From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement

Does Dynamic Anterior Plate Fixation Provide Adequate Stability for Traumatic Subaxial Cervical Spine Fractures at Mid-Term Follow-Up?

Background: It remains questionable if the treatment of cervical fractures with dynamic plates in trauma surgery provides adequate stability for unstable fractures with disco-ligamentous injuries. The primary goal of this study was to assess the radiological and mid-term patient-reported outcome of traumatic subaxial cervical fractures treated with different plate systems. Patients and Methods: Patients, treated with anterior cervical discectomy and fusion (ACDF) between 2001 and 2015, using either a dynamic plate (DP: Mambo™, Ulrich, Germany) or a rigid locking plate (RP: CSLP™, Depuy Synthes, USA), were identified. For radiological evaluation, the sagittal alignment, the sagittal anterior translation and the bony consolidation were evaluated. After at least two years, the patient-reported outcome measures (PROM) were evaluated using the German Short-Form 36 (SF-36), Neck Disability Index (NDI) and the EuroQol in 5 Dimensions (EQ-5D) scores. Results: 33 patients met the inclusion criteria (DP: 13; RP:20). Twenty-six patients suffered from AO Type B or C fractures. Both the sagittal alignment and the sagittal translation could be sufficiently improved in both groups (p ≥ 0.05). No significant loss of reduction could be observed at the follow-up in both groups (p ≥ 0.05). Bony consolidation could be observed in 30 patients (DP: 12/13 (92%); RP: 18/20 (90%); (p ≥ 0.05)). In 20 patients, PROMs could be evaluated (follow-up: 71.2 ± 25.5 months). The whole cohort showed satisfactory PROM results (EQ-5D: 72.0 ± 4.9; SF-36 PCS: 41.9 ± 16.2, MCS: 45.4 ± 14.9; NDI: 11.0 ± 9.1). without significant differences between the DP and RP group (p ≥ 0.05) Conclusion: The dynamic plate concept provides enough stability without a difference in fusion rates in comparison to rigid locking plates in a population that mostly suffered fragile fractures

Long-Term Patient-Related Quality of Life after Knee Periprosthetic Joint Infection

Background: We aimed to evaluate the impact of knee periprosthetic joint infection (PJI) by assessing the patients’ long-term quality of life and explicitly their psychological wellbeing after successful treatment. Methods: Thirty-six patients with achieved eradication of infection after knee PJI were included. Quality of life was evaluated with the EQ-5D and SF-36 outcome instruments as well as with an ICD-10 based symptom rating (ISR) and compared to normative data. Results: At a follow-up of 4.9 ± 3.5 years the mean SF-36 score was 24.82 ± 10.0 regarding the physical health component and 46.16 ± 13.3 regarding the mental health component compared to German normative values of 48.36 ± 9.4 (p < 0.001) and 50.87 ± 8.8 (p = 0.003). The mean EQ-5D index reached 0.55 ± 0.33 with an EQ-5D VAS rating of 52.14 ± 19.9 compared to reference scores of 0.891 (p < 0.001) and 68.6 ± 1.1 (p < 0.001). Mean scores of the ISR revealed the psychological symptom burden on the depression scale. Conclusion: PJI patients still suffer from significantly lower quality of life compared to normative data, even years after surgically successful treatment. Future clinical studies should focus on patient-related outcome measures. Newly emerging treatment strategies, prevention methods, and interdisciplinary approaches should be implemented to improve the quality of life of PJI patients

Radiological and mid- to long-term patient-reported outcome after stabilization of traumatic thoraco-lumbar spinal fractures using an expandable vertebral body replacement implant

