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  • Two patients developed diffuse mesangio

    2024-06-11

    Two patients developed diffuse mesangio-proliferative glomerulonephritis (DMPG) postoperatively, presenting as nephrotic syndrome and benign haematuria, respectively. DMPG has been reported in an adult patient with thymomatous MG following thymectomy [35], and various types of glomerulonephritis have been associated with MG with or without thymoma [36], [37], attributed to the use of immune-modulating agents as the cause in some patients. Both our patients had no thymoma and had not received immune-modulating agents other than KC7F2 prior to the onset of renal symptoms. Although both patients developed glomerulonephritis following thymectomy, it is difficult to establish a causal relationship in view of the recognised association of MG with glomerulonephritis. Thymectomy in very young children has caused some controversy. Impaired immune development following thymectomy has been reported in animal studies [20], and immunological abnormalities have been suggested in young infants undergoing thymectomy [38], [39]. However, the clinical significance of these abnormalities remains controversial, and others have indicated that thymectomy in young children is usually tolerated well without serious adverse effects [13], [22], [40]. The reported response to thymectomy in very young children has been inconsistent [13], [17], [40], probably reflecting the fact that some of those may have had unrecognised CMS. Both patients in our series who underwent thymectomy below 3years of age achieved grade B response, but one required steroid sparing agents (MMF following a failed trial with azathioprine) due to persistent steroid dependency. In conclusion, all children in our series with non-thymomatous, AChR antibody positive generalised MG had improvement in their disease severity post thymectomy, with about one third having achieved complete remission at the time of their last follow-up. Surgical morbidity was low, with a hospital stay of usually less than 7days. In view of the hazards of long term steroid and immune-modulating drug therapy in children, thymectomy should be considered as a treatment option early in the course of generalised AChR antibody positive JMG, if possible prior to immune-modulating drug therapy. However, only a randomised controlled trial will robustly evaluate the effects of thymectomy in JMG; such a study will require an international collaborative effort alongside a clinical trial methodology which considers borrowing strength from results of currently ongoing studies in adults with MG.
    Acknowledgements
    Acetylcholine receptors (AChRs) are allosteric proteins that isomerize (‘gates’) between resting and active conformations. We used single-channel electrophysiology to study gating of mouse adult-type endplate AChRs in the absence of agonists (free energy change, ΔG). Many different point mutations in AChRs change ΔG. For pairs of mutations, the net change in ΔG was about the same as the sum of the individual changes, indicating that mutations were independent and had mostly local effects. By correlating changes in ΔG with side chain partition coefficients, we could infer the hydrophobicity and volume of each residue's local environment. The kinetics of unliganded gating is complex, but was explained by schemes having 3-shut and 2-open states that all produced the same ΔG. The longest-lived open component was eliminated by some mutations (aromatic residues at the agonist-binding site and in M1) and α-conotoxin (a specific blocker of the α-δ binding site), without affecting ΔG. This suggests that long-lived unliganded openings are outside of the main activation sequence. In diliganded gating, in the α subunit there is a coarse-grained gradient in gating ϕ values (a conformational ‘wave’) that is less distinct in unliganded gating. Furthermore, without agonists the relative position of the gating transition state was more malleable compared to with agonists (larger Hammond shifts). The degree of shift (dϕ/dΔG) was a function of the residue ϕ-value, and was largest at ϕ∼0.5. We hypothesize that without agonists, there are multiple activation pathways that traverse a rugged potential energy surface.