Perceptions of patients and their relatives about schadenfreude towards doctors.

Background: Violence in healthcare is a global issue that healthcare professionals experience. The concerning increase in violent incidents in Turkiye particularly makes it a significant problem to explore by examining the underlying psychological factors. In this sense, this study focuses on the concept of Schadenfreude, the malicious joy of someone else's misfortune, towards doctors, which is an under-researched topic in healthcare violence. Particularly, there is a lack of research on patients' and relatives' perceptions of doctors. Objective: This study aims to determine the level of schadenfreude in Turkish society towards the violence experienced by doctors and to develop a model revealing the underlying causes. Methods: Using a convenience sampling method, we recruited 402 participants, who are not first-degree relatives of healthcare professionals, for this quantitative study. For data collection, we developed a survey instrument to measure the level of schadenfreude and six different psychological factors including empathy, sympathy, anger, aggression, and deservingness. For data analysis, we used structural equation modeling. Results: The results showed that the lower the levels of empathy and sympathy towards doctors were, the higher the levels of both schadenfreude and aggression were. Envy had no significant effect on either schadenfreude or aggression, while deservingness directly affected aggression. The perceptions of participants regarding doctors that they deserve violence increased their aggression levels. Schadenfreude had a positive and significant effect on anger and aggression. Implications: The examination of underlying factors of violence towards doctors points to a lack of mutual understanding between patients and doctors. The results of this study indicate a need for increasing empathy towards health professionals by creating societal awareness of their experiences. Local authorities and healthcare organizations can create environments that bring together the public and health professionals to share their experiences with each other or conduct campaigns to draw public attention to the issue. Moreover, training sessions on effective communication can be offered for health professionals to help improve patient-doctor relationships and healthcare outcomes.

Lysosomal proteomics reveals mechanisms of neuronal apoE4associated lysosomal dysfunction.

ApoE4 is the primary risk factor for Alzheimer's Disease. While apoE is primarily expressed by astrocytes, AD pathology including endosomal abnormalities and mitochondrial dysfunction first occurs in neurons. Lysosomes are poised at the convergence point between these features. We find that apoE4-expressing cells exhibit lysosomal alkalinization, reduced lysosomal proteolysis, and impaired mitophagy. To identify driving factors for this lysosomal dysfunction, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in lysosomal depletion of Lgals3bp and accumulation of Tmed5 in both Neuro-2a cells and postmitotic human neurons. Modulating the expression of both proteins affected lysosomal function, with Tmed5 knockdown rescuing lysosomal alkalinization in apoE4 cells, and Lgals3bp knockdown causing lysosomal alkalinization and reduced lysosomal density in apoE3 cells. Taken together, our work reveals that apoE4 exerts gain-of-toxicity by alkalinizing the lysosomal lumen, pinpointing lysosomal Tmed5 accumulation and Lgals3bp depletion as apoE4-associated drivers for this phenotype.

Quantitative Proteomic Analysis Reveals apoE4-Dependent Phosphorylation of the Actin-Regulating Protein VASP.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here, we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in vasodilator-stimulated phosphoprotein (VASP) S235 phosphorylation in a protein kinase A (PKA)-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.

Effect of coolant spray on rib fracture pain of geriatric blunt thoracic trauma patients: a randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the effectiveness of cryotherapy in elderly patients with rib fractures due to blunt thoracic trauma. METHODS: In this prospective randomized controlled study, geriatric patients were assigned to groups to receive either coolant spray (n=51) or placebo spray (n=50). The visual analog scale scores of all patients were recorded before starting spray application (V0), as well as at 10th (V1), 20th (V2), 30th (V3), 60th (V4), 120th (V5), and 360th (V6) minute. The mean decreases in the visual analog scale scores were calculated. RESULTS: The differences between V0 and V1, V0 and V2, V0 and V3, and V0 and V4 mean visual analog scale scores measured in the coolant spray group were found to be significantly higher (p<0.001). In V1, V2, V3, and V4 measurements, the incidence of "clinical effectiveness" in the coolant spray group was significantly higher than in the placebo group (p=0.001). CONCLUSIONS: Coolant spray therapy can be used as a component of multimodal therapy to provide adequate analgesia due to rib fractures in geriatric patients.

