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The inhibitory action of Nogo-A on axonal growth has been well described. However, much less is known about the effects that Nogo-A could exert on the plasticity of neuronal circuits under physiological conditions. We investigated the effects of Nogo-A knock-out (KO) on visual function of adult mice using the optokinetic response (OKR) and the monocular deprivation (MD)-induced OKR plasticity and analyzed the anatomical organization of the eye-specific retinal projections. The spatial frequency sensitivity was higher in intact Nogo-A KO than in wild-type (WT) mice. After MD, Nogo-A KO mice reached a significantly higher spatial frequency and contrast sensitivity. Bilateral ablation of the visual cortex did not affect the OKR sensitivity before MD but reduced the MD-induced enhancement of OKR by approximately 50% in Nogo-A KO and WT mice. These results suggest that cortical and subcortical brain structures contribute to the OKR plasticity. The tracing of retinal projections to the dorsal lateral geniculate nucleus (dLGN) revealed that the segregation of eye-specific terminals was decreased in the adult Nogo-A KO dLGN compared with WT mice. Strikingly, MD of the right eye led to additional desegregation of retinal projections in the left dLGN of Nogo-A KO but not in WT mice. In particular, MD promoted ectopic varicosity formation in Nogo-A KO dLGN axons. The present data show that Nogo-A restricts visual experience-driven plasticity of the OKR and plays a role in the segregation and maintenance of retinal projections to the brain.

Microcirculatory dysfunctions play a central role in the pathophysiology of sepsis and shock. Modern methods enable microvascular monitoring in man and offer the possibility to test the effect of novel therapeutical strategies for sepsis. Furthermore, these techniques may be future tools for the monitoring of critically ill patients. In this review, we will describe four microvascular monitoring devices and give an overview of the microcirculatory changes observed during the course of sepsis. Laser Doppler fluxmetry is an easy to use noninvasive technique to measure tissue perfusion enabling monitoring of the effect of different catecholamines on the gastric perfusion during sepsis. Increased microvascular permeability and altered blood flow in septic patients can be quantified by venous congestion plethysmography. Alterations in sublingual microvascular blood flow are detected by intravital microscopy in septic patients and were identified as an outcome predictor. Furthermore, the role of gastrointestinal pCO2-tonometry for microcirculatory monitoring of the perfusion of splanchnic organs during sepsis is discussed. The true clinical value of these techniques has yet to be established and will depend on larger clinical trials showing an impact on diagnostics and patient management.

The preclinical diagnosis of shock is still based on the patient's history, the physical examination, the injury pattern and a few hemodynamic parameters available in the emergency set-up. The clinical picture is characterised by hypotension and tachycardia, tachypnoe and dyspnoea as well as cerebral impairment. Results from recent clinical trials indicate, that a adapted and specific therapeutic approach for the various shock forms is necessary. In case of traumatic hypovolemic-hemorrhagic shock it is of particular relevance if penetrating trauma and/or uncontrolled bleeding exists. Under these conditions an immediate definite surgical treatment is required ("scoop and run") and a moderate hypotension should be tolerated. ("treat and run"). Fluid substitution and therapy with catecholamines should be used conservatively. In all other forms of shock the treatment approach can and should be more aggressive in order to improve microvascular perfusion as early as possible. Besides adequate fluid resuscitation in a combination of crystalloid and colloid solutions catecholamines and-under specific circumstances-also vasopressin should be used. Of utmost importance in the pre-clinical management of patients in shock is the optimal selection of the centre that the patient is referred to in order to establish the fastest and best possible definite treatment for the patient.

Various methods are available for measuring the production of reactive oxygen species by phagocytes, but they are limited in their use by the need for their immediate application, cell isolation and of cell-activation by unphysiological stimuli. In addition, after measurement of reactive oxygen metabolites using oxidizing agents, the reduced compounds formed have to be determined during or immediately after their formation. In the present study, an improved cytochrome C assay was investigated which allowed measurements of superoxide anions in whole blood samples following activation of phagocytes by physiological stimuli such as the bacterial tripeptide N-formyl-methionyl-leucyl-phenylalanine (fMLP). The fMLP-stimulated production of superoxide anion (O(2)(-)) showed a sigmoidal-shaped fMLP dose-response curve, and constant O(2)(-) production rates (nmol.1(-1)x10(6) granulocytes) could be determined reliably up to a blood granulocyte concentration of 1 x 10(4) x microl(-1). To allow the determination of reduced cytochrome C later after its formation, the effect of long-term storage at -20 degrees C on the stability of reduced cytochrome C was tested up to 16 weeks. The results obtained show that the determination of reduced cytochrome C in whole blood represents a simple and reliable method. Most importantly, O(2)(-)-reduced cytochrome C can be frozen and stored without any alterations, at least up to 2 weeks. Thus the method seems to be superior to other methods of detection, especially when the experimental conditions do not allow immediate spectrophotometry (e.g. mountain medicine, space medicine). Under such conditions the present assay would allow reliable measurement of reduced cytochrome C, even after weeks of cryopreservation.

