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The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein production. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiac atrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Antithetically, Thbs1 −/− mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6α, CD36 or CD47 does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encoding PERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largely corrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9 gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2α-ATF4-induced autophagy as a critical regulator of cardiomyocyte size in the stressed heart. Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2α-ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart.

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability. Thrombospondin 4 has been shown to protect the heart and the skeletal muscle by enhancing matrix secretion and membrane stability thanks to its intracellular function. Here the authors show that thrombospondin 3 exacerbates injury-induced cardiomyopathy and promotes destabilization of the cardiomyocyte membrane by impairing integrin trafficking to the sarcolemma.

Revision arthroplasty is an invasive procedure with increased morbidity relative to primary joint arthroplasty. Therefore, patients with metastatic cancer (Met) undergoing revision total joint arthroplasty (rTJA) may be at greater risk. This study assesses early postoperative outcomes among Met patients undergoing rTJA. We reviewed the National Surgical Quality Improvement Program (NSQIP) database from 2015 to 2020 to evaluate rTHA/rTKA with Met and Non-Met. Univariate analysis and multivariate logistic regression were used to evaluate associations of Met patients compared with outcomes using odds ratio (OR) and 95% confidence interval (CI). Discriminatory accuracy was assessed using Receiver operating characteristic (ROC) curve and quantified using C-statistic. Adjusted analysis revealed Met patients undergoing rTKA were more likely to experience any complication (OR: 2.56, CI: [1.48-4.43]), major complication (OR: 2.17, CI: [1.24-3.82]), and mortality (OR: 7.99, CI: [2.70-23.65]). Met patients undergoing rTHA had higher associations with any complication (OR: 2.40, CI: [1.65-3.49]), major complication (OR: 2.19, CI: [1.47-3.25]), DVT (OR: 4.82, CI: [1.92-12.10]), and mortality (OR: 3.67, CI: [1.43-9.41]). Frailty had superior predictability of extended length of stay (C: 0.625 [0.619-0.630]) and mortality (C: 0.851 [0.824-0.880]). Patients with metastatic cancer have elevated risk of complications after revision arthroplasty but may have moderate predictability by frailty assessment. Surgeons can utilize this information to emphasize protective strategies to mitigate risk during and following total joint arthroplasty. III.

OBJECTIVEOperation Iraqi Freedom has resulted in a significant number of closed and penetrating head injuries, and a consequence of both has been the accompanying neurovascular injuries. Here we review the largest reported population of patients with traumatic neurovascular disease and offer our experience with both endovascular and surgical management.METHODSA retrospective analysis of all military casualties returning to the Walter Reed Army Medical Center and the National Naval Medical Center, Bethesda, Maryland, from April 2003 until April 2008 was performed. All patients undergoing diagnostic cerebral angiography during their inpatient stay were included in the study.RESULTSA total of 513 war trauma-related consults were performed from April 2003 to April 2008, resulting in the evaluation of 408 patients with closed and penetrating head injuries. In this population, 279 angiographic studies were performed in 187 patients (25 closed craniocervical injuries, 162 penetrating craniocervical injuries), resulting in the detection of 64 vascular injuries in 48 patients (26.2% of those studied, 34% prevalence). Vascular injuries were characterized by traumatic intracranial aneurysms (TICAs) (n = 31), traumatic extracalvarial aneurysms (TECAs) (n = 19), arterial dissections (n = 11), and arteriovenous fistulae (n = 3). The average TICA size on admission was 4.1 mm, with an observed increase in aneurysm size in 11 cases. In the TICA/TECA group, 24 aneurysms in 23 patients were treated endovascularly with either coiling or stent-assisted coiling, resulting in preservation of the parent artery in 12 of 24 vessels (50%). The injuries in 3 patients in this group progressed despite endovascular treatment and required definitive clip exclusion. Thirteen additional aneurysms in 8 patients were treated surgically, resulting in parent artery preservation in 4 cases (30.8%). Eleven of the 13 remaining TICAs/TECAs resolved spontaneously without treatment. A total of 6 aneurysm ruptures (average size, 8.25 mm) occurred, resulting in 3 deaths. Four of 6 ruptures occurred in TICAs in which the interval size increase was noted angiographically.CONCLUSIONThe management of traumatic vascular injury has evolved with technological advancement and the willingness of the neurosurgeon to intervene. Although open surgical intervention remains a viable solution, endovascular options are available and safe and can effectively temporize a patient while acute sequelae of serious head injury resolve.

