[Surgical Education of Medical Students in Times of COVID-19 - Necessary Adjustments are Chances for the Future]. / Chirurgische Lehre in Zeiten von COVID-19: Aus notwendigen Kompromissen werden Chancen für die Zukunft.

BACKGROUND: Education of medical students in surgery not only consists of knowledge about diseases and their treatment but also of practical skills like i.e. suturing. In the clinical training of medical students, professional interaction and communication with patients is a key component. Due to the circumstances of distancing and reduced exposure to patients during the COVID-19 pandemic, clinical training of medical students has been challenging. To combat these restrictions, digital modern teaching concepts had to be implemented. MATERIAL AND METHODS: Surgical education of medical students was reorganised during the summer semester 2020 and winter semester 2020/2021 and the necessary adjustments, as well as their evaluation by students, were analysed. Results were compared to the pre-COVID evaluations of the summer semester 2019. Furthermore a survey of all university surgical departments in Germany (n = 39) was conducted to compare the different approaches to handling this very new situation. RESULTS: All participating centres were performing surgical education with medical students during the COVID-19 pandemic. Overall, digital teaching methods were well accepted by students and teachers, even though short-term changes were necessary during the second wave of the pandemic. Both students and teachers missed the direct mutual interaction as well as with patients (summer semester 2020 36%, winter semester 2020/2021 40%). Modern and digital teaching concepts were assessed positively (summer semester 2020 45%, winter semester 2020/2021 40%) and long term implementation was desired by students and teachers (winter semester 2020/2021 60%). CONCLUSION: Training of practical surgical skills, as well as communication skills, can only be taught in presence. Digital learning concepts can support, but not replace, surgical courses held in presence, including contact to patients and manual training. Blended learning concepts facilitate a leap towards modern teaching concepts and increase the quality of classes spent in presence.

Cerebrospinal fluid penetration of very high-dose meropenem: a case report.

BACKGROUND: Standard dosing of meropenem (2 g t.i.d.) produces CSF concentrations of only 1-2 mg/L which is inferior to the clinical breakpoint for most Gram-negative bacteria. There is therefore concern that dosing must be increased in order to achieve therapeutic CSF concentrations for bacteria with susceptibility close to clinical breakpoints. Yet, the effects of high-dose meropenem on CSF concentrations are not well described in literature. We therefore determined meropenem CSF-levels in a patient who was treated with 15 g/day of meropenem. CASE PRESENTATION: Our patient suffered from a brain trauma and an external ventricular drainage was implanted. Later, a carbapenemase-producing Acinetobacter baumannii (OXA-23, NDM-1) was isolated from blood cultures and CSF. The MIC for meropenem was > 32 mg/L (R), and we opted for a combination therapy of meropenem, colistin and fosfomycin. Meropenem was given at an unusual high-dose (15 g/day) with the aim of achieving high CSF concentrations. CSF concentrations peaked at 64 mg/L. Yet, the patient succumbed to an intracranial bleed into a preexisting cerebral contusion. CONCLUSIONS: High-dose meropenem can achieve CSF levels largely superior to those achieved with commonly recommended dosing regimens. Though our patient succumbed to an intracranial bleed which could be regarded as a severe adverse event, we suggest that meropenem dosing can be increased when pathogens with increased MICs are found in the CSF. More in vivo data are however needed to determine the safety of high-dose meropenem.

Image-guided implantation of pre-calibrated catheters in the ICU: a feasibility study.

