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Changes occur during the postnatal development of the rat glutamatergic mossy fibre to granule cell synapse: to the morphology of synapses, glutamate transporter expression, AMPA receptor expression and the kinetics of AMPA receptor-mediated synaptic transmission. For example, both the rise and decay times of AMPA receptor-mediated excitatory postsynaptic currents significantly shorten. To further define the development of mossy fibre to granule cell synaptic transmission, the properties and mechanisms of short-term plasticity have been described. The characterization of short-term plasticity will aid our understanding of the mechanisms that define the parameters of synaptic transmission during development and furthermore short-term plasticity may play an important role in determining information transfer between mossy fibres and granule cells. In response to pairs of stimuli (2-100-ms interval), depression (second excitatory postsynaptic current amplitude smaller than the first) was observed at both mature (older than 40 postnatal days) and immature (between 8 and 12 postnatal days) synapses. The degree of depression was similar at both stages of development, although recovery from depression was slower at mature synapses (tau 22 vs 12.5 ms). Several experimental approaches (coefficient of variation, low-affinity antagonists and cyclothiazide) suggest that depression at immature synapses results from multiple mechanisms. At mature synapses, postsynaptic receptor desensitization appears to be the major cause of depression.

There is considerable evidence that the transition metal zinc plays an important role in mammalian neural development, physiology and pathology. The most compelling evidence for a synaptic role for zinc comes from hippocampal studies: zinc is concentrated in the synaptic vesicles of some glutamatergic neurons, zinc can be released during neural activity and zinc can modulate postsynaptic GABA and glutamate receptors. The possibility that zinc is involved in cerebellar synaptic transmission is supported by the expression of specific zinc transporters (ZnT, including the synaptic vesicle transporter ZnT-3) in the cerebellar cortex. Furthermore, some subtypes of neurotransmitter receptors, expressed by cerebellar neurones, are highly sensitive to low concentrations of exogenous zinc. However there appears to be little chelatable (synaptic) zinc in the cerebellum, deletion of the ZnT-3 gene has no effect on motor phenotype and there is currently no evidence that zinc is released from cerebellar neurones to have physiological actions. Thus it is possible that the different types of zinc transporter found in the cerebellum play a neuroprotective rather than a signalling role.

A recent study has shown that cerebellar GABAergic interneuron (Golgi cell) terminals contain the zinc transporter znt3, raising the possibility that zinc is synaptically released to modulate GABAergic transmission. To test this possibility, the actions of exogenous zinc on Golgi cell to granule cell synaptic transmission were investigated and then the effects of removing endogenous zinc were examined. Application of zinc markedly reduced the tonic GABA(A)-receptor-mediated current in granule cells but produced a much smaller heterogeneous inhibitory effect on evoked phasic GABAergic currents. Neither the tonic current, single evoked synaptic currents nor trains of synaptic currents were modulated when endogenous zinc was chelated. Thus, there is no physiological evidence that zinc is released from Golgi cells to modulate GABAergic transmission.

Background: Resuscitative thoracotomy (TCY) after trauma has an overall dismal survival rate, yet patients with isolated penetrating chest wounds have the best chance of meaningful recovery. Although the major factor in outcome is presenting physiology, the site of the TCY may influence survival, with the operating room offering a superior environment to the emergency room., Purpose: The purpose of this study was to evaluate the impact of location of TCY on outcome after penetrating chest injury., Methods: This was a multicenter study of patients admitted with either stab (SW) or gunshot wound (GSW) to the chest, with systolic blood pressure < or = 90 mm Hg, and who underwent TCY within 60 minutes of arrival. Time to TCY, Injury Severity Score, location of TCY (emergency room, operating room, or resuscitation room), and detectable systolic pressure at admission were among the factors studied., Results: Over a 4-year period, 78 SW and 140 GSW victims underwent TCY. GSW victims had greater Injury Severity Scores (39.4 +/- 23.1 for GSW vs. 27.2 +/- 15.7 for SW, p < 0.001) and mortality (69% for GSW vs. 37% for SW, p < 0.001). No parameter studied was found to be significantly associated with survival after SW. After GSW, survival was 13.5 times more likely if TCY was performed in the resuscitation room (confidence interval, 3.3-54.6) and 22 times more likely if it was performed in the operating room (confidence interval, 6.7-73.7)., Conclusion: Although patient selection is the primary factor determining outcome, there may be an independent benefit for performing TCY after GSW in a specialized resuscitation room or the operating room.