Background For the treatment of unstable thoraco-lumbar burst fractures, a combined posterior and anterior stabilization instead of a posterior-only instrumentation is recommend in the current literature due to the instability of the anterior column. Data on restoring the bi-segmental kyphotic endplate angle (BKA) with expandable vertebral body replacements (VBR) and on the mid- to long-term patient-reported outcome measures (PROM) is sparse. Methods A retrospective cohort study of patients with traumatic thoraco-lumbar spinal fractures treated with an expandable VBR implant (Obelisc™, Ulrich Medical, Germany) between 2001 and 2015 was conducted. Patient and treatment characteristics were evaluated retrospectively. Radiological data acquisition was completed pre- and postoperatively, 6 months and at least 2 years after the VBR surgery. The BKA was measured and fusion-rates were assessed. The SF-36, EQ-5D and ODI questionnaires were evaluated prospectively. Results Ninety-six patients (25 female, 71 male; age: 46.1 ± 12.8 years) were included in the study. An AO Type A4 fracture was seen in 80/96 cases (83.3%). Seventy-three fractures (76.0%) were located at the lumbar spine. Intraoperative reduction of the BKA in n = 96 patients was 10.5 ± 9.4° (p < 0.01). A loss of correction of 1.0 ± 2.8° at the first follow-up (t1) and of 2.4 ± 4.0° at the second follow-up (t2) was measured (each p < 0.05). The bony fusion rate was 97.9%. The total revision rate was 4.2%. Fifty-one patients (53.1% of included patients; age: 48.9 ± 12.4 years) completed the PROM questionnaires after 106.4 ± 44.3 months and therefore were assigned to the respondent group. The mean ODI score was 28.2 ± 18.3%, the mean EQ-5D VAS reached 60.7 ± 4.1 points. Stratified SF-36 results (ISS < and ≥ 16) were lower compared to a reference population. Conclusion The treatment of traumatic thoraco-lumbar fractures with an expandable VBR implant lead to a high rate of bony fusion. A significant correction of the BKA could be achieved and no clinically relevant loss of reduction occurred during the follow-up. Even though health related quality of life did not reach the normative population values, overall satisfactory results were reported

Neutralization of insulin by photocleavage under high vacuum

Charge reduction and neutralization of electro-sprayed peptides are realized by selective gas-phase photocleavage of tailored covalent tags. The concept is demonstrated with four model peptides in positive and negative ion modes and tagged insulin as the largest construct

Revision arthroplasty after unicompartimental knee arthroplasty

Background Unicompartimental knee arthroplasty (UKA) is a promising and increasing application to treat unicompartimental knee osteoarthritis. However, revision arthroplasty numbers after UKA are unknown. Therefore, aim of this study was to determine the nationwide burden of revision after UKA by answering the following questions: (1) How did numbers of revision UKA procedures developed over the last decade as a function of age and gender? (2) How high is the percentage of revision UKA procedures due to infection? (3) Which therapy strategy was chosen for surgical treatment of aseptic revision UKA? Methods Revision arthroplasty rates as a function of age, gender, infection and type of prosthesis were quantified based on Operation and Procedure Classification System codes using revision knee arthroplasty data from 2008 to 2018, provided by the Federal Statistical Office of Germany (Destatis). Results Over the last decade, revision UKA increased by 46.3% up to 3105 procedures in 2018. A trend towards higher numbers in younger patients was observed. Septic interventions constituted 5.7% of all revisions, whereby total procedures increased by 67.1% from 2008 through 2018. The main treatment strategy was an exchange to a bicondylar surface replacement prosthesis, which was done in 63.70% of all cases, followed by exchange to a femoral and tibial shaft-anchored (16.2% of all revisions). Conclusion The increasing number of revision arthroplasty after UKA in Germany, especially in younger patients and due to infection, underlines the need for future efforts to improve treatment strategies beyond UKA to delay primary arthroplasty and avoid periprosthetic joint infection

A retrospective analysis of trends in primary knee arthroplasty in Germany from 2008 to 2018