The orthogonal polarization spectral (OPS) imaging technology is a new non-invasive method to directly visualize multiple conditions of the microcirculation which has several clinical applications in humans. Quantitative measurement of the diameter of vessels, the velocity of red blood cells and functional capillary density (FCD) can be made. Activation of leukocytes can be monitored and also quantified. A transdermal approach can be used in premature babies and neonates to view the microcirculation and has also been used experimentally to determine haemoglobin levels. The application to various surfaces and solid organs allows a variety of pathophysiologies and phases to be examined.

Emergency medicine is characterized by rapid decision making to help patients in life-threatening situations. Teaching these skills requires a high level of interaction between medical students and the lecturer. We designed, implemented, and evaluated a generic computer-based training (CBT) system to provide a more active way of learning emergency medicine. The content of the training program is adapted to the knowledge of third year medical students and is focused on basic skills and real-world problems. The teacher presents the case with authentic video sequences and slides. The cases are classified into four groups: heart (e.g., myocardial infarction), respiration (e.g., asthma bronchiale), trauma (e.g., car accident), and loss of consciousness (e.g., coma). Within a realistic time frame, the students have to answer free text and multiple choice questions on a work-station. All answers given by the students are processed anonymously by the CBT system via a central server and displayed on a large video screen, thus enabling a detailed discussion without intimidation of individual students. This interactive technique allows for immediate feedback from the lecturer based on the specific knowledge of his group and his own experience. The IT concept, which is scalable to many subjects, is based on state of the art internet technology and therefore suitable for teleteaching. A major design objective for the program was a self-explaining and robust user interface. The system has been in routine use since 1998. We designed an evaluation form consisting of 21 items focused on subjective rating of learning success, acceptance of CBT, and technical feasibility. We analyzed forms from 138 students and found high scores for acceptance and learning success (median 5 on a 6-point scale). user problems with the program were denied (median 1 on a 6-point scale). Computer-based training with Internet technology can provide a successful method for interactive teaching of emergency medicine and is well accepted by students.

Unlabelled: Patients undergoing major vascular surgery frequently require a substantial intraoperative fluid replacement to assure hemodynamic stability, which is in excess of the expected fluid requirements due to starving, blood and insensible losses. This leads to a positive fluid balance which can not be readily explained., Method: We have used venous congestion plethysmography (VCP) a non-invasive method for measurement of microvascular parameters in limbs to investigate the changes in microvascular permeability (FFK) and the balance of Starling forces of patients undergoing surgery for unilateral femoral artery reconstruction (FEM) under epidural anaesthesia or abdominal aortic aneurysm repair (AAA) under general anaesthesia. The control group consisted of patients scheduled for inguinal hernia repair or hand surgery under general anaesthesia. All patients were measured 24 hours pre-operatively, immediately after the induction of anaesthesia or completion of epidural anaesthesia and on the 1st, 5th and 10th postoperative day. The perioperative patient management followed a standard protocol and all patients with vascular disease were invasively monitored using indwelling arterial lines and central venous catheters. Continuous infusion of Ringers lactate and 6% Dextran 60 was sustained during the induction period. Each patient gave informed consent., Results: Preoperatively we found no significant difference in the mean FFK-values of controls (4.1 +/- 0.4, ml.min-1 100 ml tissue-1 mmHg-1 x 10(-3) = FFKU), the AAA (3.6 +/- 0.3 FFKU) and FEM (4.2 +/- 0.3 FFKU). After induction of anaesthesia the mean FFK value in the controls fell to 3.5 +/- 0.5 FFKU (p = 0.07), whereas in the AAA patients we observed a significant increase to 4.7 +/- 0.2 FFKU (p < 0.005) and after epidural anaesthesia in FEM to 5.5 +/- 0.4 FFKU (p < 0.001) respectively. Those post anaesthetic FFK values where significantly higher in FEM and AAA than in the controls (p < 0.02). In AAA we found a significant positive correlation between the increase in FFK and the intraoperative fluid balance (r2 = 0.69, p < 0.01). No such correlation was found in controls and FEM. The postoperative values of FFK where unchanged in the control group, whereas a further increase was seen in both patient groups with vascular disease, with a maximum in AAA on the 1st postoperative day (to 5.4 +/- 0.4 FFKU mean both legs) and the 5th postoperative day in FEM (to 7.3 +/- 1.7 non-ischemic leg, 7.1 +/- 1.2 ischemic leg FFKU). In both groups normal FFK values where found on the 10th day after the operation., Conclusion: The data presented suggests an increase in extravascular fluid loss in patients undergoing vascular surgery, which becomes evident after the induction of general anaesthesia or completion of epidural anaesthesia. The positive correlation with the intraoperative fluid requirements may partially explain the often reported large intraoperative fluid requirements of patients undergoing AAA repair. The fact that the maximum change in fluid filtration capacity is found postoperatively may be explained by the additional effect of an ischemia/reperfusion injury in response to both the clamping an declamping of the artery and the increase in arterial blood flow to the limb due to the successful reconstruction of the blood vessel.

Unlabelled: An increased microvascular water permeability has been reported after ischemia/reperfusion both in animal models and in human studies. We studied the changes in fluid filtration capacity (FFK) after ischemia/reperfusion due to tourniquet in patients undergoing arthroscopy of the knee., Method: Healthy male volunteers (n = 24, mean age 46.9 +/- 3.5) were studied prior to, 1 and 6 hours after arthroscopy of the knee, during which a tourniquet was applied to the thigh. FFK, isovolumetric venous pressure (Pvi) and arterial blood flow in the limb was measured in both legs (tourniquet leg and control leg) using computer assisted venous congestion plethysmography. Venous blood samples were obtained from a cubital vein prior to and from the femoral vein 2 mins after deflation of the tourniquet cuff. 12 patients received preoperatively an infusion of 6% Dextran (D) and 12 patients 500 ml of electrolyte solution (VE) an., Results: The mean duration of the tourniquet was (D) 56.0 +/- 6.9 min and (VE) 53.9 +/- 4.2 min which resulted in a significant increase in venous lactate concentration from (D) 1.4 +/- 0.1 mmol.l-1 to 2.7 +/- 0.3 mmol.l-1 and (VE) 1.3 +/- 0.1 mmol.l-1 to 2.7 +/- 0.3 mmol.l-1 (p < 0.001). A significant decrease in pH from (D) 7.39 +/- 0.01 to 7.32 +/- 0.01 (p < 0.001) and from (VE) 7.39 +/- 0.01 to 7.32 +/- 0.01 (p < 0.001) was also seen. Preoperatively no significant differences in the FFK values of the tourniquet leg (D = 5.3 (4.8-10.7) ml. x 10(-3) min-1.100 ml tissue-1 mmHg-1 = FFKU) and the control leg (5.2 (4.7-8.6 FFKU)) were observed. The maximum FFK value in D was seen 1 hour after ischemia/reperfusion in both, the tourniquet leg (7.5 (4.6-14.2 FFKU) and the control leg (7.8 (5.5-9.4 FFKU). In VE however the maximal FFK value were measured 6 hours after ischemia/reperfusion with an increase in the tourniquet leg from 5.2 (4.2-6.2 FFKU) to 8.1 (3.7-10.4 FFKU) and the control leg from 6.1 (3.6-7.0 FFKU) to 7.3 (6.1-8.3 FFKU) (Median (Range). One-way ANOVA). There were no significant differences in the FFK values between D and VE except for a lower Pvi in VE at the third measurement. No significant changes in the arterial blood flow were seen perioperatively as well as between the operated and non-operated leg., Conclusion: A tourniquet of < 1 hour does impair tissue oxygenation as indicated by the increase in lactate and the decrease in pH. The duration of the tourniquet was however to short to have caused sufficient microvascular damage result in a more pronounced increase in fluid filtration capacity.

The concept of small-volume resuscitation, the rapid infusion of a small volume (4 ml/kg BW) of hyperosmolar 7.2-7.5% saline solution for the initial therapy of severe hypovolemia and shock was advocated more than a decade ago. Numerous publications have established that hyperosmolar saline solution can restore arterial blood pressure, cardiac index and oxygen delivery as well as organ perfusion to pre-shock values. Most prehospital studies failed to yield conclusive results with respect to a reduction in overall mortality. A meta-analysis of preclinical studies from North and South America, however, has indicated an increase in survival rate by 5.1% following small-volume resuscitation when compared to standard of care. Moreover, small-volume resuscitation appears to be of specific impact in patients suffering from head injuries with increased ICP and in severest trauma requiring immediate surgical intervention. Results from clinical trials in Austria, Germany and France have demonstrated positive effects of hyperosmolar saline solutions when used for fluid loading or fluid substitution in cardiac bypass and in aortic aneurysm surgery, respectively. A less positive perioperative fluid balance, a better hemodynamic stability and improved pulmonary function were reported. In septic patients oxygen consumption could significantly be augmented. The most important mechanism of action of small-volume resuscitation is the mobilisation of endogenous fluid primarily from oedematous endothelial cells, by which the rectification of shock-narrowed capillaries and the restoration of nutritional blood, flow is efficiently promoted. Moreover, after ischemia reperfusion a reduction in sticking and rolling leukocytes have been found following hyperosmolar saline infusion. Both may be of paramount importance in the long-term preservation of organ function following hypovolemic shock. An increased myocardial contractility in addition to the fluid loading effects of hyperosmolar saline solutions has been suggested as a mechanism of action. This, however, could not be confirmed by pre-load independent measures of myocardial contractility. Some concerns have been raised regarding the use of hyperosmolar saline solutions in patients with a reduced cardiac reserve. A slower speed of infusion and adequate monitoring is recommended for high risk patients. Recently, hyperosmolar saline solutions in combination with artificial oxygen carriers have been proposed to increase tissue oxygen delivery through enhanced O2 content. This interesting perspective, however, requires further studies to confirm the potential indications for such solutions. Many hyperosmolar saline colloid solutions have been investigated in the past years, from which 7.2-7.5% sodium chloride in combination with either 6-10% dextran 60/70 or 6-10% hydroxyethyl starch 200,000 appear to yield the best benefit-risk ratio. This has led to the registration of the solutions in South America, Austria, The Czech Republic, and is soon awaited for North America.

This case report describes paralysis of the plantar flexors and extensors after a total hip replacement in a 33-year-old woman performed under epidural anaesthesia (PDA). Six years previously, the patient had undergone a bone marrow transplantation for chronic myeloid leukaemia. She had developed a deep vein thrombosis, a pulmonary embolus, and a severe graft-versus-host reaction of the skin, leading to markedly reduced mouth opening. The hip operation was performed using PDA following antithrombotic prophylaxis with low-molecular-weight heparin. Blood could initially be aspirated after advancing the PDA catheter, and a second puncture of the epidural space 1 segment higher enabled correct placement of the catheter. The patient received 500 ml Dextran 60 perioperatively and the operation was completed without any further problems. The PDA catheter was removed 2 h after the operation following the return of movement of both thighs. Fourteen hours after the completion of surgery it was noticed that the dressing over the epidural puncture site was bloodstained, the patient was incontinent, and complete loss of movement of the operated leg was present. An epidural haematoma was the suspected cause, but could not be definitely confirmed by a CT scan. Nevertheless, a laminectomy was undertaken to evacuate the suspected haematoma. As expected, tracheal intubation was only possible bronchoscopically. Intraoperatively, some low-grade epidural oozing at the level of the initial puncture site was observed, and a hemilaminectomy of 5 was performed. For the first time postoperatively, the bleeding time was measured and was markedly prolonged to 20 min (as described by Mielke, normal value up to 8 min). A coagulopathy was suggested, with the differential diagnosis of impaired platelet function. The paralysis of the plantar flexors and extensors and some sensory loss were still present 6 months after the operation. It remains uncertain whether the PDA in a patient receiving low-molecular-weight heparin resulting in a the suspected epidural haematoma was the cause of the neurological sequelae and in agreement with the consultant neurologist, we believe that a direct traumatic lesion of the L5/S1 segment or damage to the sciatic nerve are also likely causes of the symptoms. Undoubtedly, the lack of adequate postoperative neurological monitoring and the intraoperative administration of dextran despite the known epidural vascular lesion deserve criticism. This case report demonstrates the often complex development of neurological complications after nerve blocks, where a definite cause can frequently not be determined.