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Challenges and pitfalls in the perioperative management of mediastinal mass syndrome: an up-to-date review.
Get PDFThe perioperative management of patients undergoing mediastinal mass operations presents a persistent challenge across multiple clinical specialties. General anesthesia administration further increases the risk of perioperative cardiorespiratory decompensation. The interdisciplinary team plays a crucial role in ensuring a safe perioperative period. However, due to the rarity and variability of mediastinal mass syndromes, specific management protocols are lacking. This review aims to outline the multitude of challenges and pitfalls encountered during perioperative management in patients with the mediastinal mass syndrome. We describe diagnostic evaluation, preoperative optimization, intraoperative considerations, and postoperative care strategies, emphasizing the paramount significance of a multidisciplinary approach and personalized treatment plans. Preoperative multidisciplinary discussions, meticulous anesthetic management, and well-established protocols for emergency situations are pivotal to ensuring patient safety. Healthcare providers involved in the care of patients with mediastinal mass syndrome must grasp these challenges and pitfalls, enabling them to deliver safe and effective perioperative management
Msp1 in Trypanosoma brucei mitochondrial quality control
No full textMitochondria are vital organelles, prominently known for their role in ATP production. Even though mitochondria contain their own DNA, almost all mitochondrial proteins are encoded in the nucleus. These nuclear encoded mitochondrial proteins are translated in the cytosol and subsequently imported into the organelle. Disturbance of mitochondrial proteostasis by mislocalized or destabilized proteins, whose accumulation can lead to mitochondrial dysfunction, is an issue that demands immediate resolution. Therefore, eukaryotes contain a wide range of pathways to prevent and restore dysfunctional mitochondria. The ATPase-associated with diverse cellular activities (AAA) Msp1 contributes to mitochondrial proteostasis by extracting mislocalised tail-anchored proteins from the mitochondrial outer membrane (OM). Yeast Msp1 can extract substrate proteins from a lipid bilayer independently from associated proteins and substrate modifications. However, little is known about Msp1 orthologs outside the eukaryotic supergroup of the Opisthokonts, which includes animals and fungi. Trypanosoma brucei is a well-established eukaryotic model organism which belongs to the Discoba group and thus is essentially unrelated to Opisthokonts. The trypanosome-specific pATOM36 mediates complex assembly of α-helically anchored mitochondrial outer membrane proteins, such as proteins of the atypical protein translocase of the outer mitochondrial membrane (ATOM), into their respective complexes. Inhibition of ATOM complex assembly via RNAi knockdown of pATOM36 triggers a pathway that results in the degradation of unassembled ATOM subunits by the cytosolic proteasome.
Here we have investigated this novel trypanosomal mitochondria-associated degradation pathway. We show that the trypanosomal Msp1 homolog (TbMsp1) and the trypanosomal homolog of the AAA-ATPase VCP (TbVCP) are involved in this quality control pathway. The RNAi knockdown of pATOM36 in combination with either TbMsp1 RNAi or TbVCP RNAi does not affect the pathway as pATOM36 substrates are still being degraded by the cytosolic proteasome. However, the simultaneous knockdown of TbMsp1 and TbVCP in the pATOM36 RNAi background prevents the removal of pATOM36 substrates from the OM despite the ablation of pATOM36. This suggests that there is some redundancy between TbMsp1 and TbVCP in this pathway. Furthermore, we show by in situ tagging, coimmunoprecipitation and mass spectrometry that TbMsp1 localises to both, glycosomes and the OM. Additionally, we demonstrate by reciprocal coimmunoprecipitations that TbMsp1 forms a stable complex with the four OM proteins POMP19, POMP31, TbJ31 and TbTsc13. Interestingly, upon pATOM36 and TbVCP ablation, POMP31, TbJ31 and TbTsc13 are required for efficient proteasomal degradation of pATOM36 substrates, suggesting these three TbMsp1-interacting proteins assist TbMsp1 in extracting the destabilized OM proteins. pATOM36 is a functional analogue of the yeast OM MIM complex and likely of the animal-specific OM protein MTCH2, suggesting that similar mitochondrial quality control pathways linked to Msp1 might also exist in yeast and humans. The molecular details underlaying the interactions within the TbMsp1-containing complex, and the role of the individual TbMsp1-associated proteins in the extraction of pATOM36 substrates have yet to be elucidated. Additionally, it is unclear whether these interaction partners are required for the extraction of all TbMsp1 substrates. It is possible that their activity might be limited to a specific subset of TbMsp1 substrates which includes the pATOM36 substrates. Other TbMsp1 substrates than those extracted upon pATOM36 and TbVCP ablation could not yet be identified. Furthermore, it also remains unclear whether TbMsp1 functions independently of ubiquitin, as has been suggested for yeast Msp1
Insights from the Alpine Periphery: Settlements and (rare) Burials 3400–2400 BC
No full text"In the context of the widespread European distribution of the pottery decorated with cord impressions, usually described as ‘Corded Ware Culture’ or ‘Corded Ware Phenomena’, the sites situated in Switzerland and along the western Alps occupy a distinctive position on the southwestern periphery. Most Corded Ware areas are featuring typical single graves with gender-differentiated crouched burials and related typical grave goods. This type of graves is completely absent in the western Alpine forelands. Instead, the primary sources of insight into the societies of the early 3rd millennium BC come exclusively from submerged lake shore settlements. Burials previously categorized as Corded Ware graves or roughly fitting within the timeframe of this phenomenon exhibit markedly different architectural styles and feature distinct grave goods. The Alpine foreland exhibits peculiar characteristics that deviate from the known conventional Corded Ware features, sparking prolonged scholarly discourse. This lecture will delve into the distinctive traits of a peripheral Corded Ware region focusing on the time from 3400 to 2400 BC. This also covers the centuries before the first signs of the emergence of a pottery decorated with cord impressions. Novel insights into settlement architecture have been found recently, illuminating long-enduring settlement traditions. These results raise new questions about the impact of the general transformations in the early 3rd millennium BC on peripheral regions. It cannot be ruled out that the Alpine region played a special role and was resistant to new trends.
