RESUMO
BACKGROUND: Major histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity. Most MHCI are transmembrane proteins. The extracellular domain of MHCI interacts with immunoreceptors, peptides, and co-receptors to mediate immune signaling. While the cytoplasmic domain also plays important roles in endocytic trafficking, cross-presentation of extracellularly derived antigens, and CTL priming, the molecular mediators of cytoplasmic signaling by MHCI remain largely unknown. RESULTS: Here we show that the cytoplasmic domain of MHCI contains putative protein-protein interaction domains known as PDZ (PSD95/disc large/zonula occludens-1) ligands. PDZ ligands are motifs that bind to PDZ domains to organize and mediate signaling at cell-cell contacts. PDZ ligands are short, degenerate motifs, and are therefore difficult to identify via sequence homology alone, but several lines of evidence suggest that putative PDZ ligand motifs in MHCI are under positive selective pressure. Putative PDZ ligands are found in all of the 99 MHCI proteins examined from diverse species, and are enriched in the cytoplasmic domain, where PDZ interactions occur. Both the position of the PDZ ligand and the class of ligand motif are conserved across species, as well as among genes within a species. Non-synonymous substitutions, when they occur, frequently preserve the motif. Of the many specific possible PDZ ligand motifs, a handful are strikingly and selectively overrepresented in MHCI's cytoplasmic domain, but not elsewhere in the same proteins. Putative PDZ ligands in MHCI encompass conserved serine and tyrosine residues that are targets of phosphorylation, a post-translational modification that can regulate PDZ interactions. Finally, proof-of-principle in vitro interaction assays demonstrate that the cytoplasmic domains of particular MHCI proteins can bind directly and specifically to PDZ1 and PDZ4&5 of MAGI-1, and identify a conserved PDZ ligand motif in the classical MHCI H2-K that is required for this interaction. CONCLUSIONS: These results identify cryptic protein interaction motifs in the cytoplasmic domain of MHCI. In so doing, they suggest that the cytoplasmic domain of MHCI could participate in previously unsuspected PDZ mediated protein-protein interactions at neuronal as well as immunological synapses.
Assuntos
Motivos de Aminoácidos/genética , Citoplasma/metabolismo , Antígenos H-2/metabolismo , Antígenos HLA/metabolismo , Sinapses Imunológicas/metabolismo , Sistema Nervoso/imunologia , Domínios PDZ/genética , Domínios e Motivos de Interação entre Proteínas/genética , Animais , Apresentação de Antígeno , Antígenos H-2/genética , Antígenos HLA/genética , Humanos , Vigilância Imunológica , Camundongos , Fosforilação , Análise de Sequência de Proteína , Serina , Transdução de Sinais , TirosinaRESUMO
Congenital myasthenic syndromes are a group of genetic neuromuscular disorders caused by mutations that impair synaptic transmission at the neuromuscular junction. Developing an anesthetic plan for patients with this diagnosis is difficult, as they are at risk for prolonged neuromuscular blockade. Sugammadex is an alternative to neostigmine for neuromuscular blockade reversal that does not produce muscarinic side effects, yet there is a little literature assessing sugammadex in congenital myasthenic syndromes. We present the case of a 6-year-old boy with a congenital myasthenic syndrome who received sugammadex without complication. This case provides support for clinicians to consider sugammadex in these patients.
Assuntos
Síndromes Miastênicas Congênitas , Fármacos Neuromusculares não Despolarizantes , gama-Ciclodextrinas , Criança , Humanos , Masculino , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genética , Neostigmina , SugammadexRESUMO
PURPOSE: To evaluate the impact of gender and year at surgery on clinical presentation and postoperative outcomes in acromegaly. METHODS: Retrospective review of patients operated between 1994 and 2016 to compare presentation and outcomes in groups defined by gender and year of surgery. Kaplan-Meier survival analyses with a composite endpoint (recurrence, reoperation, and radiation) were used for gender comparison and Youden indices for biochemical remission rates changes during study period. RESULTS: Primary indications for evaluation were phenotype, neurological symptoms, incidentaloma, hypogonadism, and galactorrhea. At surgery, men (N = 54) were younger (43.6 ± 12.7 years) than women (N = 58, 48.7 ± 12.3, P = 0.04). Male:female ratios before and after age 50 were 1.4 and 0.6 respectively. Men had higher mean IGF-1 levels (874 ± 328 vs 716 ± 296, P < 0.01) and smaller tumors (1.8 ± 1.3 cm vs 2.3 ± 1.5, P = 0.04). Postoperative remission rates were comparable (51% men, 56% women) and inversely associated with cavernous sinus invasion and GH levels. Women had longer mean follow-up (5.2 ± 3.4 years vs 3.6 ± 3.6 men, P = 0.02) and longer endpoint-free survival (P < 0.01). At last follow-up, 89.6% women and 70% men had normal IGF-1 levels (P = 0.03). Postoperative remission rates were higher in patients operated after February 15, 2011 (67.35 vs 43.5% previously, P = 0.01). In late vs early surgery group, physical changes as main indication for screening decreased (54 vs 30%, P < 0.01), while incidentaloma and hypogonadism increased. Median GH levels were lower in late vs early surgery group (P = 0.03). CONCLUSION: We demonstrate gender-specific characteristics and an evolving spectrum of clinical presentation with implications for earlier diagnosis and personalized management of acromegaly.
Assuntos
Acromegalia , Hormônio do Crescimento Humano , Hipogonadismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Caracteres Sexuais , Resultado do TratamentoRESUMO
We present the first case of iatrogenic hypothyroidism as a result of compounded thyroid hormone (T4/T3) therapy. The thyroid replacement was changed from 175 µg levothyroxine (LT4) to 57/13.5 µg compounded T4/T3 daily in order to improve the T3 level, despite normal thyroid-stimulating hormone (TSH). This resulted in clinical manifestations of hypothyroidism and high TSH level (150 µIU/mL). Six months later, the patient was referred to our clinic for abnormal pituitary magnetic resonance imaging. On reinitiating a physiologic dose of LT4, clinical and biochemical abnormalities resolved and the pituitary gland size decreased. Our case emphasizes the importance of using TSH level to gauge dose adjustments in primary hypothyroidism. Also, it underscores the current American Thyroid Association recommendation against routine use of compounded thyroid hormone therapy.