BACKGROUND: Image-guided implantation of intracranial catheters is a routine procedure. Although time for surgery is short, transport from the intensive care unit (ICU) to the operation room (OR) is time-consuming and endangers patients in vulnerable intracranial pressure phases. Unfortunately, technical aspects of image guidance have so far required surgery to be performed in the operation room. In this observational study we investigated the feasibility of image-guided catheter placement in the ICU using a pre-calibrated stylet for implantation of intracranial catheters for a variety of indications and compare the results of procedures performed in the OR. METHODS: Twenty-three patients received implantation of 31 image-guided intracranial catheters or external ventricular drains using a pre-calibrated stylet in the ICU or in the OR. The times required for navigation planning, transport and surgery were assessed. Pre-operative trajectory planning, intra-operative screenshots of the navigation system and postoperative computed tomography (CT) scans were compared. RESULTS: Eleven external ventricular drains and nine intracranial catheters for fibrinolytic therapy of intracerebral haemorrhage were implanted in the OR, whereas ten external ventricular drains and one catheter for fibrinolytic therapy were implanted in the ICU. All catheters implanted on the ICU, 81.8 % of external ventricular drains and 88.8 % of lysis catheters placed in the OR had an optimal position to function. CONCLUSION: A pre-calibrated stylet in combination with the flexible headband equipped with reference arrays allows the application of image guidance in the ICU. It reduced time expended for patients and employees, and avoided the risks of ICU transport to the OR.

Influence of traumatic brain injury on ipsilateral and contralateral cortical perfusion in mice.

Traumatic brain injury (TBI) is one of the most important causes of death in young adults. After brain injury cortical perfusion is impaired by cortical spreading depression, cerebral microvasospasm or microvascular thrombosis and contributes to secondary expansion of lesion into surrounding healthy brain tissue. The present study was designed to determine the regional cortical perfusion pattern after experimental TBI induced by controlled cortical impact (CCI) in male C57/BL6N mice. We performed a longitudinal time series analysis by Laser speckle contrast imaging (LSCI). Measurements were carried out before, immediately and 24 h after trauma. Immediately after CCI cortical perfusion in the lesion core dropped to 10 % of before injury (baseline; %BL) and to 21-24 %BL in the cortical area surrounding the core. Interestingly, cortical perfusion was also significantly reduced in the contralateral non-injured hemisphere (41-58 %BL) matching the corresponding brain region of the injured hemisphere. 24 h after CCI perfusion of the contralateral hemisphere returned to baseline level in the area corresponding to the lesion core, whereas the lateral area of the parietal cortex was hyperperfused (125 %BL). The lesion core region itself remained severely hypoperfused (18 to 26 %BL) during the observation period. TBI causes a maldistribution of both ipsi- and contralateral cerebral perfusion immediately after trauma, which persist for at least 24 h. Higher perfusion levels in the lesion core 24 h after trauma were associated with increased tissue damage, which supports the role of reperfusion injury for secondary brain damage after TBI.

Impact of pre-hospital handling and initial time to cranial computed tomography on outcome in aneurysmal subarachnoid hemorrhage patients with out-of-hospital sudden cardiac arrest-a retrospective bi-centric study.

Background: Aneurysmal subarachnoid hemorrhage (SAH) presents occasionally with cardiac arrest (CA). The impact of pre-hospital and emergency room (ER) treatment on outcome remains unclear. Therefore, we investigated the impact of pre-hospital treatment, focusing on lay cardiopulmonary resuscitation (CPR), and ER handling on the outcome of SAH patients with out-of-hospital CA (OHCA). Methods: In this bi-centric retrospective analysis, we reviewed SAH databases for OHCA and CPR from January 2011 to June 2021. Patients were analyzed for general clinical and epidemiological parameters. CPR data were obtained from ambulance reports and information on ER handling from the medical records. Data were correlated with patient survival at hospital discharge as a predefined outcome parameter. Results: Of 1,120 patients with SAH, 45 (4.0%) were identified with OHCA and CPR, 38 of whom provided all required information and were included in this study. Time to resuscitation was significantly shorter with lay resuscitation (5.3 ± 5.2 min vs. 0.3 ± 1.2 min, p = 0.003). Nineteen patients were not initially scheduled for cranial computed tomography (CCT), resulting in a significantly longer time interval to first CCT (mean ± SD: 154 ± 217 min vs. 40 ± 23 min; p < 0.001). Overall survival to discharge was 31.6%. Pre-hospital lay CPR was not associated with higher survival (p = 0.632). However, we observed a shorter time to first CCT in surviving patients (p = 0.065). Conclusions: OHCA in SAH patients is not uncommon. Besides high-quality CPR, time to diagnosis of SAH appears to play an important role. We therefore recommend considering CCT diagnostics as part of the diagnostic algorithm in patients with OHCA.