Unicompartimental and total knee arthroplasty is one of the most successful and most performed operations worldwide. In the last years the number of primary knee arthroplasty increased constantly. The aim of this study is to analyze the rising numbers of primary knee arthroplasty and to see how it is used in Germany. In this retrospective study data, provided by the Federal Statistical Office of Germany from 2008 to 2018 was analyzed, using operation codes from the German procedure classification system and characteristics like age, sex and type of the prosthesis. We found a slight increase of unicompartimental and total knee arthroplasty over the investigated 10 years from 150.504 in 2008 up to 168.479 procedures in 2018, with a maximum of 169.334 in 2017. Most patients were female and over 65 years old. Interestingly, there was an obvious decrease of regular TKA in the year 2013, with a relevant impact on the total number of procedures. In the following years the number rised again reaching the former level in 2015 and is still increasing. The highest increase was found in partial knee arthroplasty, with a constant rise every year, starting with 7988 in 2008 up to 21.072 in 2018. In contrast, we found a relevant reduction of constrained prosthesis in primary TKA, whereas the number of semi-constrained prosthesis in primary TKA is again rising after a decrease in 2015. We found that the number of bicondylar TKA and especially UKA increased from 2008 to 2018. Regarding an aging population, we can expect a rising number for Primary knee arthroplasty and in consequence a rising number of revision arthroplasty in the future. This will be a challenging cost factor for the healthcare system in Germany

Anterior Column Reconstruction of Destructive Vertebral Osteomyelitis at the Thoracolumbar Spine with an Expandable Vertebral Body Replacement Implant: A Retrospective, Monocentric Radiological Cohort Analysis of 24 Cases

Background: Vertebral osteomyelitis (VO) often necessitates surgical intervention due to bone loss-induced spinal instability. Anterior column reconstruction, utilizing expandable vertebral body replacement (VBR) implants, is a recognized approach to restore stability and prevent neurological compromise. Despite various techniques, clinical evidence regarding the safety and efficacy of these implants in VO remains limited. Methods: A retrospective cohort analysis, spanning 2000 to 2020, was conducted on 24 destructive VO cases at a Level 1 orthopedic trauma center. Diagnosis relied on clinical, radiological, and microbiological criteria. Patient demographics, clinical presentation, surgical interventions, and radiological outcomes were assessed. Results: The study included 24 patients (62.5% male; mean age 65.6 ± 35.0 years), with 58% having healthcare-associated infections (HAVO). The mean radiological follow-up was 137.2 ± 161.7 weeks. Surgical intervention significantly improved the bi-segmental kyphotic endplate angle (BKA) postoperatively (mean −1.4° ± 13.6°). However, a noticeable loss of correction was observed over time. The study reported a mortality rate of 1/24. Conclusions: Anterior column reconstruction using expandable VBR effectively improved local spinal alignment in destructive VO. However, the study underscores the necessity for prolonged follow-up and continuous research to refine surgical techniques and postoperative care. Addressing long-term complications and refining surgical approaches will be pivotal as the field progresses

Joint awareness in posttraumatic osteoarthritis of the knee: validation of the forgotten joint score in long term condition after tibial plateau fracture

Background: Evaluating patient-reported outcomes (PRO) in early osteoarthritis (OA) of the knee is difficult. Established measurement tools are focused on one of the two major patient groups in knee surgery: young, highly active patients, or older patients with advanced degenerative OA of the knee. Joint awareness in everyday life is a crucial criterion in measuring PRO. The purpose of this study was to validate a German version of the "Forgotten Joint Score" (FJS) in patients after surgical treatment of tibial plateau fractures. Methods: In this prospective cohort study, clinical and radiological outcomes data were collected from patients after surgical treatment of tibial plateau fractures following a skiing accident. Functional outcome questionnaires were administered including the FJS, the Lysholm-Score, the Tegner-Activity Scale (TAS), the EuroQol-5D (EQ 5-D), and a subjective rating of change. The validation study was carried out according to the COSMIN checklist protocol. The KLS was used to measure the presence and severity of OA on knee radiographs, and correlation with the FJS was measured. Results: Cronbach's alpha was .96 (95%-CI.92, .99) confirming good internal consistency. Test-retest reliability of the FJS was high with an ICC(67) = .91 (95%-CI.85, .95). Furthermore, no relevant floor or ceiling effects were observed. FJS significantly differed in patients with different OA degrees (p = .041). Symptomatic patients had significant lower FJS than asymptomatic patients (p < .001). Conclusions: This is the first study validating a disease-specific PRO, the FJS, in long-term outcomes after joint fracture. We demonstrated good psychometric properties and a significant correlation between the FJS and the radiologic degree of OA in patients with a history of tibial plateau fracture