Introduction: This study tracks the microbiology of packs and infections in damage-control trauma patients to determine whether the packs cause infections., Methods: The peritoneum and abdominal packs were cultured in patients who survived to re-operation. The study recorded all positive cultures, pack count, packing duration, number of operations, and infections., Results: Thirty-five patients were studied. Twenty-eight patients survived; seven died. Packs were cultured in 29 patients. Data for 291 cultures collected. Pack cultures were positive in 20 patients and negative in nine. Positive pack cultures grew skin and gut flora. Twenty-one patients had infections, 14 did not. Organisms from positive pack cultures did not contribute to subsequent infections or mortality. Microbes and sites of infections were consistent with SICU patients., Conclusions: Intra-abdominal packs are contaminated with skin and gut flora. These contaminants, however, do not contribute to subsequent infections. Pathogens from subsequent infections were typical for ICU infections.

Background: Surgical treatment of traumatic pulmonary injuries requires knowledge of multiple approaches and operative interventions. We present a 15year experience in treatment of traumatic pulmonary injuries. We hypothesize that increased extent of lung resection correlates with higher mortality., Methods: Surgical registry data of a level 1 trauma center was retrospectively reviewed from 1984 to 1999 for traumatic lung injuries requiring operative intervention. Epidemiologic, operative, and hospital mortality data were obtained., Results: Operative intervention for traumatic pulmonary injuries was required in 397 patients, of whom 352 (89%) were men. Penetrating trauma was seen in 371 (93%) patients. Location of the injuries was noted in the left side of the chest in 197 (50%), right side of the chest in 171 (43%), and bilateral in 29 (7%). Operative interventions included pneumonorraphy (58%), wedge resection or lobectomy in (21%), tractotomy (11%), pneumonectomy (8%), and evacuation of hematoma (2%). Overall mortality was 27%. If concomitant laparotomy was required, mortality increased to 33%. The mortality rate in the pneumonectomy group was 69.7%., Conclusions: The majority of lung injuries occurred in males due to penetrating trauma. Surgical treatment options ranged from simple oversewing of bleeding injury to rapid pneumonectomy. Mortality increased as the complexity of the operative intervention increased. Rapid intraoperative assessment and appropriate control of the injury is critical to the successful management of traumatic lung injury.

Purpose of Review: The purpose of this review is to evaluate the current indications and results of treatment of combined coronary and carotid disease. Synchronous carotid stenosis in patients with coronary artery disease poses a management challenge in patients with advanced atherosclerosis., Recent Findings: Recent case series continue to demonstrate concomitant coronary and carotid disease with significant carotid stenosis greater than 70% in approximately 8% of patients evaluated for coronary artery bypass grafting. Surgical management options include staged operations addressing the carotid stenosis first, reverse staged operations addressing the coronary disease first, and combined synchronous operations addressing both territories during the same anesthetic. Recent reports demonstrate safety and acceptable risks with each operative approach. Lower trends in stroke rates were noted following staged procedures when compared with combined procedures. However, several metaanalyses showed no significant difference in rates of combined morbidity and mortality for all three strategies. Total morbidity and mortality risks for combined disease tended to be higher than for isolated coronary artery bypass grafting or carotid endarterectomy procedures performed for disease in a single vascular territory., Summary: Despite a large volume of data present in the literature, the treatment indications and surgical options remain controversial. We currently advocate treatment of symptomatic territory first in favor of staged procedures and reserve combined procedures for patients with critical stenosis or symptoms in both territories.

The penultimate catalytic step of the purine de novo synthesis pathway is the conversion of aminoimidazole-4-carboxamide ribonucleotide (AICAR) to 5-formyl-AICAR that requires the cofactor N(10)-formyl-tetrahydrofolate as the formyl donor. This reaction is catalyzed by the AICAR transformylase domain of the bifunctional enzyme AICAR transformylase/inosine monophosphate cyclohydrolase (ATIC). Identification of the location of the AICAR transformylase active site was previously elucidated from the crystal structure of the avian ATIC with bound substrate AICAR; however, due to the absence of any bound folate, the folate binding region of the active site could not be identified. Here, we have determined the homodimeric crystal structure of avian ATIC in complex with the ATIC-specific multisubstrate adduct inhibitor beta-DADF to 2.5 A resolution. Beta-DADF encompasses both the AICAR and folate moieties into a single covalently linked entity, thereby allowing for the characterization of the folate binding pocket of the AICAR transformylase active site. Beta-DADF is intimately bound at the dimer interface of the transformylase domains with the majority of AICAR moiety interactions occurring within one subunit, whereas the primary interactions to the folate occur with the opposing subunit. The crystal structure suggests that a buried Lys(267) is transiently protonated during formyl transfer allowing for the stabilization of the oxyanion transition state and subsequent protonation of N10 on the tetrahydrofolate leaving group. Furthermore, the beta-DADF-bound structure provides a more optimal three-dimensional scaffold to improve the design of specific antineoplastic agents.

Nitric oxide (NO) is a gaseous neurotransmitter which plays an important role in neuronal signalling and plasticity throughout the brain. In the cerebellum, NO synthase (NOS) is expressed in parallel fibres and within the internal granule cell layer (IGL). During development there are changes in NOS concentration, distribution and activity within the IGL, suggesting NO may play a role in IGL function. Therefore, the actions of NO in the IGL were investigated. The similar actions of a range of NOS inhibitors and NO scavengers strongly suggested the presence of a tonic level of endogenous NO in the IGL. Both the neuronal and inducible forms of NOS appeared to be sources of this endogenous NO. The effects observed following a reduction in the concentration of endogenous NO were consistent with enhanced granule cell GABAA receptor activation. For example, a reduction in NO concentration led to an increase in the frequency of action potential-dependent phasic GABAergic inhibitory postsynaptic currents (IPSCs) and produced a TTX-insensitive GABAA receptor-mediated current. A direct action of NO on Golgi cell membrane potential and input resistance accounted for the increase in the frequency of phasic GABA release. The mechanism underlying the tonic GABA current is unclear but does not appear to be via the modulation of GABA uptake or the activation of nicotinic acetylcholine receptors. NO is a potentially novel mechanism for tuning GABAergic signalling to granule cells and therefore modulating the throughput of an important cerebellar circuit.

Background: Damage control techniques have been developed and applied to abdominal, vascular and thoracic injuries. Thoracic damage control techniques must be rapid and simple., Methods: This report describes the successful use of pulmonary hilum twist as an effective damage control technique to control hemorrhage for severe lung trauma., Results: The procedure involves division of the inferior pulmonary ligament then anterior rotation of the lower lobe over the upper lobe. The technique can be utilized in multiple settings including the emergency center, operating room, and during resuscitation. When vascular occlusion is maintained throughout resuscitation in the intensive care unit, pneumonectomy most likely will be required, but can be performed when the physiologic parameters have improved. Complications are similar to pneumonectomy and can include right-side heart failure, dysrrythmias, and hypoxia., Conclusions: Pulmonary hilar twist is an effective technique that should be considered when a damage control approach is needed.

Traumatic coagulopathy manifests as a hypocoagulable state associated with hypothermia, acidosis, and coagulation factor dilution. The diagnosis must be made clinically because traditional coagulation tests are neither sensitive nor specific and take too long to be used for intraoperative monitoring. We hypothesized that the activated coagulation time (ACT) would reflect the global coagulation status of traumatized patients and would become elevated as coagulation reserves become exhausted. A prospective protocol was used to study 31 victims of major trauma who underwent immediate surgical Intervention. Victims of major head trauma were excluded and patients were selected at random over an 8-month period. At least two serial intraoperative blood samples were obtained at 15-min intervals via indwelling arterial catheters. A Hemochron model 801 coagulation monitor was used to measure the ACT. Of the 31 patients studied, 7 became clinically coagulopathic and 24 did not. The ACT measurements of coagulopathic and noncoagulopathic trauma patients were significantly different by multiple statistical comparisons. Both groups differed from normal, nontraumatized patients. The coagulopathic trauma patients had significantly elevated values when compared with other trauma patients or to normal values. We conclude that a low ACT reflects the initial hypercoagulability associated with major trauma and an elevated ACT is an objective indicator that the coagulation system reserve is near exhaustion. An elevated ACT may represent an indication for considering damage control maneuvers or more aggressive resuscitation.

Background: Current massive transfusion guidelines are derived from washout equations that may not apply to bleeding trauma patients. Our aim was to analyze these guidelines using a computer simulation., Methods: A combined hemodilution and hemodynamic model of an exsanguinating patient was developed to calculate the changes in prothrombin time (PT), fibrinogen, and platelets with bleeding. The model was calibrated to data from 44 patients. Time intervals to subhemostatic values of each coagulation test were calculated for a range of replacement options., Results: Prolongation of PT is the sentinel event of dilutional coagulopathy and occurs early in the operation. The key to preventing coagulopathy is plasma infusion before PT becomes subhemostatic. The optimal replacement ratios were 2:3 for plasma and 8:10 for platelets. Concurrent transfusion of plasma with blood is another effective strategy for minimizing coagulopathy., Conclusion: Existing protocols underestimate the dilution of clotting factors in severely bleeding patients. The model presents an innovative approach to optimizing component replacement in exsanguinating hemorrhage.

To investigate the properties of alpha6 subunit-containing GABA(A) receptors, whole-cell patch-clamp recordings were made from granule cells in adult rat cerebellar slices. In control, only currents evoked by low concentrations of GABA were significantly reduced in amplitude by furosemide, the alpha6 subunit-containing receptor antagonist. However, in the presence of competitive GABA(A) receptor antagonists, the furosemide block of currents evoked by higher GABA concentrations was markedly increased. Zinc, which preferentially blocks alpha6 subunit-containing receptors, also produced an increased block in the presence of bicuculline. To investigate whether similar effects occurred at synaptic receptors, inhibitory postsynaptic currents (IPSCs) were recorded. In most cells, furosemide produced little or no reduction in evoked IPSC amplitude. However in the presence of SR95531, a competitive antagonist, furosemide markedly reduced IPSC amplitude. One hypothesis, which could account for these observations, is that competitive antagonists prevent the continual activation of alpha6beta2/3gamma2 receptors by endogenous GABA and thus prevent their desensitisation. This hypothesis appears feasible as prolonged applications of low concentrations of GABA to recombinant alpha6beta2gamma2s receptors resulted in their desensitisation.

The authors analyzed the early outcomes in two groups of patients undergoing coronary artery bypass grafting (CABG) with single versus bilateral internal thoracic arteries (ITA) in their institution. One thousand sixty-nine patients underwent CABG with single or bilateral ITAs from 1990 to 2000. Of these patients, 911 (85.2%) had single ITA and 158 had bilateral ITA (14.8%). The incidence of tobacco abuse was 40.3% in the single ITA group and 56.7% in the double ITA group (P = 0.0001). The incidence of perioperative myocardial infarction, renal failure, reoperation for bleeding, stroke, or operative mortality did not differ in the two groups. There was a 4.4% incidence of mediastinitis in the bilateral ITA group versus 2.2% in the single ITA group (P = 0.0602). Early outcomes after bilateral ITA grafting for CABG are similar to single ITA grafting. Careful judgment should be exercised in selecting patients for bilateral ITA grafting, particularly if the patient smokes.

The contribution that alpha6 subunit-containing GABA(A) receptors make to inhibitory synaptic transmission to granule cells was investigated by making whole-cell patch clamp recordings from granule cells in adult rat cerebellar slices and applying furosemide, the specific alpha6 subunit-containing GABA(A) receptor antagonist. Endogenous, extracellular GABA continually activated GABA(A) receptors producing a tonic current. Since this current was markedly reduced by furosemide it was probably produced by alpha6 subunit-containing receptors. In contrast, furosemide had little effect on the amplitude or kinetics of fast spontaneous inhibitory postsynaptic currents (sIPSCs), although such sIPSCs were abolished by bicuculline and SR95331. However, the amplitude of evoked IPSCs with a very slow rise and decay were markedly reduced by furosemide. These IPSCs probably resulted from the spillover of GABA from neighbouring synapses activating high affinity alpha6 subunit-containing receptors. In the rest of the cells (40 out of 46), evoked IPSCs had rise and decay kinetics that lay in-between fast sIPSCs and slow 'spillover' IPSCs. Such IPSCs had variable kinetics and also exhibited considerable variation in the magnitude of furosemide block. Thus the GABA(A) receptors present at adult Golgi cell-granule cell synapses, at a developmental stage where receptor expression is complete, are highly heterogeneous.

Background: Effective use of damage control in trauma hinges on an early decision to use it. Bullet trajectory has never been studied as a marker for damage control. We hypothesize that this decision can be predicted by an artificial neural network (ANN) model based on the bullet trajectory and the patient's blood pressure., Methods: A multilayer perceptron ANN predictive model was developed from a data set of 312 patients with single abdominal gunshot injuries. Input variables were the bullet path, trajectory patterns, and admission systolic pressure. The output variable was either a damage control laparotomy or intraoperative death. The best performing ANN was implemented on prospectively collected data from 34 patients., Results: The model achieved a correct classification rate of 0.96 and area under the receiver operating characteristic curve of 0.94. External validation showed the model to have a sensitivity of 88% and specificity of 96%. Model implementation on the prospectively collected data had a correct classification rate of 0.91. Sensitivity analysis showed that systolic pressure, bullet path across the midline, and trajectory involving the right upper quadrant were the three most important input variables., Conclusion: Bullet trajectory is an important, hitherto unrecognized, factor that should be incorporated into the decision to use damage control.

Cardiorrhaphy is a relatively common procedure performed in a trauma center. However, there is a subgroup of patients with more complicated cardiac injuries such as coronary artery injuries, septal defects, and valvular injuries. Cardiac valvular injuries are often diagnosed subacutely when a new murmur is heard. Transesophageal echocardiography has been increasingly performed to diagnosis these injuries and may be helpful intraoperatively. Cardiac catheterization may be indicated in selected patients. Techniques to address these injuries may involve repair or prosthetic replacement. A high index of suspicion is needed to diagnose these relatively rare injuries.

Several factors contribute to the shape of excitatory postsynaptic currents (EPSCs) in CNS neurons, among them the kinetics of presynaptic release, transmitter clearance, and the properties and distribution of postsynaptic receptors. The decays of AMPA receptor-mediated EPSCs at rat cerebellar mossy fibre-granule cell (MF-gc) synapses follow a bi-exponential time-course. The fast component dominates the decay, accounting for 84-94% of the peak amplitude. Here we show that both components of decay, and also the risetimes, became faster during postnatal maturation. At adult, but not immature, synapses, the risetimes and decays of evoked multiquantal EPSCs were similar to those of monoquantal miniature (m)EPSCs. The faster risetimes at mature synapses reflected increased synchrony of multivesicular release, whereas the faster decays appeared to reflect changes in the properties of postsynaptic receptors. Inhibition of glutamate uptake was without effect on evoked EPSCs at both ages. Furthermore, after slowing receptor desensitization with cyclothiazide, the EPSCs at mature synapses decayed as slowly as EPSCs at immature synapses, suggesting that faster glutamate clearance does not account for the developmental speeding of EPSC decay. Our results support previous conclusions that glutamate clearance and receptor deactivation are important determinants of the fast decay component at immature synapses. Desensitization becomes increasingly important during development and plays a major role in shaping EPSC decay at mature synapses.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Abdominal packing and planned reoperation is a lifesaving technique for temporary control of hemorrhage in severely injured patients. Morbidity and mortality in this group of patients, however, remain significant. It is unclear whether the duration of packing impacts upon outcome. The purpose of this study is to evaluate the abscess, sepsis, and mortality rates associated with duration of abdominal packing. The records of 35 patients treated with abdominal packing between July 1994 and December 1995 who survived to reoperation were retrospectively reviewed. Evaluation included age; sex; mechanism; injuries; Abdominal Trauma Index; duration of packing; survival; and presence of abscess, sepsis or other infections. Patients packed for a total of 72 hours or less had lower abscess, sepsis, and mortality rates than those packed for more than 72 hours. The differences in abscess rate and mortality were statistically significant (P < 0.05). The Abdominal Trauma Index and mechanism of injury were similar for the two groups. Based on these results, we conclude that although abdominal packing is a useful technique in the severely injured patient, it is associated with greater morbidity and mortality when the duration of packing exceeds 72 hours.

Gastric rupture is a rare complication of difficult airway management. In cases of vigorous mouth-to-mouth ventilation, bag-valve-mask ventilation, or esophageal intubation, gastric rupture and massive intraperitoneal free air may cause tension pneumoperitoneum. Hemodynamic instability necessitates immediate intervention, including needle decompression of the peritoneum followed by surgical exploration. We recently encountered two cases of gastric rupture with tension pneumoperitoneum that occurred after difficult endotracheal intubation. This report describes the presentation, treatment, and prevention of this entity.

Some of the earliest damage control techniques were applied to the chest during emergency center thoracotomy. It provided a paradigm that was adapted to other areas. Damage control of chest injuries has a different philosophy than that of abdominal injuries. Damage control in the abdomen primarily consists of multiple staged operations with abbreviated closures. Damage control in the chest consists of different technical maneuvers to use quicker and technically less demanding operations to accomplish the same goal. The philosophy of doing only enough to restore a survivable physiology is still a common theme. The following are the major principles of damage control for thoracic injuries: 1. Emergency center thoracotomy is a damage control prototype. 2. Anterolateral thoracotomy is the empiric incision of choice in the patient in extremis. 3. Nonanatomically stapled lung resections, pulmonary tractotomy, and en masse lobectomy/pneumonectomy are pulmonary damage control procedures. 4. The unique physiology of the chest may require en masse closure of muscles or patch closure of the wound. 5. Cardiopulmonary physiology can be affected by packing. Packing thus has a limited role in thoracic damage control. 6. Prosthetic grafts, intravascular shunts, and ligation are common thoracic vascular damage control techniques. 7. With new technology, an increased role for cardiopulmonary bypass and cardiac assistance may develop. 8. New technology must not overly complicate a procedure if it is to be a valuable damage control adjunct.

Evolving technology provides new diagnostic and emergency management options for the surgeon caring for patients with thoracic trauma. Abdominal ultrasound performed by surgeons in the emergency department makes pericardiocentesis and subxyphoid pericardiotomy obsolete. Transesophageal echocardiography supplements aortography in the diagnosis of thoracic aortic injury. New terminologies replace the overused term myocardial contusion. Pulmonary tractotomy is an innovative approach to through-and-through pulmonary penetrating injuries. Centrifugal pumps add new options to thoracic great-vessel injury management. Endovascular stented grafts will be added to the armentarium of the thoracic surgeon for injured vessels.

The postnatal development of spontaneous GABAergic transmission between cerebellar Golgi cells and granule cells was investigated with voltage-clamp recording from rat cerebellar slices, in symmetrical Cl- conditions. Between postnatal days 7 and 14 (P7-14), bicuculline- and TTX (tetrodotoxin)-sensitive spontaneous inhibitory postsynaptic currents (sIPSCs), occurred at high frequency in 56% of granule cells. Between P10 and P14, sIPSCs were superimposed on a tonic current of -12 +/- 1.8 pA at -70 mV, that was accompanied by noise with a variance of 17 +/- 3 pA2. Both the current and noise were inhibited by bicuculline. TTX blocked the bicuculline-sensitive current and noise by approximately 60%. Between P18 and P25, sIPSCs were less frequent; all cells showed tonic, bicuculline-sensitive currents, but these were partially inhibited by TTX (approximately 35%). Between P40 and P53, sIPSCs were rare; tonic, bicuculline-sensitive currents and noise were greater in amplitude, with mean values of -17 pA and 22 pA2 at -70 mV, they were present in all cells but they were not inhibited by TTX. Glycine receptor channels that were expressed in immature, but not adult cells, did not mediate spontaneous currents. Our results indicate that spontaneous transmission onto cerebellar granule cells in immature animals consists primarily of action potential-dependent, phasic release of vesicular GABA. This generates GABAA receptor-mediated sIPSCs. The effects of GABA transporter blockers suggest that it also produces the TTX-sensitive current-noise, as GABA spills out of synapses to activate extrasynaptic receptors or receptors in neighbouring synapses. In older animals, action potential-independent release of transmitter is predominant and results in tonic activation of GABAA receptors. This does not appear to be spontaneous vesicular release of GABA. Neither does it appear to be reversed uptake of GABA, although further work is required to rule out these possibilities.

Background: Staphylococcus aureus is the most frequently isolated pathogen in the trauma patient and uses multiple virulent factors to cause infection. At the cellular level, infection begins with the prokaryotic bacterial cell manipulating the eukaryotic host cell through its virulent factors. Researching this cellular interaction by describing the mechanisms of actions of various virulent factors may lead to new preventive therapies which will make the trauma patient less susceptible to S aureus infections., Methods: Surgical, medical, and microbial literature was reviewed to provide an update on S aureus pathogenesis., Results: Novel future therapies, in addition to antibiotics, are being devised based on understanding the molecular nature of S aureus pathogenesis., Conclusion: The impact of S aureus on trauma will increase as S aureus develops more antibiotic resistance and as the trauma population becomes older and includes an increasing proportion of immunocompromised patients. To meet the challenge of increased virulence, trauma surgeons should be directly involved in the research of microbial pathogenesis.

1. Known injuries to the ascending aorta and arch are exposed by median sternotomy. Known injuries to the descending thoracic aorta can be exposed through a posterolateral thoracotomy. These injuries are more commonly diagnosed through emergent exploration by means of anterolateral thoracotomies. 2. Preoperative arteriography is extremely useful in managing penetrating injuries to the thoracic outlet, as it allows the choice of appropriate incisions for exposure and control. 3. Innominate artery, right common carotid or subclavian artery, as well as left intrathoracic common carotid artery injuries are best managed via median sternotomy with appropriate extension. 4. Left subclavian arteries are managed with high left anterolateral thoracotomy for proximal control combined with supraclavicular incision. 5. Distal subclavian arteries are managed with proximal control by a supraclavicular incision and distal control by an infraclavicular incision. 6. The bypass principle is useful for managing innominate or left carotid artery injuries. Ligation with brachiocephalic bypass can be a simple solution to a complex problem. 7. Soft grafts, fine sutures, and minimal mobilization are the techniques of choice. 8. Adjuncts such as Fogarty balloon catheters, Foley catheters, autotransfusion, shunts, and pulmonary tractotomy can be useful in managing these injuries. 9. Documentation of the preoperative neurovascular status of the patient should be performed, as well as discussion with the patient and the family, if available, of the potential outcome with appropriate documentation in the chart. 10. Rehabilitation services should be involved as appropriate to care for these patients. 11. Ligation is always an option to save the patient's life.

Background: Popliteal artery injuries continue to result in limb loss. This study identifies risk factors that predict amputation., Methods: Over a 5-year period, a retrospective chart review was conducted of 80 consecutive patients with 81 popliteal artery injuries., Results: The overall amputation rate was 16.5%. Blunt trauma carried a higher rate of amputation (47%) than penetrating injuries (6.2%); P < 0.0001). Associated fractures had a higher amputation rate, regardless of mechanism (odds ratio +2.7, 95% confidence limits 1.2 to 6.2). Fasciotomy at the time of operation was associated with reduced amputation rate., Conclusions: Blunt injuries and associated fractures carry an increased risk for amputation. Compartmental pressures should be appropriately monitored postoperatively. Fasciotomy at the time of vascular repair may be considered even without evidence of compartment syndrome.

1. Acutely isolated Xenopus spinal neurons possess a slowly activating Ca(2+)-dependent outward current which was revealed either by removal of external Ca2+ or by the addition of the Ca2+ channel blocker, 150 microM Cd2+. 2. The Ca(2+)-sensitive current was very slow to activate and had a mean time constant of activation of 437 ms at 0 mV. The current also had very long tail currents which were blocked by Cd2+. The rate of decay of the slowest component of the Ca(2+)-dependent tail currents was insensitive to membrane potential suggesting that the relaxation of the Ca(2+)-dependent current may only be weakly voltage dependent. 3. The reversal potential of the Ca(2+)-sensitive tail currents depended on the concentration of external K+ in a manner predicted by the Nernst equation. Thus the Ca(2+)-sensitive current was carried by K+. 4. The toxin apamin (10 nM to 2 microM) selectively blocked the Ca(2+)-dependent K+ current without affecting voltage-gated K+ currents. This current may be analogous to a small-conductance Ca(2+)-dependent K+ (SK) current; however, unlike some SK currents, the Ca(2+)-dependent K+ current was also sensitive to 500 microM tetraethylammonium chloride (TEA). 5. Applications of 10 nM apamin to spinalized embryos did not perturb the motor pattern for swimming. However, the cycle periods over which the locomotor rhythm generator could generate appropriate motor activity were lengthened by about 10% and the mean duration of swimming episodes was increased by approximately 40%. 6. We therefore propose that the Ca(2+)-dependent K+ current plays an important role in the self-termination of motor activity.

The critical decisions in patients with thoracoabdominal trauma are establishing the need to explore either or both cavities and determining appropriate sequencing. The causes and patterns of management difficulties were analyzed in 82 consecutive patients with penetrating thoracoabdominal injuries. Nine thoracotomies (11%) and 16 laparotomies (22%) were negative, with the major causes being misleading chest tube outputs, bullet trajectories, and abdominal tenderness. Inappropriate sequencing occurred in 19 patients (23%), and 15% required reoperation within 24 hours. Pitfalls and misjudgements in management of penetrating thoracoabdominal injuries occur in distinct patterns. The unreliability of chest tube output and abdominal examination must be kept in mind, and intraoperative clues of ongoing hemorrhage outside the operative field must be sought.

Background: The operative management of penetrating lung injuries includes oversewing of small lung lacerations (pneumonorrhaphy), wedge resection, or anatomic resection. There are penetrating injuries of the lung for which oversewing of entrance and exit wounds will predispose to intrapulmonary hematoma or pulmonary venous-systemic air emboli, yet for which formal resection would be time consuming. The technique of pulmonary tractotomy with selective vascular ligation was developed in parallel with hepatotomy for liver injuries., Patients and Methods: Over the past 9 years, pulmonary tractotomy has been used 18 times in 16 patients at our institution. All patients were male. Their injuries were 12 gunshot and 4 stab wounds., Results: There were three deaths unrelated to the tractotomy. Five surviving patients developed complications., Conclusion: Pulmonary tractotomy is a straight-forward procedure that controls deep hemorrhage from lung injuries and may obviate the need for formal resection.

Missed injuries have a bad reputation and are sometimes associated with serious morbidity for the patient and personal embarrassment for the surgeon. During a 10-year period, 123 missed injuries in 117 patients requiring re-operation were encountered in one trauma center. A retrospective review of causes and patterns was undertaken. The most common presentation was delayed hemorrhage (64 injuries). The colon, thoracic vasculature, chest wall arteries, and diaphragm were the most frequently involved sites. Forty-six injuries were overlooked during the diagnostic work-up, and 43 were missed during surgery. Technical problems with diagnosis and surgery accounted for 62% of missed injuries, whereas decision and judgment errors accounted for the rest. Further insight was provided by the classification of missed injuries into three types. Type I (20%) occurred outside the body area of clinical focus, whereas type II (69%) occurred within it. Type III (11%) resulted when instability of the patient necessitated interruption of the diagnostic work-up or exploration. Each type represents a different clinical pattern and dictates a specific preventive strategy.

Planned reoperation is a new approach to severe truncal trauma. A review of 124 patients treated over two years was undertaken. Penetrating injuries predominated (78%) involving primarily the abdomen or abdomen and chest. An abbreviated procedure was performed when direct hemostasis was impossible (102 patients), abrupt termination was required (56 patients), or the abdomen or chest could not be closed (20 patients). The techniques employed included packing, rapid skin closure, gastrointestinal interruption, rapid vascular control, temporary urinary diversion, stapled lung resection, and plastic bag closure. Seventy-three patients survived to undergo 101 operations. The first reoperation was planned in 52 patients and unplanned (either for bleeding or for abdominal compartment syndrome) in 21 patients. There were 14 missed injuries. The overall mortality rate was 58%. Survival was significantly better when the decision to abruptly terminate the initial procedure was made early and in patients undergoing planned reoperation. Wider adoption and better definition of the indications will result in more effective use of this approach.

1. To assess the role that K+ currents play in the production of the swimming motor pattern in the Xenopus embryo, we have used low doses of the K+ channel blockers, 3,4-diaminopyridine (3,4-DAP; 25-100 microM) and tetraethylammonium (TEA; 500 microM), to reduce K+ currents and investigated the effects on motor output. 2. To confirm that 3,4-DAP and TEA block K+ currents and characterize their actions, we made whole-cell voltage-clamp recordings from acutely isolated spinal neurons. Both 25-100 microM 3,4-DAP and 100-500 microM TEA blocked the sustained K+ current in a dose-dependent manner. 3. Because TEA can block acetylcholine nicotinic receptors on autonomic ganglia, and nicotinic acetylcholine receptors have recently been shown to be present on Xenopus spinal neurons, we have tested both 3,4-DAP and TEA for antagonist action against the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP). Although 500 microM TEA blocked the DMPP-induced depolarization, 25 microM 3,4-DAP did not. 4. In the intact embryo, application of 25-100 microM 3,4-DAP or 500 microM TEA disrupted both the left and right alternation of ventral root discharge and the motor pattern recorded intracellularly from spinal neurons during swimming. Both blockers allowed the firing of an extra action potential at midcycle, which led to a number of different patterns. These patterns were categorized as follows: type A, cycles with midcycle action potentials; type B, the simultaneous firing of neurons on both sides of the cord; and type C, in which one side was active, whereas the other side was inhibited. In both 3,4-DAP and TEA these abnormalities tended to occur at the beginning of swimming episodes. Both blockers also caused a significant increase in the cycle period. Because both 3,4-DAP and TEA produced very similar affects to the motor pattern, we conclude that the perturbations are probably a result of reducing K+ current amplitude. 5. To investigate whether 3,4-DAP and TEA were producing disruptions in the motor pattern by increasing synaptic drive through the broadening of action potentials, we made measurements of spike width, tonic depolarization, and midcycle inhibitory postsynaptic potential (IPSP) amplitude during swimming. Both 3,4-DAP and TEA caused significant but modest spike broadening (20.8 and 29.8%, respectively); however, their effects on tonic depolarization were inconsistent although both blockers increased midcycle IPSP amplitude. 6. To test whether a reduction in K+ currents could plausibly produce the specific motor pattern perturbations that were seen, we have made computer simulations of simplified spinal networks.(ABSTRACT TRUNCATED AT 400 WORDS)

Tension pneumopericardium is a rare entity typically described in premature infants requiring positive-pressure ventilation. However, recent reports suggest an increase in its occurrence in adults. A case of delayed postoperative tension pneumopericardium in an adult patient is presented with a review of the history, pathophysiology, presentation, and treatment of this entity.

Gunshot injuries across the cervical midline are not addressed in existing trauma algorithms. A retrospective study of 41 patients with transcervical gunshot wounds was undertaken to delineate injury patterns and management principles. Thirty-four of the 41 patients (83%) sustained 52 injuries to major cervical structures. Vascular (22 injuries) and upper airway (13 injuries) structures were most commonly involved. This resulted in presentation with life-threatening problems in 16 patients (39%). The in-hospital mortality was 10%. In 30 of the 36 neck explorations (83%), the findings were positive for injuries to cervical structures. Sixteen bilateral explorations were performed; in each case, cervical injury was observed on at least one side of the neck. These results indicate that transcervical injuries are excellent markers of associated visceral injury. Therefore, a policy of mandatory neck exploration and a particularly "low threshold" for bilateral exploration are the key to managing these injuries.