wan du daz weist und des wilt nicht gelouben han. Die Küste in der ›Reise des hl. Brandan‹ als Ort der Hybridität
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Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.
Get PDFBACKGROUND
The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status.
METHOD
Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC).
RESULTS
After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [β = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [β = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04].
CONCLUSION
In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses
From standard therapies to monoclonal antibodies and immune checkpoint inhibitors - an update for reconstructive surgeons on common oncological cases.
Get PDFMalignancies represent a persisting worldwide health burden. Tumor treatment is commonly based on surgical and/or non-surgical therapies. In the recent decade, novel non-surgical treatment strategies involving monoclonal antibodies (mAB) and immune checkpoint inhibitors (ICI) have been successfully incorporated into standard treatment algorithms. Such emerging therapy concepts have demonstrated improved complete remission rates and prolonged progression-free survival compared to conventional chemotherapies. However, the in-toto surgical tumor resection followed by reconstructive surgery oftentimes remains the only curative therapy. Breast cancer (BC), skin cancer (SC), head and neck cancer (HNC), and sarcoma amongst other cancer entities commonly require reconstructive surgery to restore form, aesthetics, and functionality. Understanding the basic principles, strengths, and limitations of mAB and ICI as (neo-) adjuvant therapies and treatment alternatives for resectable or unresectable tumors is paramount for optimized surgical therapy planning. Yet, there is a scarcity of studies that condense the current body of literature on mAB and ICI for BC, SC, HNC, and sarcoma. This knowledge gap may result in suboptimal treatment planning, ultimately impairing patient outcomes. Herein, we aim to summarize the current translational endeavors focusing on mAB and ICI. This line of research may serve as an evidence-based fundament to guide targeted therapy and optimize interdisciplinary anti-cancer strategies
Stereotactic radiosurgery and radiotherapy for brainstem metastases: An international multicenter analysis.
Get PDFBrainstem metastases (BSM) present a significant neuro-oncological challenge, resulting in profound neurological deficits and poor survival outcomes. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) offer promising therapeutic avenues for BSM despite their precarious location. This international multicenter study investigates the efficacy and safety of SRS and FSRT in 136 patients with 144 BSM treated at nine institutions from 2005 to 2022. The median radiographic and clinical follow-up periods were 6.8 and 9.4 months, respectively. Predominantly, patients with BSM were managed with SRS (69.4%). The median prescription dose and isodose line for SRS were 18 Gy and 65%, respectively, while for FSRT, the median prescription dose was 21 Gy with a median isodose line of 70%. The 12-, 24-, and 36-month local control (LC) rates were 82.9%, 71.4%, and 61.2%, respectively. Corresponding overall survival rates at these time points were 61.1%, 34.7%, and 19.3%. In the multivariable Cox regression analysis for LC, only the minimum biologically effective dose was significantly associated with LC, favoring higher doses for improved control (in Gy, hazard ratio [HR]: 0.86, p < .01). Regarding overall survival, good performance status (Karnofsky performance status, ≥90%; HR: 0.43, p < .01) and prior whole brain radiotherapy (HR: 2.52, p < .01) emerged as associated factors. In 14 BSM (9.7%), treatment-related adverse events were noted, with a total of five (3.4%) radiation necrosis. SRS and FSRT for BSM exhibit efficacy and safety, making them suitable treatment options for affected patients
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