Timing of Complications in Open Airway Reconstruction.

OBJECTIVE: Tracheal resection (TR) and cricotracheal resection (CTR) are performed for patients with airway stenosis, tracheal tumor, and tracheoesophageal fistula. Post-operative complications include airway edema requiring reintubation, hematoma, anastomotic dehiscence, restenosis, and death. Although these complications and associated risk factors have been well described, the time where clinical suspicion should be highest post operatively has not been characterized. METHODS: Patients who underwent TR or CTR at a single center between 2015 and 2022 were reviewed. Variables including demographics and comorbidities were recorded. Rate, nature, and time in days of post-operative complications were evaluated. RESULTS: Sixty-nine cases were reviewed. Average patient age was 46.8 years old and 63.8% were male. The average follow-up period was 625 ± 724 days. 19 (27.5%) patients experienced one or more major complications including four (5.8%) who died. Eight (11.6%) patients required reintubation and 4 (5.8%) patients underwent revision tracheostomy. Most complications occurred within 8 days of surgery. Restenosis was noted an average of 42.6 days after surgery, with no new restenosis occurring after 3 months. CONCLUSIONS: In this single-center study, most post-operative complications after TR or CTR, including hematoma and anastomotic dehiscence, occurred within 8 days post-operatively. Restenosis was noted approximately 1-3 months after surgery. This may inform clinical decision-making regarding patient monitoring and surveillance after open airway surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3527-3531, 2024.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.

Brefeldin a induces apoptosis by activating the mitochondrial and death receptor pathways and inhibits focal adhesion kinase-mediated cell invasion.

Brefeldin A induces apoptosis in various cancer cells; however, the apoptotic process in cancer cells exposed to brefeldin A remains unclear. In addition, it is unclear whether brefeldin A-induced apoptosis is mediated by the formation of reactive oxygen species. Furthermore, the effect of brefeldin A on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effect of brefeldin A on apoptosis, cell adhesion and migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that brefeldin A may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of brefeldin A seems to be mediated by formation of reactive oxygen species and depletion of GSH, which results in the activation of apoptotic caspases. Brefeldin A inhibited foetal bovine serum-induced adhesion and migration of OVCAR-3 cells. Brefeldin A may prevent the foetal bovine serum-induced cell adhesion and migration by limiting the focal adhesion kinase-dependent activation of cytoskeletal-associated components.

Combined effect of Hsp90 inhibitor geldanamycin and parthenolide via reactive oxygen species-mediated apoptotic process on epithelial ovarian cancer cells.

Hsp90 inhibitor geldanamycin and parthenolide have been shown to induce apoptosis in cancer cells. However, the combined effect of geldanamycin and parthenolide on epithelial ovarian cancer cells has not been studied. In respect of cell death process, we investigated the promoting effect of parthenolide on geldanamycin-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels; an increase in Bax and tumour suppressor p53 levels; loss of the mitochondrial transmembrane potential; cytochrome c release; activation of caspases (-8, -9 and -3); cleavage of PARP-1; and increase in the reactive oxygen species formation. Parthenolide enhanced geldanamycin-induced changes in the apoptosis-related protein levels, reactive oxygen species formation, nuclear damage and cell death. The combined effect was inhibited by the addition of oxidant scavengers. The results suggest that parthenolide may potentiate the apoptotic effect of geldanamycin on ovarian carcinoma cell lines by the activation of the caspase-8- and Bid-dependent pathway and the mitochondria-mediated apoptotic pathway. The apoptosis-promoting effect seems to be mediated by the stimulatory effect on the formation of reactive oxygen species.

Guanylate cyclase activator YC-1 enhances TRAIL-induced apoptosis in human epithelial ovarian carcinoma cells via activation of apoptosis-related proteins.

To assess the ability of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) to promote apoptosis, we investigated the effect of YC-1 on tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in the human epithelial ovarian carcinoma cell lines. In OVCAR-3 and SK-OV-3 cell lines, we examined the stimulatory effect of YC-1 on TRAIL-induced apoptosis by monitoring cell death, nuclear damage, changes in apoptosis-related protein levels, activation of caspases and changes in the mitochondrial transmembrane potential. TRAIL induced a decrease in Bid, Bcl-2 and Bcl-xL protein levels, increase in cleaved Bid and Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3) and an increase in the tumour suppressor p53 levels. YC-1 enhanced TRAIL-induced apoptosis-related protein activation, nuclear damage and cell death. Results from this study suggest that YC-1 may enhance the apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. YC-1 may confer a benefit in TRAIL treatment of epithelial ovarian adenocarcinoma.

Huntingtin associates with acidic phospholipids at the plasma membrane.

We have identified a domain in the N terminus of huntingtin that binds to membranes. A three-dimensional homology model of the structure of the binding domain predicts helical HEAT repeats, which emanate a positive electrostatic potential, consistent with a charge-based mechanism for membrane association. An amphipathic helix capable of inserting into pure lipid bilayers may serve to anchor huntingtin to the membrane. In cells, N-terminal huntingtin fragments targeted to regions of plasma membrane enriched in phosphatidylinositol 4,5-bisphosphate, receptor bound-transferrin, and endogenous huntingtin. N-terminal huntingtin fragments with an expanded polyglutamine tract aberrantly localized to intracellular regions instead of plasma membrane. Our data support a new model in which huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids.

Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription.

Huntingtin is a protein of unknown function that contains a polyglutamine tract, which is expanded in patients with Huntington's disease (HD). We investigated the localization and a potential function for huntingtin in the nucleus. In human fibroblasts from normal and HD patients, huntingtin localized diffusely in the nucleus and in subnuclear compartments identified as speckles, promyelocytic leukemia protein bodies, and nucleoli. Huntingtin-positive nuclear bodies redistributed after treatment with sodium butyrate. By Western blot, purified nuclei had low levels of full-length huntingtin compared with the cytoplasm but contained high levels of N- and C-terminal huntingtin fragments, which tightly bound the nuclear matrix. Full-length huntingtin co-immunoprecipitated with the transcriptional corepressor C-terminal binding protein, and polyglutamine expansion in huntingtin reduced this interaction. Full-length wild-type and mutant huntingtin repressed transcription when targeted to DNA. Truncated N-terminal mutant huntingtin repressed transcription, whereas the corresponding wild-type fragment did not repress transcription. We speculate that wild-type huntingtin may function in the nucleus in the assembly of nuclear matrix-bound protein complexes involved with transcriptional repression and RNA processing. Proteolysis of mutant huntingtin may alter nuclear functions by disrupting protein complexes and inappropriately repressing transcription in HD.