Effect of coolant spray on rib fracture pain of geriatric blunt thoracic trauma patients: a randomized controlled trial

SUMMARY OBJECTIVE: This study aimed to evaluate the effectiveness of cryotherapy in elderly patients with rib fractures due to blunt thoracic trauma. METHODS: In this prospective randomized controlled study, geriatric patients were assigned to groups to receive either coolant spray (n=51) or placebo spray (n=50). The visual analog scale scores of all patients were recorded before starting spray application (V0), as well as at 10th (V1), 20th (V2), 30th (V3), 60th (V4), 120th (V5), and 360th (V6) minute. The mean decreases in the visual analog scale scores were calculated. RESULTS: The differences between V0 and V1, V0 and V2, V0 and V3, and V0 and V4 mean visual analog scale scores measured in the coolant spray group were found to be significantly higher (p<0.001). In V1, V2, V3, and V4 measurements, the incidence of "clinical effectiveness" in the coolant spray group was significantly higher than in the placebo group (p=0.001). CONCLUSIONS: Coolant spray therapy can be used as a component of multimodal therapy to provide adequate analgesia due to rib fractures in geriatric patients.

Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition. SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

A Selective Histamine H4 Receptor Antagonist, JNJ7777120, Role on glutamate Transporter Activity in Chronic Depression.

Glutamate release and reuptake play a key role in the pathophysiology of depression. glutamatergic nerves in the hippocampus region are modulated by histaminergic afferents. Excessive accumulation of glutamate in the synaptic area causes degeneration of neuron cells. The H4 receptor is defined as the main immune system histamine receptor with a pro-inflammatory role. To understand the role of this receptor, the drug JNJ7777120 was used to reveal the chronic depression-glutamate relationship. We have important findings showing that the H4 antagonist increases the glutamate transporters' instantaneous activity. In our experiment, it has been shown that blocking the H4 receptor leads to increased neuron cell viability and improvement in behavioral ability due to glutamate. Therefore, JNJ can be used to prevent neurotoxicity, inhibit membrane phospholipase activation and free radical formation, and minimize membrane disruption. In line with our findings, results have been obtained that indicate that JNJ will contribute to the effective prevention and treatment of depression.

Intradermal mesotherapy versus intravenous dexketoprofen for the treatment of migraine headache without aura: a randomized controlled trial.

BACKGROUND: Migraine is a prevalent disabling primary headache disorder that is classified into two major types: migraine without aura and migraine with aura. New therapeutic methods to reduce migraine headaches in the emergency department (ED) include intradermal mesotherapy. OBJECTIVE: Compare the efficacy of intradermal mesotherapy versus a systemic therapy in pain control in patients with headache related to migraine without aura. DESIGN: Prospective parallel-group randomized controlled trial. SETTING: University hospital in Turkey. PATIENTS AND METHODS: Patients 18 years of age and older who were admitted to the ED over a 15-month period with headache related to migraine without aura were eligible for inclusion if they had a VAS score of 4 or above. Patients were randomly allocated to one session of mesotherapy or intravenous dexketoprofen. Changes in pain intensity were measured by the score on a visual analog scale (VAS) at 30, 60, and 120 minutes and 24 hours after treatment. Efficacy was also assessed by the need for use of an analgesic drug within 24 hours, by readmission with the same complaint to the ED within 72 hours, and by adverse effect rates. MAIN OUTCOME MEASURE: Pain intensity on the VAS scale. SAMPLE SIZE: 148 patients (154 enrolled and treated; 1 patient in the mesotherapy and 5 patients in the systemic therapy group lost to follow up). RESULTS: Pain intensity on the VAS scale decreased from a median score of 8 to 4 in the mesotherapy group and from 8 to 5 in the systemic therapy group. These differences were statistically significant from baseline for all time intervals (P=.001 to 30 minutes, P=.004 to 60 minutes, P=.005 to 120 minutes, and P=.002 to 24 hours). The need to use analgesics and the rate of readmission to the ED were higher in the systemic therapy group (P=.013 and P=.030, respectively). Adverse effect rates were minimal and similar in the study groups during the one-week follow-up period. CONCLUSIONS: Mesotherapy is more efficacious than intravenous dexketoprofen in the management of acute attack of migraine without aura in the ED. LIMITATIONS: Unblinded. Valid for assessing short-term pain relief, but not sufficient to predict long-term efficacy. Not generalizable because single center and small sample size. CONFLICT OF INTEREST: None. REGISTRATION: ClinicalTrials.gov (NCT04519346).

Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth.

Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.

Effectiveness of Modified HEART Score in Predicting Major Adverse Cardiac Events.

OBJECTIVE: The most important problem for emergency physicians in patients presenting with chest pain is deciding whether to discharge the patient or not. Therefore, many scoring systems have been developed to help with this decision making process. We aim to achieve a modified HEART value by combining the VAS value with the HEART score. MATERIALS AND METHODS: Data were collected on age, sex, duration of the symptoms, pain severity using a 10-point visual analog scale (VAS), and the presence of a major adverse cardiac event (MACE). The HEART score was calculated and modified (mHEART) by adding 1 point to the total HEART score for a VAS score of ≥7. RESULTS: During the study period, 4781 patients were admitted, and 293 participants were analyzed. Of the patients, 34(11.6%) experienced MACE within a month after the encounter. The mean VAS scores were 5.65±1.44. However, 77(26.3%) patients had VAS scores ≥7. Taking 3 as the threshold, 42(14.3%) patients had HEART scores of 4 and above, where 47(16.0%) had mHEART scores ≥4. The mHEART scoring demonstrated better test indicators than the HEART score. According to the HEART score, 6(2.3%) of the 251 patients predicted as negative would develop MACE, but this number decreased to 1(0.4%) in 246 using the mHEART score. CONCLUSION: Although the HEART score performs reasonably well in discriminating patients who are MACE negative, it is possible to further improve the score by adding the VAS item. After validation by other studies, we would suggest modifying the HEART score by including the VAS item.

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Comparison of ibuprofen and piroxicam gel in the treatment of trauma pain: A randomized double-blind trial of geriatric population.

OBJECTIVE: This study aimed to compare the analgesic efficacy of topical ibuprofen and topical piroxicam for acute musculoskeletal injuries. METHODS: In this prospective, randomized, controlled, double-blinded study, geriatric patients were assigned to groups to receive either topical ibuprofen (n = 70) or topical piroxicam (n = 69). The first dose of gel was applied in the emergency department and the remaining doses were self-administered at home by the patients thrice daily for 72 h. For each patient, the initial baseline visual analog scale (VAS) score (V 0) was compared with the VAS scores at the 60 min (V1), 120 min (V2), 24 h (V3) and 72 h (V4) time points. The decreases in VAS scores, clinical effectiveness of the treatments, and incidence of adverse events were evaluated. RESULTS: In the topical ibuprofen group, the VAS scores were significantly lower at each measurement time point compared to baseline (p < .001). The results were as follows: V0 -V: 1.08, 95% CI: 0.56-1.61; V0 -V2: 1.09, 95% CI: 0.49-1.69; V0 -V3: 1.44, 95% CI: 0.81-2.07; V0 -V4: 1.59, 95% CI: 0.91-2.26. The mean percentage decrease in the VAS scores in the topical ibuprofen group was significantly higher than that in the topical piroxicam group (p < .001). The clinical effect of treatment was found to be significantly higher for the ibuprofen gel group (p < .001). There was no substantial difference in treatment-related adverse events between the groups (p > .05). CONCLUSION: Ibuprofen gel, which is a safe treatment option for geriatric patients, is more clinically effective than piroxicam gel. Response to Reviewers.

Comparison of topical capsaicin and topical piroxicam in the treatment of acute trauma-induced pain: A randomized double-blind trial.

BACKGROUND: This study aimed to compare the analgesic efficacy of topical capsaicin and topical piroxicam in acute musculoskeletal injuries. METHODS: This is a prospective, randomized, controlled, double-blinded study. The data for the 67 patients in the piroxicam group and the 69 in the capsaicin group were examined. The initial visual analog scale (VAS) scores were compared with the 60th and 120th minute as well as the 24th and 72nd hour values. Differences between the VAS scores, clinical effectiveness of the treatment and side effects were evaluated. RESULTS: In the capsaicin group, the mean difference in the delta VAS scores was significantly higher at each measurement time. The mean of the percentage of reduction in the VAS scores of the topical capsaicin group was significantly higher than that in the topical piroxicam group. The highest difference in terms of both outcomes was determined at the 72nd hour VAS change. Mean differences were 1.53 (95% CI: 0.85-2.221) and 19.7 (95% CI: 12.4-27.2) respectively (p < 0.001). In the capsaicin group, the clinical effect of the treatment was found significantly higher (p < 0.01). The difference between the clinical effectiveness of the groups regarding the treatment outcomes was also statistically significant (p < 0.001). There was no significant difference between the patient groups regarding the presence of side effects. CONCLUSION: Topical capsaicin can be used as an alternative to topical piroxicam initially and at follow-up in patients presenting to the emergency department with acute pain as there were no observable differences in side-effects between the two groups.

