Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures.We thank M.I. Ivanova, J. Corn, T. Kortemme, D. Anderson, M.R. Sawaya, M. Phillips, S. Sambashivan, J. Park, M. Landau, Q. Zhang, R. Clubb, F. Guo, T. Yeates, J. Nowick, J. Zheng, and M.J. Thompson for discussions, HHMI, NIH, NSF, the GATES foundation, and the Joint Center for Translational Medicine for support, R. Peterson for help with NMR experiments, E. Mandelkow for providing tau constructs, R. Riek for providing amyloid beta, J. Stroud for amyloid beta preparation. Support for JK was from the Damon Runyon Cancer Research Foundation, for HWC by the Ruth L. Kirschstein National Research Service Award, for JM from the programme for junior-professors by the ministry of science, Baden-Württemberg, and for SAS by a UCLA-IGERT bioinformatics traineeship

Repair of an acute blunt popliteal artery trauma via endovascular approach

Popliteal vascular trauma remains a challenging entity and carries the greatest risk of limb loss among the lower extremity vascular injuries. Operative management of patients presenting with traumatic popliteal vascular injuries continues to evolve. We present a case of successful endovascular repair with stent grafting of an acute blunt popliteal artery injury. Endovascular repair of traumatic popliteal vascular injuries appears as an attractive alternative to surgical repair in a very selective group of patients. Further investigation is still needed to define the safety and feasibility of endovascular approach in the management of traumatic popliteal vascular injuries

Vascular Reconstruction Is Not Warranted in Most Civilian Traumatic Shank Vascular Injuries

Operative management of traumatic shank vascular injuries (SVI) evolved significantly in the past few decades, thereby leading to a dramatic decrease in amputation rates. However, there is still controversy regarding the minimum number of patent shank arteries sufficient for limb salvage. Between January 2006 and September 2011, 191 adult trauma patients presented to an urban level I trauma center in Miami, Florida, with traumatic lower extremity vascular injuries. Variables collected included age, gender, mechanism of injury, and clinical status at presentation. Surgical data included vessel injury, technical aspects of repair, associated complications, and outcomes. A total of 48 (25.1%) patients were identified comprising 66 traumatic shank arterial injuries. Mean age was 38.2 ± 13.4 years, and the majority of patients were men (40 patients, 83.3%) presenting with blunt injuries (35 patients, 72.9%). Ligation was performed in 38 injured arteries (57.6%) and no vascular intervention was required in 20% of the patients. Vascular reconstruction was performed in only 6 patients (9.1%): 4 (6.1%) with concurrent popliteal trauma, 1 (1.5%) isolated anterior tibial, and 1 (1.5%) 3-vessel injury. Autogenous venous interposition conduit and polytetrafluoroethylene grafting were performed in 5 (7.6%) and 1 (1.5%) patient, respectively. All amputations (8 patients, 16.7%) occurred in blunt trauma patients presenting with unsalvageable limbs. The overall mortality rate in this series was 2.1%. Civilian shank arterial injuries are associated with acceptable rates of limb loss. Patients with a single-vessel patent inflow did not require vascular reconstruction in this series. Arterial reconstruction may no longer be determinant for successful management of isolated and double arterial SVI, whereas it is yet essential in the presence of 3-vessel or concurrent above-the-knee vascular injuries. Further investigation including larger number of patients is still warranted to define the role of conservative management in these complex injuries

Management of lower extremity vascular injuries in pediatric trauma patients: a single Level I trauma center experience

Traumatic vascular injuries of the lower extremity in the pediatric population are rare but can result in significant morbidity. We aimed at describing our experience with such complex injuries, with associated patterns of injury, diagnostic and therapeutic challenges, and outcomes. From January 2006 to December 2011, 2,844 pediatric trauma patients presented at the Ryder Trauma Center, an urban Level I trauma center in Miami, Florida. Among them, 18 patients (0.6%) were evaluated for lower extremity traumatic vascular injuries. Variables collected included age, sex, mechanism of injury, and clinical status at presentation. Surgical data included vessel injury, technical aspects of repair, associated complications, and outcomes. Mean (SD) age was ± 14.7 (2.6) years (range, 6-17 years), with 17 males (94.4%). Of the 18 traumatic pediatric patients, 32 vascular injuries were identified. All arterial injuries underwent definitive operative repair. Primary repair was performed in two patients (11.1%), six (33.3%) required saphenous vein interposition grafting as initial procedure, and eight (44.4%) underwent polytetrafluoroethylene grafting. Ligation was performed in major venous injuries and deep profunda branches. The overall survival in this series was 94.4%. Peripheral vascular injuries of the lower extremity in the pediatric population can result in acceptable outcomes if managed early and aggressively. Surgical principles of vascular surgery are similar to those applied to an adult. We recommend that these injuries should be managed in a tertiary specialized center with a multidisciplinary team of trauma surgeons, and pediatricians, which can potentially decrease morbidity and mortality. Epidemiologic study, level III