Abstract BACKGROUND: If a self-expanding stent has been placed during endovascular treatment of an aneurysm and subsequently an open aneurysm surgery becomes necessary in the same or an adjacent area, is it possible and safe to obtain proximal control by placing a temporary clip on the artery at a point where it contains the stent? OBJECTIVE: To evaluate the effect of temporary clip application to 3 separate stent systems in an in vitro flow model with the stated hypothesis that clip application to these stents will result in permanent stent deformation. METHODS: This is an in vitro flow model study using an accepted synthetic blood vessel substitute. The Neuroform3 (Boston Scientific), Enterprise (Cordis/Codman), and Pipeline (ev3) stents were deployed within the flow model; temporary clips were applied; and angiographic measurements subsequently made. RESULTS: Two 4 × 30-mm Neuroform3 stents, two 4.5 × 28-mm Enterprise stents, and two 3.75 × 20-mm Pipeline stents were successfully deployed and clipped repeatedly (4 iterations). Two- and 3-dimensional angiograms were obtained. After repeated clip occlusion, the Neuroform3 and Enterprise stents returned to their original configuration and diameter. Clip application to both also resulted in immediate flow arrest. In contrast, initial clip application to the Pipeline stents did not result in flow arrest, but the second single clip application did. The Pipeline stents were also irreversibly deformed after the experimental protocol, with an average luminal diameter reduction of 26.85% (P < .05). CONCLUSION: The Neuroform3 and Enterprise stents responded favorably to temporary clip application, returning to their original diameter after clip removal and showing no sign of permanent structural modification. The Pipeline flow-diverting stent, however, was irreversibly deformed by clip application. These data indicate that temporary clip application to certain stents is possible. Further in vivo study is required.

Risk-taking propensity is a critical component of judgment and decision-making in military operations. The Evaluation of Risks scale (EVAR) was recently developed to measure state and trait aspects of risk proneness. The scale, however, was psychometrically normed in French and no data are available for the English translation. We administered the English version of the EVAR to 165 U.S. soldiers to obtain reliability, validity, and normative data for English-speaking respondents. Confirmatory factor analysis suggested that the factor structure of the English EVAR differs from that obtained in the French studies. Instead, a three-factor solution, including recklessness/impulsivity, self-confidence, and need for control, emerged. Internal consistency was comparable to the French version. EVAR scores correlated with age, military rank, and years of service, and discriminated soldiers with histories of high-risk behavior. The data support the reliability and validity of the English version of the EVAR for evaluating risk propensity in U.S. soldiers.

Cortical venous thrombosis is a rarely encountered mechanism for intracerebral hemorrhage. Multimodal monitoring may guide neurosurgical and critical care treatment in the setting of cerebral venous thrombosis. We report a 37-year-old service member who was admitted to a local field hospital for complaints of severe headache and left ear pain during Operation Iraqi Freedom. CT scan revealed a left temporal intracranial hematoma and subarachnoid hemorrhage. Angiogram revealed thrombosis of the vein of Labbe. Intracranial pressure (ICP), brain tissue oxygenation (PbO2), and cerebral blood flow (CBF) were monitored. There was a progressive increase in ICP despite ventricular drainage, sedation, and intubation. There was an ominous decrease in brain tissue oxygen and CBF became undetectable concomitantly with the increase in ICP. There was a dramatic decrease in ICP and improvement in brain tissue oxygenation and CBF after decompression and evacuation of the hematoma. Six weeks after the hemorrhage, the patient was able to follow simple commands and complete short sentences. To our knowledge, this is the first description of the use of ICP, PbO2, and laser Doppler method for obtaining CBF in the same setting. Information obtained from monitoring may lead to timely decompression and avoidance of poor outcome.

This study examined the effects on personality of transplantation of fetal tissue into the brains of participants in a double-blind placebo control trial for the treatment of Parkinson's disease (PD). Thirty persons with PD (equal numbers of males and females) participated in a larger study investigating the efficacy of transplantation of fetal neural tissue versus placebo surgery. Participants were randomly assigned to receive either the fetal transplant or placebo surgery. The blind was lifted for all patients approximately 13 months after surgery, at which time individuals who had received the placebo surgery could choose to receive the transplant surgery. In this study 12 persons originally received the transplant and 18 received placebo surgery. The NEO Five-Factor Inventory (NEO-FFI), a commonly used measure of personality characteristics, was administered to participants at baseline, 12, and 24 months after surgery. Scores at baseline for the Openness and Agreeableness scales were significantly higher for this sample of PD patients than scores for the normative group. There were no changes on any of the five scales from baseline to 12 months for the total group. The only significant change in the original transplant group was a decrease in Conscientiousness from baseline to 24 months. There were no changes over time among the group who had placebo surgery first and then the transplant. Results indicate that personality, as measured by the NEO-FFI, basically remained stable during the two-year follow-up period of this study. In this case, no change is regarded as a positive outcome.