Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons.

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.

Human iPSC-Derived Neurons with Reliable Synapses and Large Presynaptic Action Potentials.

Understanding the function of the human brain requires determining basic properties of synaptic transmission in human neurons. One of the most fundamental parameters controlling neurotransmitter release is the presynaptic action potential, but its amplitude and duration remain controversial. Presynaptic action potentials have so far been measured with high temporal resolution only in a limited number of vertebrate but not in human neurons. To uncover properties of human presynaptic action potentials, we exploited recently developed tools to generate human glutamatergic neurons by transient expression of Neurogenin 2 (Ngn2) in pluripotent stem cells. During maturation for 3 to 9 weeks of culturing in different established media, the proportion of cells with multiple axon initial segments decreased, while the amount of axonal tau protein and neuronal excitability increased. Super-resolution microscopy revealed the alignment of the pre- and postsynaptic proteins, Bassoon and Homer. Synaptic transmission was surprisingly reliable at frequencies of 20, 50, and 100 Hz. The synchronicity of synaptic transmission during high-frequency transmission increased during 9 weeks of neuronal maturation. To analyze the mechanisms of synchronous high-frequency glutamate release, we developed direct presynaptic patch-clamp recordings from human neurons. The presynaptic action potentials had large overshoots to ∼25 mV and short durations of ∼0.5 ms. Our findings show that Ngn2-induced neurons represent an elegant model system allowing for functional, structural, and molecular analyses of glutamatergic synaptic transmission with high spatiotemporal resolution in human neurons. Furthermore, our data predict that glutamatergic transmission is mediated by large and rapid presynaptic action potentials in the human brain.

NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome usually including memory impairment. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the amino-terminal domains of either GluN1 or combinations of GluN1 with GluN2A or GluN2B. Surprisingly, both GluN1 and GluN2 subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient CSF containing high-titre NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cell-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons and rescued memory defects in passive-transfer mouse models using intrahippocampal injections. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which could complement immunotherapy.

Electron-hole asymmetry of the topological surface states in strained HgTe.

Topological insulators are a new class of materials with an insulating bulk and topologically protected metallic surface states. Although it is widely assumed that these surface states display a Dirac-type dispersion that is symmetric above and below the Dirac point, this exact equivalence across the Fermi level has yet to be established experimentally. Here, we present a detailed transport study of the 3D topological insulator-strained HgTe that strongly challenges this prevailing viewpoint. First, we establish the existence of exclusively surface-dominated transport via the observation of an ambipolar surface quantum Hall effect and quantum oscillations in the Seebeck and Nernst effect. Second, we show that, whereas the thermopower is diffusion driven for surface electrons, both diffusion and phonon drag contributions are essential for the hole surface carriers. This distinct behavior in the thermoelectric response is explained by a strong deviation from the linear dispersion relation for the surface states, with a much flatter dispersion for holes compared with electrons. These findings show that the metallic surface states in topological insulators can exhibit both strong electron-hole asymmetry and a strong deviation from a linear dispersion but remain topologically protected.

Apparent calcium dependence of vesicle recruitment.

KEY POINTS: Synaptic transmission relies on the recruitment of neurotransmitter-filled vesicles to presynaptic release sites. Increased intracellular calcium buffering slows the recovery from synaptic depression, suggesting that vesicle recruitment is a calcium-dependent process. However, the molecular mechanisms of vesicle recruitment have only been investigated at some synapses. We investigate the role of calcium in vesicle recruitment at the cerebellar mossy fibre to granule cell synapse. We find that increased intracellular calcium buffering slows the recovery from depression following physiological stimulation. However, the recovery is largely resistant to perturbation of the molecular pathways previously shown to mediate calcium-dependent vesicle recruitment. Furthermore, we find two pools of vesicles with different recruitment speeds and show that models incorporating two pools of vesicles with different calcium-independent recruitment rates can explain our data. In this framework, increased calcium buffering prevents the release of intrinsically fast-recruited vesicles but does not change the vesicle recruitment rates themselves. ABSTRACT: During sustained synaptic transmission, recruitment of new transmitter-filled vesicles to the release site counteracts vesicle depletion and thus synaptic depression. An elevated intracellular Ca2+ concentration has been proposed to accelerate the rate of vesicle recruitment at many synapses. This conclusion is often based on the finding that increased intracellular Ca2+ buffering slows the recovery from synaptic depression. However, the molecular mechanisms of the activity-dependent acceleration of vesicle recruitment have only been analysed at some synapses. Using physiological stimulation patterns in postsynaptic recordings and step depolarizations in presynaptic bouton recordings, we investigate vesicle recruitment at cerebellar mossy fibre boutons. We show that increased intracellular Ca2+ buffering slows recovery from depression dramatically. However, pharmacological and genetic interference with calmodulin or the calmodulin-Munc13 pathway, which has been proposed to mediate Ca2+ -dependence of vesicle recruitment, barely affects vesicle recovery from depression. Furthermore, we show that cerebellar mossy fibre boutons have two pools of vesicles: rapidly fusing vesicles that recover slowly and slowly fusing vesicles that recover rapidly. Finally, models adopting such two pools of vesicles with Ca2+ -independent recruitment rates can explain the slowed recovery from depression upon increased Ca2+ buffering. Our data do not rule out the involvement of the calmodulin-Munc13 pathway during stronger stimuli or other molecular pathways mediating Ca2+ -dependent vesicle recruitment at cerebellar mossy fibre boutons. However, we show that well-established two-pool models predict an apparent Ca2+ -dependence of vesicle recruitment. Thus, previous conclusions of Ca2+ -dependent vesicle recruitment based solely on increased intracellular Ca2+ buffering should be considered with caution.

Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission.

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how trans-synaptic bridges change to reflect the functional states of the synapse. Here, we develop optical tools to visualize in firing synapses the molecular behavior of two trans-synaptic proteins, LGI1 and ADAM23, and find that neuronal activity acutely rearranges their abundance at the synaptic cleft. Surprisingly, synaptic LGI1 is primarily not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitates the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Accordingly, we find that patient-derived autoantibodies against LGI1 reduce its surface fraction and cause increased glutamate release. Our findings suggest that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical control point for synaptic function.

Hippocampal and cerebellar mossy fibre boutons - same name, different function.

Over a century ago, the Spanish anatomist Ramón y Cajal described 'mossy fibres' in the hippocampus and the cerebellum, which contain several presynaptic boutons. Technical improvements in recent decades have allowed direct patch-clamp recordings from both hippocampal and cerebellar mossy fibre boutons (hMFBs and cMFBs, respectively), making them ideal models to study fundamental properties of synaptic transmission. hMFBs and cMFBs have similar size and shape, but each hMFB contacts one postsynaptic hippocampal CA3 pyramidal neuron, while each cMFB contacts ∼50 cerebellar granule cells. Furthermore, hMFBs and cMFBs differ in terms of their functional specialization. At hMFBs, a large number of release-ready vesicles and low release probability (<0.1) contribute to marked synaptic facilitation. At cMFBs, a small number of release-ready vesicles, high release probability (∼0.5) and rapid vesicle reloading result in moderate frequency-dependent synaptic depression. These presynaptic mechanisms, in combination with faster postsynaptic currents of cerebellar granule cells compared with hippocampal CA3 pyramidal neurons, enable much higher transmission frequencies at cMFB compared with hMFB synapses. Analysing the underling mechanisms of synaptic transmission and information processing represents a fascinating challenge and may reveal insights into the structure-function relationship of the human brain.

Comparative Effects of Domain-Specific Human Monoclonal Antibodies Against LGI1 on Neuronal Excitability.

BACKGROUND AND OBJECTIVES: Autoantibodies to leucine-rich glioma inactivated protein 1 (LGI1) cause an autoimmune limbic encephalitis with frequent focal seizures and anterograde memory dysfunction. LGI1 is a neuronal secreted linker protein with 2 functional domains: the leucine-rich repeat (LRR) and epitempin (EPTP) regions. LGI1 autoantibodies are known to interfere with presynaptic function and neuronal excitability; however, their epitope-specific mechanisms are incompletely understood. METHODS: We used patient-derived monoclonal autoantibodies (mAbs), which target either LRR or EPTP domains of LGI1 to investigate long-term antibody-induced alteration of neuronal function. LRR- and EPTP-specific effects were evaluated by patch-clamp recordings in cultured hippocampal neurons and compared with biophysical neuron modeling. Kv1.1 channel clustering at the axon initial segment (AIS) was quantified by immunocytochemistry and structured illumination microscopy techniques. RESULTS: Both EPTP and LRR domain-specific mAbs decreased the latency of first somatic action potential firing. However, only the LRR-specific mAbs increased the number of action potential firing together with enhanced initial instantaneous frequency and promoted spike-frequency adaptation, which were less pronounced after the EPTP mAb. This also led to an effective reduction in the slope of ramp-like depolarization in the subthreshold response, suggesting Kv1 channel dysfunction. A biophysical model of a hippocampal neuron corroborated experimental results and suggests that an isolated reduction of the conductance of Kv1-mediated K+ currents largely accounts for the antibody-induced alterations in the initial firing phase and spike-frequency adaptation. Furthermore, Kv1.1 channel density was spatially redistributed from the distal toward the proximal site of AIS under LRR mAb treatment and, to a lesser extant, under EPTP mAb. DISCUSSION: These findings indicate an epitope-specific pathophysiology of LGI1 autoantibodies. The pronounced neuronal hyperexcitability and SFA together with dropped slope of ramp-like depolarization after LRR-targeted interference suggest disruption of LGI1-dependent clustering of K+ channel complexes. Moreover, considering the effective triggering of action potentials at the distal AIS, the altered spatial distribution of Kv1.1 channel density may contribute to these effects through impairing neuronal control of action potential initiation and synaptic integration.

Direct whole-cell patch-clamp recordings from small boutons in rodent primary neocortical neuron cultures.

Direct electrical recordings from conventional boutons in the mammalian central nervous system have proven challenging due to their small size. Here, we provide a protocol for direct whole-cell patch-clamp recordings from small presynaptic boutons of primary dissociated cultured neurons of the rodent neocortex. We describe steps to prepare primary neocortical cultures and recording pipettes, followed by identifying boutons and establishing a whole-cell bouton recording. We then provide details on precise pipette capacitance compensation required for high-resolution current-clamp recordings from boutons. For further details on the use and execution of this protocol, please refer to Ritzau-Jost et al.1.

An action potential initiation mechanism in distal axons for the control of dopamine release.

Information flow in neurons proceeds by integrating inputs in dendrites, generating action potentials near the soma, and releasing neurotransmitters from nerve terminals in the axon. We found that in the striatum, acetylcholine-releasing neurons induce action potential firing in distal dopamine axons. Spontaneous activity of cholinergic neurons produced dopamine release that extended beyond acetylcholine-signaling domains, and traveling action potentials were readily recorded from dopamine axons in response to cholinergic activation. In freely moving mice, dopamine and acetylcholine covaried with movement direction. Local inhibition of nicotinic acetylcholine receptors impaired dopamine dynamics and affected movement. Our findings uncover an endogenous mechanism for action potential initiation independent of somatodendritic integration and establish that this mechanism segregates the control of dopamine signaling between axons and somata.

Large, Stable Spikes Exhibit Differential Broadening in Excitatory and Inhibitory Neocortical Boutons.

Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here, we report direct recordings from boutons of neocortical pyramidal neurons and interneurons. Our data reveal rapid and large presynaptic action potentials in layer 5 neurons and fast-spiking interneurons reliably propagating into axon collaterals. For in-depth analyses, we establish boutons of mature cultured neurons as models for excitatory neocortical boutons, demonstrating that the presynaptic spike amplitude is unaffected by potassium channels, homeostatic long-term plasticity, and high-frequency firing. In contrast to the stable amplitude, presynaptic spikes profoundly broaden during high-frequency firing in layer 5 pyramidal neurons, but not in fast-spiking interneurons. Thus, our data demonstrate large presynaptic spikes and fundamental differences between excitatory and inhibitory boutons in the neocortex.

How to maintain active zone integrity during high-frequency transmission.

In the central nervous system, the frequency at which reliable synaptic transmission can be maintained varies strongly between different types of synapses. Several pre- and postsynaptic processes must interact to enable high-frequency synaptic transmission. One of the mechanistically most challenging issues arises during repetitive neurotransmitter release, when synaptic vesicles fuse in rapid sequence with the presynaptic plasma membrane within the active zone (AZ), potentially interfering with the structural integrity of the AZ itself. Here we summarize potential mechanisms that help to maintain AZ integrity, including arrangement and mobility of release sites, calcium channel mobility, as well as release site clearance via lateral diffusion of vesicular proteins and via endocytotic membrane retrieval. We discuss how different types of synapses use these strategies to maintain high-frequency synaptic transmission.

Neuroplastin and Basigin Are Essential Auxiliary Subunits of Plasma Membrane Ca2+-ATPases and Key Regulators of Ca2+ Clearance.

Plasma membrane Ca2+-ATPases (PMCAs), a family of P-type ATPases, extrude Ca2+ ions from the cytosol to the extracellular space and are considered to be key regulators of Ca2+ signaling. Here we show by functional proteomics that native PMCAs are heteromeric complexes that are assembled from two pore-forming PMCA1-4 subunits and two of the single-span membrane proteins, either neuroplastin or basigin. Contribution of the two Ig domain-containing proteins varies among different types of cells and along postnatal development. Complex formation of neuroplastin or basigin with PMCAs1-4 occurs in the endoplasmic reticulum and is obligatory for stability of the PMCA proteins and for delivery of PMCA complexes to the surface membrane. Knockout and (over)-expression of both neuroplastin and basigin profoundly affect the time course of PMCA-mediated Ca2+ transport, as well as submembraneous Ca2+ concentrations under steady-state conditions. Together, these results establish neuroplastin and basigin as obligatory auxiliary subunits of native PMCAs and key regulators of intracellular Ca2+ concentration.

Performance and customization of 4 prognostic models for postoperative onset of nausea and vomiting in ear, nose, and throat surgery.

OBJECTIVE: To evaluate the performance of 4 published prognostic models for postoperative onset of nausea and vomiting (PONV) by means of discrimination and calibration and the possible impact of customization on these models. DESIGN: Prospective, observational study. SETTING: Tertiary care university hospital. PATIENTS: 748 adult patients (>18 years old) enrolled in this study. Severe obesity (weight > 150 kg or body mass index > 40 kg/m) was an exclusion criterion. INTERVENTIONS: All perioperative data were recorded with an anesthesia information management system. A standardized patient interview was performed on the postoperative morning and afternoon. MEASUREMENTS: Individual PONV risk was calculated using 4 original regression equations by Koivuranta et al, Apfel et al, Sinclair et al, and Junger et al Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was tested using Hosmer-Lemeshow goodness-of-fit statistics. New predictive equations for the 4 models were derived by means of logistic regression (customization). The prognostic performance of the customized models was validated using the "leaving-one-out" technique. MAIN RESULTS: Postoperative onset of nausea and vomiting was observed in 11.2% of the specialized patient population. Discrimination could be demonstrated as shown by areas under the receiver operating characteristic curve of 0.62 for the Koivuranta et al model, 0.63 for the Apfel et al model, 0.70 for the Sinclair et al model, and 0.70 for the Junger et al model. Calibration was poor for all 4 original models, indicated by a P value lower than 0.01 in the C and H statistics. Customization improved the accuracy of the prediction for all 4 models. However, the simplified risk scores of the Koivuranta et al model and the Apfel et al model did not show the same efficiency as those of the Sinclair et al model and the Junger et al model. This is possibly a result of having relatively few patients at high risk for PONV in combination with an information loss caused by too few dichotomous variables in the simplified scores. CONCLUSIONS: The original models were not well validated in our study. An antiemetic therapy based on the results of these scores seems therefore unsatisfactory. Customization improved the accuracy of the prediction in our specialized patient population, more so for the Sinclair et al model and the Junger et al model than for the Koivuranta et al model and the Apfel et al model.

Impact of inadequate surgical antibiotic prophylaxis on perioperative outcome and length of stay on ICU in general and trauma surgery. Analysis using automated data collection.

Within surgical departments, a large amount of antibiotics is used for perioperative prophylaxis. Despite the existence of several guidelines and recommendations for administering antibiotic prophylaxis, mistakes still do occur and have an unknown impact on outcome severity. Based on the electronic anaesthesia records of 4304 patients undergoing defined surgical procedures requiring perioperative antibiotic prophylaxis, a matched pairs approach was used to evaluate the impact of inadequate antibiotic prophylaxis on hospital mortality and prolonged length of stay on intensive care. Stepwise regression models were developed to predict the impact of inadequate antibiotic prophylaxis on outcome measures. An inadequate antibiotic prophylaxis was found for a total of 877 cases. 77.9% of cases were successfully matched, leading to 683 cases and controls each. The crude mortality ratio of cases to controls was 1.5 (cases = 21 versus controls = 14; P = 0.19). The case group had a significantly (P < 0.01) prolonged stay on ICU when analysed as a metric variable. Using logistic regression analysis, we could determine that inadequate antibiotic prophylaxis had no impact on either hospital mortality or prolonged length of stay on ICU (>1 day; yes or no).

Increased body mass index and peri-operative risk in patients undergoing non-cardiac surgery.

BACKGROUND: Increased BMI is a well known risk factor for morbidity and mortality in hospitalized nonsurgical patients. However, the published evidence for a comparable effect in surgical patients is scarce. METHODS: This retrospective study was designed to assess the attributable effects of increased BMI (>30 kg/m2) on outcome (hospital mortality, admission to the intensive care unit (ICU), and incidence of intraoperative cardiovascular events (CVE)) in patients undergoing non-cardiac surgery by a computerized anesthesia record-keeping system. The study is based on data-sets of 28065 patients. Cases were defined as patients with BMI >30; controls (BMI 20-25) were automatically selected according to matching variables (ASA physical status, high risk and urgency of surgery, age and sex) in a stepwise fashion. Differences in outcome measures were assessed using univariate analysis. Stepwise regression models were developed to predict the impact of increased BMI on the different outcome measures. RESULTS: 4726 patients (16.8%) were found with BMI >30. Matching was successful for 41.5% of the cases, leading to 1962 cases and controls. The crude mortality rates were 1.1% (cases) vs 1.2% (controls); P =0.50, power=0.88). Admission to ICU was deemed necessary in 6.8% (cases) vs 7.5% (controls), P =0.42, power=0.65, and CVE were detected from the database in 22.3% (cases) vs 21.6% (controls), P =0.30, power=0.60. Using logistic regression analyses, no significant association between higher BMI and outcome measures could be verified. CONCLUSION: Increased BMI alone was not a factor leading to an increased perioperative risk in non-cardiac surgery. This fact may be due to an elevated level of attention while caring for obese patients.

Automatic calculation of a modified APACHE II score using a patient data management system (PDMS).

OBJECTIVE: To investigate a fully automated and modified APACHE II score calculation exclusively based on routine data supplied by patient data management system, the ICUData, and to assess the predictive performance of this score using analysis of discrimination and calibration at an operative ICU. METHOD: SQL scripts (calculation programs) were developed to calculate the scores of 524 patients who stayed at the ICU between April 1st, 1999 and March 31st, 2000. The calculation programs considered unavailable data as 'not pathological'. The main outcome measure was survival status at ICU discharge. The discriminative power on mortality of this modified APACHE II score was checked with a receiver operating characteristic (ROC) curve. Calibration was tested using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The 459 survivors had an average APACHE score of 17.8+/-5.3. The score of the 65 deceased patients averaged 22.7+/-4.6. The area under the ROC curve of 0.790 was significantly >0.5 (P<0.01) and had a 95% confidence interval (CI) of 0.712-0.825. The goodness-of-fit test showed a good calibration (H=4.89, P=0.70, dof 7, C=6.96, P=0.541, dof 8). CONCLUSION: A prediction model based on completely automatically calculated 'modified APACHE II scores' can be constructed using data collected with PDMS. However, due to differences in the patient collective and methods used, the results need validation and can only be partially compared to results from other studies.

Ultrafast action potentials mediate kilohertz signaling at a central synapse.

Fast synaptic transmission is important for rapid information processing. To explore the maximal rate of neuronal signaling and to analyze the presynaptic mechanisms, we focused on the input layer of the cerebellar cortex, where exceptionally high action potential (AP) frequencies have been reported in vivo. With paired recordings between presynaptic cerebellar mossy fiber boutons and postsynaptic granule cells, we demonstrate reliable neurotransmission up to ∼1 kHz. Presynaptic APs are ultrafast, with ∼100 µs half-duration. Both Kv1 and Kv3 potassium channels mediate the fast repolarization, rapidly inactivating sodium channels ensure metabolic efficiency, and little AP broadening occurs during bursts of up to 1.5 kHz. Presynaptic Cav2.1 (P/Q-type) calcium channels open efficiently during ultrafast APs. Furthermore, a subset of synaptic vesicles is tightly coupled to Ca(2+) channels, and vesicles are rapidly recruited to the release site. These data reveal mechanisms of presynaptic AP generation and transmitter release underlying neuronal kHz signaling.

Corrected incidences of co-morbidities - a statistical approach for risk-assessment in anesthesia using an AIMS.

OBJECTIVE: In anesthesia and intensive care logistic regression analysis are often used to generate predictive models for risk assessment. Strictly seen only independent variables should be represented in such prognostic models. Using anesthesia-information-management-systems a lot of (depending) information is stored in a database during the preoperative ward round. The objective of this study was to evaluate a statistical algorithm to process the different dependent variables without losing the information of each variable on patient's conditions. METHOD: Based on data about prognostic models in anesthesia an iterative statistical algorithm was initiated to summarize dependent variables to subscores. Seven subscores out of several preoperative variables were calculated corresponding to the proper incidence and the correlation to the occurrence of intraoperative cardiovascular events was evaluated. After that first step logistic regression was used to build a predictive model out of the seven subscores, 10 patient-related, and two surgery-related variables. Performance of the prognostic model was assessed using analysis of discrimination and calibration. RESULT: Four out of seven subscores together with age, type and urgency of surgery are represented in the prognostic model to predict the occurrence of intraoperative cardiovascular events. The prognostic model demonstrated good discriminative power with an area under the ROC curve (AUC) of 0.734. CONCLUSION: Due to reduced calibration, the clinical use of the prediction model is limited.