Intradermal injection for hiccup therapy in the Emergency Department.

Hiccup is a condition caused by involuntary contraction of inspiratory muscles, especially the diaphragm. Although it is generally considered as a physiological. response, if hiccup persists for a long time, it can lead to many undesirable conditions such as depression, weight loss, insomnia, and fatigue. A 35-year-old male patient was admitted to our emergency department with hiccup lasting for 15 h. He had a history of several hiccup attacks. Classical non-pharmacological and pharmacological therapies were used to treat the condition without any response. As an alternative method, an intradermal injection was applied. A mixture of thiocolchicoside and lidocaine was administered intradermally to a depth of 1-3 mm at the epigastric region and adjacent to the sternocleidomastoid muscle. The patient's hiccup ended after the intradermal injection procedure. During 48 h of follow-up the hiccup attack did not develop again. No complications related to the process were detected. This is the first case in the literature demonstrating the use of intradermal injection to terminate hiccups. The intradermal injection approach can be administered in cases of hiccups that do not respond to medical treatment.

Comparison of effectiveness coolant spray and placebo in patients with acute ankle trauma prospective randomized controlled trial.

INTRODUCTION: Coolant spray application in musculoskeletal injuries is an effective and harmless method to treat pain and reduce functional limitation. This study assessed the clinical value of coolant spray application on patient comfort before and during the radiographic imaging process along with its early analgesic and anti-edema effects. METHODS: A total of 155 patients, admitted to the emergency department between April 1, 2019, and June 31, 2019, were included in this study. The patients were randomly assigned to either a coolant spray or a saline spray (placebo) group. To the coolant spray group patients, Cryos ®Spray (Phyto Performance, Italy) was applied. To the placebo group patients, a normal saline solution in a bottle covered with white opaque paper and refrigerated at 4 °C was sprayed. Radiographic images of the patients were scored for appropriateness of the standard imaging characteristics. RESULTS: The mean scores were 8.13 ± 1.8 and 6.58 ± 2.2 for the coolant spray and normal saline spray groups, respectively; the differences were statistically significant between the two groups (mean difference: -1.56, 95% CI:-2.20 to -0.92; p = .000). Patients with fractures on their radiographs and treated with coolant spray received higher scores than similar patients treated with normal saline spray (mean difference:-1.92, 95% CI:-3.28 to -0.55; p = .009). The proportion of patients requesting analgesic treatment before discharge was statistically lower in the coolant spray group compared to the normal saline group (p = .025). CONCLUSIONS: The radiographic images taken after coolant spray intervention in patients with acute ankle trauma were more successful in showing the target structures.

Comparison of two scores of short term serious outcome in COPD patients.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) related visits to the emergency department have increased substantially during the past decade. An important challenge facing emergency physicians when treating COPD patients is deciding on disposition. The aim of this study was to evaluate Integrated Pulmonary Index scoring to guide the disposition decisions of emergency physicians by comparing its compatibility with Ottawa COPD Risk Score. METHODS: This is a prospective methodological study, in which we compared the accuracies of the Integrated Pulmonary Index and Ottawa COPD Risk Score in predicting of the short-term serious outcomes in patients admitted to the emergency department with COPD exacerbation. Patients who admitted to our emergency department between 01.01.2019-31.03.2019 were evaluated. THE RESULTS: Among the 208 patients, there were 154 (74.0%) short-term serious outcomes. The AUCs were 0.915 and 0.943 for Integrated Pulmonary Index and Ottawa COPD Risk Score, respectively. The difference between AUCs for two scores was not statistically significant. The best cut-off point for Integrated Pulmonary Index and Ottawa COPD Risk Score were ≤3 and >4, respectively. For these best cut-off points, the sensitivity and specificity of Integrated Pulmonary Index were 92.9 and 87.1, respectively. The sensitivity and specificity of Ottawa COPD Risk Score were 99.3 and 85.2, respectively. Besides, the accuracy of Integrated Pulmonary Index was 91.3, and the accuracy of Ottawa COPD Risk Score was 95.7. CONCLUSIONS: Integrated Pulmonary Index was a potential candidate for evaluating respiratory status and prediction of short-term severe events in patients with acute COPD exacerbation in emergency departments.

Comparison of intradermal mesotherapy with systemic therapy in the treatment of low back pain: A prospective randomized study.

INTRODUCTION: Musculoskeletal pain such as low back pain (LBP) are routinely encountered in the ED and contribute to ED overcrowding. The aim of our study was to compare the efficiency of mesotherapy with systemic therapy in pain control in patients with lumbar disk herniation. METHODS: We conducted this prospective parallel randomized controlled trial with the patients admitted to the emergency department with low back pain related to herniated lumbar disk. Mesotherapy was performed to one group, while intravenous dexketoprofen was administered to the control group. Changes in pain intensity at 15th minute, 30th minute, 60th minute and 24th hours after treatment using Visual Analogue Scale (VAS), need to use analgesic drug within 24 h after treatment, and adverse effect of the treatment methods were compared between groups. RESULTS: The decreases in pain intensity were statistically significantly higher in mesotherapy group for all time intervals. The need to use analgesics was statistically significantly three fold higher in the systemic therapy group. There was no statistically significant difference in having any adverse effect between study groups during one-week follow-up period. CONCLUSIONS: Changes in medical practices, from the systemic administration of NSAIDs to the minimally invasive techniques such as mesotherapy with potent efficacy and minimal side effects, may enhance the ability of EDs to meet the waiting time targets and improve patient's satisfaction.

Prognostic value of blood gas parameters and end-tidal carbon dioxide values in out-of-hospital cardiopulmonary arrest patients

Background/aim: This study aimed to evaluate the usefulness of blood gas and end-tidal carbon dioxide (EtCO2) measurements for predicting return of spontaneous circulation (ROSC) and for evaluating post-ROSC neurological survival. Materials and methods: This was a prospective case control study utilizing Atatürk University's database of adult nontraumatic patients (over 18 years old) with out-of-hospital cardiac arrest (OHCA) over the course of a year. The neurological status of the patients was evaluated after 1 h at ROSC and at hospital discharge, as defined by the cerebral performance category score. The blood gas parameters pH, PO2, PCO2, lactate, and BE were compared with EtCO2 from capnography and arteriol/alveolar carbon dioxide difference (AaDCO2) by using both blood gas and capnography upon admission to the emergency department and at ROSC. Results: A total of 155 patients were included in the study to form the control group with ROSC. The PO2, PCO2, and AaDCO2 values showed a prognostic marker for the supply of ROSC (P < 0.05). The EtCO2,lactate, and BE values measured by the blood gas were found to be insignificant in the prediction of ROSC (P > 0.05). Conversely, AaDCO2 was found to be significant in ROSC estimation (P < 0.05), but not in neurological evaluation (P > 0.05). Conclusion: Blood gas parameters and EtCO2 are sufficient in predicting ROSC. The value of AaDCO2 calculated using EtCO2 and PO2may be used in predicting the prognosis of OHCA patients, but this value does not provide any conclusions concerning neurological survival.

Parkin promotes proteasomal degradation of misregulated BAX.

The pro-apoptotic BCL-2 protein BAX commits human cells to apoptosis by permeabilizing the outer mitochondrial membrane. BAX activation has been suggested to require the separation of helix α5 from α6 - the 'latch' from the 'core' domain - among other conformational changes. Here, we show that conformational changes in this region impair BAX translocation to the mitochondria and retrotranslocation back into the cytosol, and therefore BAX inhibition, but not activation. Redirecting misregulated BAX to the mitochondria revealed an alternative mechanism of BAX inhibition. The E3 ligase parkin, which is known to trigger mitochondria-specific autophagy, ubiquitylates BAX K128 and targets the pro-apoptotic BCL-2 protein for proteasomal degradation. Retrotranslocation-deficient BAX is completely degraded in a parkin-dependent manner. Although only a minor pool of endogenous BAX escapes retrotranslocation into the cytosol, parkin-dependent targeting of misregulated BAX on the mitochondria provides substantial protection against BAX apoptotic activity.