Management of traumatic popliteal vascular injuries in a level I trauma center: A 6-year experience

Popliteal vascular trauma remains a challenging entity, and carries the greatest risk of limb loss among the lower extremity vascular injuries. Operative management of traumatic popliteal vascular injuries continues to evolve. We aim at describing our experience with such complex injuries, with associated patterns of injury, diagnostic and therapeutic challenges, and outcomes. From January 2006 to September 2011, 191 adult trauma patients presented to an urban level I trauma center in Miami, Florida with traumatic lower extremity vascular injuries. Variables collected included age, gender, mechanism of injury, and clinical status at presentation. Surgical data included vessel injury, technical aspects of repair, associated complications and outcomes. Forty-seven (24.6%) patients were diagnosed with traumatic popliteal vascular injuries. Mean age was 38.1 ± 16.1 years, and the majority of patients were males (43 patients, 91.4%). There were 21 (44.7%) penetrating injuries, and 26 (55.3%) blunt injuries. Vascular repair with saphenous venous interposition graft and PTFE (polytetrafluoroethylene) grafting were performed in 36 (70.7%) and 2 (3.9%) patients, respectively. Blunt popliteal injuries were significantly more associated with major tissue loss, and length of hospital and intensive care unit (ICU) stays. The risk for amputation is increased with longer ICU stays and the use of PTFE grafting for vascular repair. The overall mortality rate in this series was 8.5%. Blunt popliteal vascular injuries are associated with increased morbidity compared to penetrating trauma. Early restoration of blood perfusion, frequent use of interposition grafts with autogenous saphenous vein, and liberal use of fasciotomies play important role to achieve acceptable outcomes

Multidisciplinary team approach in the management of popliteal artery injury.

Popliteal artery injuries (PAIs) remain a challenging entity and carry the greatest risk of limb loss among traumatic lower extremity vascular injuries. Operative management of traumatic popliteal vascular injuries continues to evolve. Improved diagnostic imaging and the introduction of endovascular techniques offered alternative modalities to traditional surgical management. Despite major efforts in establishing protocols and guidelines in the management of vascular trauma, optimal strategies of traumatic PAIs are still under investigation. Herein, we discussed the role of multidisciplinary team, involving trauma and endovascular surgeons, emergency department personnel, and interventional radiologists in the management of complex PAIs

A western trauma association multicenter comparison of mesh versus non-mesh repair of blunt traumatic abdominal wall hernias

BACKGROUND: Blunt traumatic abdominal wall hernias (TAWH) occur in \u3c1 % of trauma patients. Optimal repair techniques, such as mesh reinforcement, have not been studied in detail. We hypothesize that mesh use will be associated with increased surgical site infections (SSI) and not improve hernia recurrence. MATERIALS AND METHODS: A secondary analysis of the Western Trauma Association blunt TAWH multicenter study was performed. Patients who underwent TAWH repair during initial hospitalization (1/2012-12/2018) were included. Mesh repair patients were compared to primary repair patients (non-mesh). A logistic regression was conducted to assess risk factors for SSI. RESULTS: 157 patients underwent TAWH repair during index hospitalization with 51 (32.5 %) having mesh repair: 24 (45.3 %) synthetic and 29 (54.7 %) biologic. Mesh patients were more commonly smokers (43.1 % vs. 22.9 %, p = 0.016) and had a larger defect size (10 vs. 6 cm, p = 0.003). Mesh patients had a higher rate of SSI (25.5 % vs. 9.5 %, p = 0.016) compared to non-mesh patients, but a similar rate of recurrence (13.7 % vs. 10.5%, p = 0.742), hospital length of stay (LOS), and mortality. Mesh use (OR 3.66) and higher ISS (OR 1.06) were significant risk factors for SSI in a multivariable model. CONCLUSION: Mesh was used more frequently in flank TAWH and those with a larger defect size. Mesh use was associated with a higher incidence and risk of SSI but did not reduce the risk of hernia recurrence. When repairing TAWH mesh should be employed judiciously, and prospective randomized studies are needed to identify clear indications for mesh use in TAWH

Management of femoral vessel injuries: a 6-year single-center experience

Femoral vessel injuries are a familiar injury treated in busy urban trauma centers. The majority of peripheral vascular injuries to the lower extremity occur most commonly to the femoral vessels. The increasing incidence of civilian violence provides an opportunity to perform a comprehensive review and management of these injuries