemljištu (luvisolu) planinskog masiva Radočelo. Primenjena mineralna đubriva su uticala na značajno povećanje prinosa u odnosu na kontrolu, pri čemu je značajno veći prinos postignut na varijanti sa većom količinom đubriva u odnosu na ostale varijante. Primena iste doze NPK đubriva različitim načinima unošenja nije značajno uticala na prinos i kvalitet krtola krompira. Analizom krtola krompira je utvrđeno da je sadržaj svih elemenata bio veći u kori u odnosu na srž krtole, kao i da je najveći sadržaj bio na varijanti sa najvećom dozom NPK đubriva

Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study

BACKGROUND: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. METHODS: We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. RESULTS: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. CONCLUSION: The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM

A community-powered search of machine learning strategy space to find NMR property prediction models

The rise of machine learning (ML) has created an explosion in the potential strategies for using data to make scientific predictions. For physical scientists wishing to apply ML strategies to a particular domain, it can be difficult to assess in advance what strategy to adopt within a vast space of possibilities. Here we outline the results of an online community-powered effort to swarm search the space of ML strategies and develop algorithms for predicting atomic-pairwise nuclear magnetic resonance (NMR) properties in molecules. Using an open-source dataset, we worked with Kaggle to design and host a 3-month competition which received 47,800 ML model predictions from 2,700 teams in 84 countries. Within 3 weeks, the Kaggle community produced models with comparable accuracy to our best previously published "in-house" efforts. A meta-ensemble model constructed as a linear combination of the top predictions has a prediction accuracy which exceeds that of any individual model, 7-19x better than our previous state-of-the-art. The results highlight the potential of transformer architectures for predicting quantum mechanical (QM) molecular properties

Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment?

Abstract Background Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy. Methods Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment. Results Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia. Conclusion An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients