α-Synuclein Aggregates Increase the Conductance of Substantia Nigra Dopamine Neurons, an Effect Partly Reversed by the KATP Channel Inhibitor Glibenclamide.

Dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and coordination. A hallmark of Parkinson's disease (PD) is the degeneration of these SNpc DNs leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric α-synuclein (α-syn) is one of the major pathologic species in PD, with its deposition in Lewy bodies (LBs) closely correlated with disease progression. However, the precise mechanisms underlying the effects of oligomeric α-syn on DN function have yet to be fully defined. Here, we have combined electrophysiological recording and detailed analysis to characterize the time-dependent effects of α-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc DNs. The introduction of α-syn aggregates into single DNs via the patch electrode significantly reduced both the input resistance and the firing rate without changing the membrane potential. These effects occurred after 8-16 min of dialysis but did not occur with the monomeric form of α-syn. The effects of α-syn aggregates could be significantly reduced by preincubation with the ATP-sensitive K+ channel (KATP) inhibitor glibenclamide. These data suggest that accumulation of α-syn aggregates in DNs may chronically activate KATP channels leading to a significant loss of excitability and dopamine release.

Management of traumatic lung injury: a Western Trauma Association Multicenter review.

BACKGROUND: Improved outcomes following lung injury have been reported using "lung sparing" techniques. METHODS: A retrospective multicenter 4-year review of patients who underwent lung resection following injury was performed. Resections were categorized as "minor" (suture, wedge resection, tractotomy) or "major" (lobectomy or pneumonectomy). Injury severity, Abbreviated Injury Scale (AIS) score, and outcome were recorded. RESULTS: One hundred forty-three patients (28 blunt, 115 penetrating) underwent lung resection after sustaining an injury. Minor resections were used in 75% of cases, in patients with less severe thoracic injury (chest AIS scores "minor" 3.8 +/- 0.9 vs. "major" 4.3 +/- 0.7, p = 0.02). Mortality increased with each step of increasing complexity of the surgical technique (RR, 1.8; CI, 1.4-2.2): suture alone, 9% mortality; tractotomy, 13%; wedge resection, 30%; lobectomy, 43%; and pneumonectomy, 50%. Regression analysis demonstrated that blunt mechanism, lower blood pressure at thoracotomy, and increasing amount of the lung resection were each independently associated with mortality. CONCLUSION: Blunt traumatic lung injury has higher mortality primarily due to associated extrathoracic injuries. Major resections are required more commonly than previously reported. While "minor" resections, if feasible, are associated with improved outcome, trauma surgeons should be facile in a wide range of technical procedures for the management of lung injuries.

Cis-4-amino-crotonic acid activates alpha 6 subunit-containing GABA(A) but not GABA(C) receptors in granule cells of adult rat cerebellar slices.

The expression of GABA(C) receptors in granule cells of adult rat cerebellar slices was investigated. The GABA(C) receptor agonist cis-4-amino-crotonic acid (CACA) evoked currents in granule cells. However, CACA-evoked currents were not blocked by the GABA(C) receptor antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), but were blocked by the GABA(A) receptor antagonist bicuculline. CACA activated alpha6 subunit-containing GABA receptors as CACA-evoked currents were reduced by furosemide and CACA activated alpha6beta2gamma2s receptors expressed in HEK 293 cells. The channels opened by CACA had conductances which were larger than those described for GABA(C) receptors but were similar to those described for GABA(A) receptors. GABAergic synaptic currents were blocked by low concentrations of bicuculline, but not by TPMPA. Thus, cerebellar granule cells express functional GABA(A) but not GABA(C) receptors.

Feature mining and predictive model construction from severe trauma patient's data.

In management of severe trauma patients, trauma surgeons need to decide which patients are eligible for damage control. Such decision may be supported by utilizing models that predict the patient's outcome. The study described in this paper investigates the possibility to construct patient outcome prediction models from retrospective patient's data at the end of initial damage control surgery by using feature mining and machine learning techniques. As the data used comprises rather excessive number of features, special attention was paid to the problem of selecting only the most relevant features. We show that a small subset of features may carry enough information to construct reasonably accurate prognostic models. Furthermore, the techniques used in our study identified two factors, namely the pH value when admitted to ICU and the worst partial active thromboplastin time, to be of highest importance for prediction. This finding is pathophysiologically reasonable and represents two of three major problems with severe trauma patients, metabolic acidosis, hypothermia, and coagulopathy.

Timing of urgent thoracotomy for hemorrhage after trauma: a multicenter study.

HYPOTHESIS: It is possible to quantify an amount of thoracic hemorrhage, after blunt and penetrating injury, at which delay of thoracotomy is associated with increased mortality. DESIGN: A retrospective case series. SETTING: Five urban trauma centers. STUDY SELECTION: Patients undergoing urgent thoracotomy (within 48 hours of injury) for hemorrhage (excluding emergency department thoracotomy). DATA EXTRACTION: Respective registries identified patients who underwent urgent thoracotomy. Injury characteristics, initial and subsequent chest tube outputs, time before thoracotomy, and outcomes were evaluated. MAIN OUTCOME MEASURE: Death. RESULTS: One hundred fifty-seven patients (36 with blunt and 121 with penetrating injuries) underwent urgent thoracotomy for hemorrhage between January 1, 1995, and December 31, 1998. Mortality correlated with mean (+/- SD) Injury Severity Score (38 +/- 19 vs 22 +/- 12.6 for survivors; P<.01) and mechanism (24 [67%] for blunt vs 21 [17%] for penetrating injuries; P<.01). Mortality increased as total chest blood loss increased, with the risk for death at blood loss of 1500 mL being 3 times greater than at 500 mL. Blunt-injured patients waited a significantly longer time to thoracotomy than penetrating-injured patients (4.4 +/- 9.0 h vs 1.6 +/- 3.0 h; P =.02) and also had a greater total chest tube output before thoracotomy (2220 +/- 1235 mL vs 1438 +/- 747 mL; P =.001). CONCLUSIONS: The risk for death increases linearly with total chest hemorrhage after thoracic injury. Thoracotomy is indicated when total chest tube output exceeds 1500 mL within 24 hours, regardless of injury mechanism.

Interligand Overhauser effects in type II dihydrofolate reductase.

R67 dihydrofolate reductase (DHFR) is a type II DHFR produced by bacteria as a resistance mechanism to the increased clinical use of the antibacterial drug trimethoprim. Type II DHFRs are not homologous in either sequence or structure with chromosomal DHFRs. The type II enzymes contain four identical subunits which form a homotetramer containing a single active site pore accessible from either end. Although the crystal structure of the complex of R67 DHFR with folate has been reported [Narayana et al. (1995) Nat. Struct. Biol. 2, 1018], the nature of the ternary complex which must form with substrate and cofactor is unclear. We have performed transferred NOE and interligand NOE (ILOE) studies to analyze the ternary complexes formed from NADP(+) and folate in order to probe the structure of the ternary complex. Consistent with previous studies of the binary complex formed from another type II DHFR, the ribonicotinamide bond of NADP(+) was found to adopt a syn conformation, while the adenosine moiety adopts an anti conformation. Large ILOE peaks connecting NADP(+) H4 and H5 with folate H9 protons are observed, while the absence of a large ILOE connecting NADP(+) H4 and H5 with folate H7 indicates that the relative orientation of the two ligands differs significantly from the orientation in the chromosomal enzyme. To obtain more detailed insight, we prepared and studied the folate analogue 2-deamino-2-methyl-5,8-dideazafolate (DMDDF) which contains additional protons in order to provide additional NOEs. For this analogue, the exchange characteristics of the corresponding ternary complex were considerably poorer, and it was necessary to utilize higher enzyme concentrations and higher temperature in order to obtain ILOE information. The results support a structure in which the NADP(+) and folate/DMDDF molecules extend in opposite directions parallel to the long axis of the pore, with the nicotinamide and pterin ring systems approximately stacked at the center. Such a structure leads to a ternary complex which is in many respects similar to the gas-phase theoretical calculations of the dihydrofolate-NADPH transition state by Andres et al. [(1996) Bioorg. Chem. 24, 10-18]. Analogous NMR studies performed on folate, DMDDF, and R67 DHFR indicate formation of a ternary complex in which two symmetry-related binding sites are occupied by folate and DMDDF.

Thoracic aortic and thoracic vascular injuries.

Patients with thoracic vascular injuries fall into two groups: those who are exsanguinating and require an empiric operation with a high mortality and those with contained injuries that permit preoperative evaluation. The unstable group requires judgment to determine the appropriate empiric position, exposure, and operation. Unlike abdominal trauma, which is addressed by way of a midline incision, there are multiple thoracic incisions that can be used to access thoracic vascular injuries. Thus, the stable group may benefit from preoperative imaging, which then can suggest a patient position, incision, and operative approach. Avoiding overaggressive resuscitation, obtaining appropriate imaging studies, choosing an operative strategy to achieve proximal and distal control, and using adjuncts based on the injury can make the care of these patients a rewarding but challenging activity.

Historical review of blunt injury to the thoracic aorta.

This article addresses the history of blunt injury to the aorta by reviewing the epidemiology, military accounts, ancient history, and recent history during the last five decades of the twentieth century. Although they are a bit arbitrary and overlap somewhat, significant groupings regarding blunt injury to the thoracic aorta have occurred in ten-year blocks. It is important that any surgeon not be locked into a previous time period but be continually knowledgeable of ever-changing approaches. These approaches should always be based on the best evidence-based information available.

Predictive model for survival at the conclusion of a damage control laparotomy.

BACKGROUND: We employed modern statistical and data mining methods to model survival based on preoperative and intraoperative parameters for patients undergoing damage control surgery. METHODS: One hundred seventy-four parameters were collected from 68 damage control patients in prehospital, emergency center, operating room, and intensive care unit (ICU) settings. Data were analyzed with logistic regression and data mining. Outcomes were survival and death after the initial operation. RESULTS: Overall mortality was 66.2%. Logistic regression identified pH at initial ICU admission (odds ratio: 4.4) and worst partial thromboplastin time from hospital admission to ICU admission (odds ratio: 9.4) as significant. Data mining selected the same factors, and generated a simple algorithm for patient classification. Model accuracy was 83%. CONCLUSION: Inability to correct pH at the conclusion of initial damage-control laparotomy and the worst PTT can be predictive of death. These factors may be useful to identify patients with a high risk of mortality.

Thoracic aortic injury.

Most traumatic aortic injuries are the result of penetrating causes, whereas blunt aortic injury is less common. The initial treatment is determined by the patient's condition. Diagnostic studies include catheter arteriography, computed tomography, and transesophageal echo cardiography. This article summarizes the initial evaluation and management of patients with an aortic injury and describes the various treatment options such as delayed selective management, endovascular solutions, and surgical repair.

Analysis of thoracoscopy in trauma.

BACKGROUND: The role of video-assisted thoracic surgery (VATS) in trauma has yet to be established. Up to the time of this writing, reviews of thoracoscopy in trauma have been primarily descriptive rather than analytic. This article analyzes the results of thoracoscopy (nonvideo and VATS) in trauma. METHODS: Analysis was done by reviewing 28 nonoverlapping studies since the introduction of thoracoscopy in 1910, with a combined total of more than 500 patients. RESULTS: Diagnostically, thoracoscopy has been used primarily to evaluate diaphragmatic injury, continued chest tube bleeding, and suspected cardiac injury. Thoracoscopy has a 98% (188/191 patients) accuracy rate in diagnosing diaphragmatic injuries. Therapeutically, thoracoscopy has been used primarily to control chest tube bleeding, evacuate retained hemothoraces, and evacuate empyemas. Thoracoscopy is 90% (89/99 patients) effective in evacuating retained hemothoraces, 86% (19/22 patients) effective in evacuating empyemas, and 82% (33/40 patients) effective in controlling chest tube bleeding. Thoracoscopy benefits include preventing 62% (323/514) of trauma patients from having a thoracotomy or laparotomy. Risks include a 2% (11/534 patients) procedure-related complication rate and a 0.8% (4/471 patients) missed injury rate. Technical failure rates are 10% (10/99 patients) and 4% (7/199 patients) in evacuation of retained hemothoraces and evaluation of diaphragmatic injuries, respectively. CONCLUSIONS: Analysis suggests that thoracoscopy (nonvideo and VATS) can be applied safely and effectively in the care of the injured patient.

Pulmonary tractotomy as an abbreviated thoracotomy technique.

BACKGROUND: Operative abbreviated thoracotomy techniques in thoracic trauma include emergency center thoracotomy, ligation of major arterial branches, packing the thoracic cavity for diffuse bleeding, towel clip or Bogota bag closure of the chest, and pulmonary tractotomy. Pulmonary tractotomy with selective vascular ligation was originally described for deep through-and-through lung injuries that did not involve hilar vessels or airways. Pulmonary tractotomy has evolved into use as an abbreviated thoracotomy technique in patients with severe thoracic or multivisceral trauma. As with any operative technique in high-risk patients, specific procedure-related complications may occur and are analyzed herein. The objective of this manuscript is to review the indications, techniques, and results for pulmonary tractotomy in trauma patients requiring abbreviated thoracotomy. METHODS: Medical records were retrospectively reviewed for 30 of 32 consecutive tractotomy patients treated at Ben Taub General Hospital, during a 3-year period. By using a model for logistic regression analysis, the characteristics of each patient and their clinical course were tested for impact on mortality. RESULTS: Seventy percent of patients had at least one intraoperative parameter indicative of acidosis (pH < 7.2), coagulopathy (prothrombin time > 13.8 or partial thromboplastin time > 38.0 seconds), or hypothermia (core temperature < 34 degrees C), and 50% of patients manifested two of these three parameters. The mortality rate among the 30 patients was 17%. Three of the five patients who died were noted to be acidotic, coagulopathic, and hypothermic. Twelve of 25 patients who survived more than 1 day had at least one thoracic complication. There were no late deaths. There was one failed tractotomy and one missed injury. A second thoracotomy was not required for control of a lung injury in any patient. Logistic regression analysis showed that intraoperative blood loss was the only predictive factor for mortality. CONCLUSION: Pulmonary tractotomy is a simple and effective technique in injured patients who require an abbreviated thoracotomy and has an acceptable mortality and complication rate. This follow-up report notes that as definitive therapy, tractotomy continues to allow for direct control of bleeding and air leak and obviates the need for formal resection.

Needle embolus causing cardiac puncture and chronic constrictive pericarditis.

We present a case in which a needle broke off during intravenous injection and embolized to the right heart. After cardiac perforation, the needle entered the pericardial space and ultimately caused chronic constrictive pericarditis, which presented as congestive heart failure. Pericardectomy and removal of the foreign body via a median sternotomy were successful. Early surgical removal of contaminated intrapericardial foreign bodies remains a safe and effective approach to preventing such complications.

Ruptured aortic pseudoaneurysm 28 years after gunshot wound: case report and review of the literature.

Penetrating injuries to the abdominal aorta most often result in rapid exsanguination and death. Immediate surgical intervention may result in control of hemorrhage and survival of the patient. Rarely, hemorrhage after aortic injury may be contained by surrounding tissues, resulting in pseudoaneurysm formation. Traumatic pseudoaneurysms may rupture at any time, and this is usually a fatal event. A 47-year-old man recently presented with a supraceliac abdominal aortic pseudoaneurysm that ruptured into the right chest 28 years after a gunshot wound to the back. This report describes the pathophysiology, diagnosis, and treatment of traumatic pseudoaneurysms of the abdominal aorta and includes a review of the literature. This is a case in which a traumatic pseudoaneurysm of the abdominal aorta was successfully repaired by surgery after rupture into the thorax and is the first such case to be reported in the literature.

Development of the quantal properties of evoked and spontaneous synaptic currents at a brain synapse.

In many studies of central synaptic transmission, the quantal properties of miniature synaptic events do not match those derived from synaptic events evoked by action potentials. Here we show that at mossy fiber-granule cell (MF-gc) synapses of mature cerebellum, evoked excitatory postsynaptic currents (EPSCs) are multiquantal, and their amplitudes vary in discrete steps, whereas miniature (m)EPSCs are monoquantal or multiquantal with quantal parameters identical to those of the EPSCs. In contrast, at immature MF-gc synapses, EPSCs are multiquantal, but their amplitudes do not vary in discrete steps, whereas most mEPSCs seem to be monoquantal with a broad and skewed amplitude distribution. The results demonstrate that quantal variance decreases during synaptic development. They also directly confirm the quantal hypothesis of neurotransmission at a mature brain synapse.

Remote clinical assessment for acute trauma: an initial experience.

Optimal care of the injured patient requires an organized approach, dedicated resources and clinical expertise. Victims of major trauma, however, frequently present to rural and suburban hospitals regardless of whether a dedicated trauma system in place. Immediate consultation by a trauma expert could potentially expedite effective evaluation and management of trauma victims, reducing the occurrence of unnecessary transport and leading to efficient stabilization and transport when needed. Remote assessment of trauma patients must be assesses for feasibility, safety and efficacy before widespread implementation. This project represents the initial steps towards the development of a functional telemedicine system for trauma care.