DSA-Based 2D Perfusion Measurements in Delayed Cerebral Ischemia to Estimate the Clinical Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Technical Feasibility Study.

(1) Background: To predict clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI) by assessment of the cerebral perfusion using a 2D perfusion angiography (2DPA) time-contrast agent (CA) concentration model. (2) Methods: Digital subtraction angiography (DSA) data sets of n = 26 subjects were acquired and post-processed focusing on changes in contrast density using a time-concentration model at three time points: (i) initial presentation with SAH (T0); (ii) vasospasm-associated acute clinical impairment (T1); and (iii) directly after endovascular treatment (T2) of SAH-associated large vessel vasospasm (LVV), which resulted in n = 78 data sets. Maximum slope (MS in SI/ms), time-to-peak (TTP in ms), and maximum amplitude of a CA bolus (dSI) were measured in brain parenchyma using regions of interest (ROIs). First, acquired parameters were standardized to the arterial input function (AIF) and then statistically analyzed as mean values. Additionally, data were clustered into two subsets consisting of patients with regredient or with stable/progredient symptoms (or Doppler signals) after endovascular treatment (n = 10 vs. n = 16). (3) Results: Perfusion parameters (MS, TTP, and dSI) differed significantly between T0 and T1 (p = 0.003 each). Significant changes between T1 and T2 were only detectable for MS (0.041 ± 0.016 vs. 0.059 ± 0.026; p = 0.011) in patients with regredient symptoms at T2 (0.04 ± 0.012 vs. 0.066 ± 0.031; p = 0.004). For dSI, there were significant differences between T0 and T2 (5095.8 ± 2541.9 vs. 3012.3 ± 968.3; p = 0.001), especially for those with stable symptoms at T2 (5685.4 ± 2967.2 vs. 3102.8 ± 1033.2; p = 0.02). Multiple linear regression analysis revealed that a) the difference in MS between T1 and T2 and b) patient's age (R = 0.6; R2 = 0.34; p = 0.009) strongly predict the modified Rankin Scale (mRS) at discharge. (4) Conclusions: 2DPA allows the direct measurement of treatment effects in SAH associated DCI and may be used to predict outcomes in these critically ill patients.

Early DNase-I therapy delays secondary brain damage after traumatic brain injury in adult mice.

Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) is a DAMP known to cause disruption of the blood-brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume (p = 0.003), brain water content (p < 0.0001) and to stabilize BBB integrity (p = 0.019) 1 day post-injury (dpi). At 6 h post injury LD-treated animals showed less cleavage of fibrin (p = 0.0014), and enhanced perfusion as assessed by micro-computer-tomography (p = 0.027). At 5 dpi the number of Iba1-positive cells (p = 0.037) were reduced, but the number of CD45-positive cells, motoric function and brain lesion volume was not different. Posttraumatic-treatment with DNase-I therefore stabilizes the BBB, reduces the formation of brain edema, immune response, and delays secondary brain damage. DNase-I might be a new approach to extend the treatment window after TBI.

Continuous Intraarterial Nimodipine Infusion for the Treatment of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Retrospective, Single-Center Cohort Trial.

Background: Delayed cerebral ischemia (DCI) occurs after aneurysmal subarachnoid hemorrhage (aSAH). Continuous intraarterial nimodipine infusion (CIAN) is a promising approach in patients with intracranial large vessel vasospasm (LVV). The objective of this retrospective single-center cohort study was to evaluate the outcome in aSAH-patients treated with CIAN. Methods: CIAN was initiated and ended based on the clinical evaluation and transcranial Doppler (TCD), CT-angiography, CT-perfusion (PCT), and digital subtraction angiography (DSA). Nimodipine (0.5-2.0 mg/h) was administered continuously through microcatheters placed in the extracranial internal carotid and/or vertebral artery. Primary outcome measures were Glasgow Outcome Scale (GOS) at discharge and within 1 year after aSAH, and the occurrence of minor and major (<⅓ and >⅓ of LVV-affected territory) DCI-related infarctions in subsequent CT/MRI-scans. Secondary outcome measures were CIAN-associated complications. Results: A total of 17 patients underwent CIAN. Median onset of CIAN was 9 (3-13) days after aSAH, median duration was 5 (1-13) days. A favorable outcome (GOS 4-5) was achieved in 9 patients (53%) at discharge and in 13 patients within 1 year (76%). One patient died of posthemorrhagic cerebral edema. Minor cerebral infarctions occurred in five and major infarctions in three patients. One patient developed cerebral edema possibly due to CIAN. Normalization of PCT-parameters within 2 days was observed in 9/17 patients. Six patients showed clinical response and thus did not require PCT imaging. Conclusion: The favorable outcome in 76% of patients after 1 year is in line with previous studies. CIAN thus may be used to treat patients with severe therapy-refractory DCI.

Ribonuclease-1 treatment after traumatic brain injury preserves blood-brain barrier integrity and delays secondary brain damage in mice.

Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood-brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12 h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24 h and 120 h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (- 31% RNase 40 µg/kg vs. vehicle), brain water accumulation (- 5.5%), and loss of BBB integrity (- 21.6%) at 24 h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (- 53.3%) and microglial activation (- 18.3%) at 120 h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI.

Evaluation of efficacy and biocompatibility of a novel semisynthetic collagen matrix as a dural onlay graft in a large animal model.

BACKGROUND: Semisynthetic collagen matrices are promising duraplasty grafts with low risk of cerebrospinal fluid (CSF) fistulas, good tissue integration and minor foreign body reaction. The present study investigates the efficacy and biocompatibility of a novel semisynthetic bilayered collagen matrix (BCM, B. Braun Aesculap) as dural onlay graft for duraplasty. METHODS: Thirty-four pigs underwent osteoclastic trepanation, excision of the dura, and placement of a cortical defect, followed by duraplasty using BCM, Suturable DuraGen™ (Integra Neuroscience), or periosteum. CSF tightness and intraoperative handling of the grafts were evaluated. Pigs were sacrificed after 1 and 6 months for histological analysis. FINDINGS: BCM and DuraGen™ showed superior handling than periosteum with a trend for better adhesion to dura and CSF tightness for BCM. Periosteum, which was sutured unlike the synthetic grafts, had the highest intraoperative CSF tightness. Duraplasty time with periosteum was significantly higher (14.4 ± 2.7 min) compared with BCM (2.8 ± 0.8 min) or DuraGen™ (3.0 ± 0.5 min). Tissue integration by fibroblast infiltration was observed after 1 month for all devices. More adhesions between graft and cortex were observed with DuraGen™ compared with BCM and periosteum. No relevant adhesions between leptomeninges and BCM were observed and all devices showed comparable lymphocytic reaction of the brain. All devices were completely integrated after 6 months. BCM and DuraGen™ showed a trend for an enhanced lymphocytic reaction of the brain parenchyma compared with periosteum. Implant rejection was not observed. CONCLUSION: Semisythetic collagen matrices are an attractive alternative in duraplasty due to their easy handling, lower surgical time, and high biocompatibility.

Microsurgical fenestration of perineural cysts to the thecal sac at the level of the distal dural sleeve.

BACKGROUND: Surgery for symptomatic sacral perineural cysts remains an issue of discussion. Assuming micro-communications between the cyst and thecal sac resulting in a valve mechanism and trapping of CSF as a pathomechanism, microsurgical fenestration from the cyst to the thecal sac was performed to achieve free CSF communication. METHODS: In 13 consecutive patients (10 female, 3 male), MRI revealed sacral perineural cysts and excluded other pathologies. Micro-communication between the thecal sac and the cysts was shown by delayed contrast filling of the cysts on postmyelographic CT. Surgical fenestration achieved free CSF communication between the thecal sac and cysts in all patients. The patient histories, follow-up examinations and self-assessment scales were analyzed. Symptoms at initial presentation included lumbosacral pain, pseudoradicular symptoms, genital pain and urinary dysfunction. Mean follow-up was 10.7 ± 6.6 months. FINDINGS: Besides one CSF fistula, no surgical complications were observed. Five patients did not improve after surgery; in four of these cases multiple cysts were found, but small and promptly filling cysts remained untreated. Seven patients reported lasting benefit following surgery; three of these had single cysts, and all had cysts >1 cm. One patient initially benefited from cyst fenestration but experienced recurrent pain within 2 months postoperatively. Re-myelography revealed delayed contrast filling of the recurrent cyst; however, surgical revision did not lead to an improvement despite successful fenestration and collapse of the cyst revealed by postoperative imaging. CONCLUSIONS: Microsurgical fenestration of sacral perineural cysts to the thecal sac is a surgical approach that has shown success in the treatment of lumbosacral pain, pseudoradicular symptoms, genital pain and urinary dysfunction associated with sacral perineural cysts. Our analysis, however, shows that mainly patients with singular large cysts benefit from this treatment.

Comparison of Unruptured Intracranial Aneurysm Treatment Score and PHASES Score in Subarachnoid Hemorrhage Patients With Multiple Intracranial Aneurysms.

Objective: Unruptured Intracranial Aneurysm (UIA) Treatment Score (UIATS) and PHASES score are used to inform treatment decision making for UIAs (treatment or observation). We assessed the ability of the scoring systems to discriminate between ruptured aneurysms and UIAs in a subarachnoid hemorrhage (SAH) cohort with multiple aneurysms. Methods: We retrospectively applied PHASES and UIATS scoring to the aneurysms of 40 consecutive patients with SAH and multiple intracranial aneurysms. Results: PHASES score discriminated better between ruptured aneurysms and UIAs than UIATS. PHASES scores and the difference between the UIATS subscores were higher for ruptured aneurysms compared with UIAs, which reached significance for the PHASES score. PHASES score estimated a low 5-year rupture risk in a larger proportion of the UIAs (≤0.7% in 62.3%, ≤1.7% in 98.4%) than of the ruptured aneurysms (≤0.7% in 22.5%, ≤1.7% in 82.5%). In the 40 ruptured aneurysms, UIATS provided recommendation for treatment in 11 (27.5%), conservative management in 14 (35.0%), and was inconclusive in 15 cases (37.5%). In the 61 UIAs, UIATS recommended treatment in 16 (26.2%), conservative management in 29 (47.5%), and was inconclusive in 16 (26.2%) cases. Conclusion: Similar to previous SAH cohorts, a significant proportion of the ruptured aneurysms exhibited a low-rupture risk. Nevertheless, PHASES score discriminated between ruptured aneurysms and UIAs in our cohort; the lower discriminatory power of UIATS was due to high weights of aneurysm-independent factors. We recommend careful integration of the scores for individual decision making. Large-scale prospective trials are required to establish score-based treatment strategies for UIAs.

Analysis of Cerebral Vasospasm in a Murine Model of Subarachnoid Hemorrhage with High Frequency Transcranial Duplex Ultrasound.

Cerebral vasospasm that occurs in the weeks after subarachnoid hemorrhage, a type of hemorrhagic stroke, contributes to delayed cerebral ischemia. A problem encountered in experimental studies using murine models of SAH is that methods for in vivo monitoring of cerebral vasospasm in mice are lacking. Here, we demonstrate the application of high frequency ultrasound to perform transcranial Duplex sonography examinations on mice. Using the method, the internal carotid arteries (ICA) could be identified. The blood flow velocities in the intracranial ICAs were accelerated significantly after induction of SAH, while blood flow velocities in the extracranial ICAs remained low, indicating cerebral vasospasm. In conclusion, the method demonstrated here allows functional, noninvasive in vivo monitoring of cerebral vasospasm in a murine SAH model.

Correlation of cardiac function and cerebral perfusion in a murine model of subarachnoid hemorrhage.

Cerebral hypoperfusion is a key factor for determining the outcome after subarachnoid hemorrhage (SAH). A subset of SAH patients develop neurogenic stress cardiomyopathy (NSC), but it is unclear to what extent cerebral hypoperfusion is influenced by cardiac dysfunction after SAH. The aims of this study were to examine the association between cardiac function and cerebral perfusion in a murine model of SAH and to identify electrocardiographic and echocardiographic signs indicative of NSC. We quantified cortical perfusion by laser SPECKLE contrast imaging, and myocardial function by serial high-frequency ultrasound imaging, for up to 7 days after experimental SAH induction in mice by endovascular filament perforation. Cortical perfusion decreased significantly whereas cardiac output and left ventricular ejection fraction increased significantly shortly post-SAH. Transient pathological ECG and echocardiographic abnormalities, indicating NSC (right bundle branch block, reduced left ventricular contractility), were observed up to 3 h post-SAH in a subset of model animals. Cerebral perfusion improved over time after SAH and correlated significantly with left ventricular end-diastolic volume at 3, 24, and 72 h. The murine SAH model is appropriate to experimentally investigate NSC. We conclude that in addition to cerebrovascular dysfunction, cardiac dysfunction may significantly influence cerebral perfusion, with LVEDV presenting a potential parameter for risk stratification.

Multicolor 3D Printing of Complex Intracranial Tumors in Neurosurgery.

Three-dimensional (3D) printing technologies offer the possibility of visualizing patient-specific pathologies in a physical model of correct dimensions. The model can be used for planning and simulating critical steps of a surgical approach. Therefore, it is important that anatomical structures such as blood vessels inside a tumor can be printed to be colored not only on their surface, but throughout their whole volume. During simulation this allows for the removal of certain parts (e.g., with a high-speed drill) and revealing internally located structures of a different color. Thus, diagnostic information from various imaging modalities (e.g., CT, MRI) can be combined in a single compact and tangible object. However, preparation and printing of such a fully colored anatomical model remains a difficult task. Therefore, a step-by-step guide is provided, demonstrating the fusion of different cross-sectional imaging data sets, segmentation of anatomical structures, and creation of a virtual model. In a second step the virtual model is printed with volumetrically colored anatomical structures using a plaster-based color 3D binder jetting technique. This method allows highly accurate reproduction of patient-specific anatomy as shown in a series of 3D-printed petrous apex chondrosarcomas. Furthermore, the models created can be cut and drilled, revealing internal structures that allow for simulation of surgical procedures.

Image-Guided Transcranial Doppler Ultrasound for Monitoring Posthemorrhagic Vasospasms of Infratentorial Arteries: A Feasibility Study.

BACKGROUND: A considerable number of patients with subarachnoid hemorrhage (SAH) develop vasospasms of the infratentorial arteries. Transcranial Doppler sonography (TCD) is used to screen for vasospasm. In this study, we used a technical modification that combines TCD with an image guidance device that the operator can use to navigate to the ultrasonic window and to predefined intracranial vascular targets. Our aim was to analyze the feasibility, spatial precision, and spatial reproducibility of serial image-guided TCD of infratentorial and-for comparison-supratentorial arteries in the clinical setting of monitoring for vasospasm after SAH. METHODS: The study included 10 SAH patients, who each received 5 serial image-guided TCD examinations. Using computed tomography angiography data, trajectories to the infratentorial and supratentorial cerebral arteries were planned and loaded into an image guidance device tracking the Doppler probe. As a measure of spatial precision and spatial reproducibility, we analyzed the distances between the positions of preplanned vascular targets and optimal Doppler signals. RESULTS: The mean distance between preplanned and optimal target points was 4.8 ± 2.1 mm (first exam), indicating high spatial precision. The spatial precision decreased with increasing depth of the vascular target. In all patients, image-guided TCD detected all predefined supratentorial and infratentorial vascular segments. There were no significant changes in spatial precision in serial exams, indicating high reproducibility. CONCLUSIONS: Image-guided TCD is feasible for supratentorial and infratentorial arteries. It shows high spatial precision and reproducibility. This study provides a basis for future clinical studies on image-guided TCD for post-SAH vasospasm screening.

Automated Grading of Cerebral Vasospasm to Standardize Computed Tomography Angiography Examinations After Subarachnoid Hemorrhage.

Background: Computed tomography angiography (CTA) is frequently used with computed tomography perfusion imaging (CTP) to evaluate whether endovascular vasospasm treatment is indicated for subarachnoid hemorrhage patients with delayed cerebral ischemia. However, objective parameters for CTA evaluation are lacking. In this study, we used an automated, investigator-independent, digital method to detect vasospasm, and we evaluated whether the method could predict the need for subsequent endovascular vasospasm treatment. Methods: We retrospectively reviewed the charts and analyzed imaging data for 40 consecutive patients with subarachnoid hemorrhages. The cerebrovascular trees were digitally reconstructed from CTA data, and vessel volume and the length of the arteries of the circle of Willis and their peripheral branches were determined. Receiver operating characteristic curve analysis based on a comparison with digital subtraction angiographies was used to determine volumetric thresholds that indicated severe vasospasm for each vessel segment. Results: The automated threshold-based volumetric evaluation of CTA data was able to detect severe vasospasm with high sensitivity and negative predictive value for predicting cerebral hypoperfusion on CTP, although the specificity and positive predictive value were low. Combining the automated detection of vasospasm on CTA and cerebral hypoperfusion on CTP was superior to CTP or CTA alone in predicting endovascular vasospasm treatment within 24 h after the examination. Conclusions: This digital volumetric analysis of the cerebrovascular tree allowed the objective, investigator-independent detection and quantification of vasospasms. This method could be used to standardize diagnostics and the selection of subarachnoid hemorrhage patients with delayed cerebral ischemia for endovascular diagnostics and possible interventions.

The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic cardiomyopathy does not alter contractile parameters in skinned murine myocardium.

The present study investigates the effects of the first mutation of troponin C (hcTnC(L29Q)) found in a patient with hypertrophic cardiomyopathy (HCM) on force-pCa relations and the interplay with phosphorylation of sarcomeric PKA substrates. In triton-skinned murine cardiac fibers, the endogenous mcTnC was extracted and the fibers were subsequently reconstituted with recombinant wild-type and mutant hcTnC. Force-pCa relations of preparations containing hcTnC(L29Q) or hcTnC(WT) were similar. Incubation of fibers reconstituted with the recombinant proteins with phosphatase to dephosphorylate sarcomeric PKA substrates induced an increase in Ca2+ sensitivity, slightly more pronounced (0.04 pCa units) in hcTnC(L29Q)-containing fibers. Incubation of the dephosphorylated fibers with PKA induced significant rightward shifts of force-pCa relations of similar magnitude with both, hcTnC(L29Q) and hcTnC(WT). No significant effects of hcTnC(L29Q) on the velocity of unloaded shortening were observed. In conclusion, no major differences in contractile parameters of preparations containing hcTnC(L29Q) compared to hcTnC(WT) were observed. Therefore, it appears unlikely that hcTnC(L29Q) induces the development of HCM by affecting the regulation of Ca2+-activated force and interference with PKA-mediated modulation of the Ca2+ sensitivity of contraction.

Lys184 deletion in troponin I impairs relaxation kinetics and induces hypercontractility in murine cardiac myofibrils.

AIMS: To understand the functional consequences of the Lys184 deletion in murine cardiac troponin I (mcTnI(DeltaK184)), we have studied the primary effects of this mutation linked to familial hypertrophic cardiomyopathy (FHC) at the sarcomeric level. METHODS AND RESULTS: Ca(2+) sensitivity and kinetics of force development and relaxation were investigated in cardiac myofibrils from transgenic mice expressing mcTnI(DeltaK184), as a model which co-segregates with FHC. Ca(2+)-dependent conformational changes (switch-on/off) of the fluorescence-labelled human troponin complex, containing either wild-type hcTnI or mutant hcTnI(DeltaK183), were investigated in myofibrils prepared from the guinea pig left ventricle. Ca(2+) sensitivity and maximum Ca(2+)-activated and passive forces were significantly enhanced and cooperativity was reduced in mutant myofibrils. At partial Ca(2+) activation, mutant but not wild-type myofibrils displayed spontaneous oscillatory contraction of sarcomeres. Both conformational switch-off rates of the incorporated troponin complex and the myofibrillar relaxation kinetics were slowed down by the mutation. Impaired relaxation kinetics and increased force at low [Ca(2+)] were reversed by 2,3-butanedione monoxime (BDM), which traps cross-bridges in non-force-generating states. CONCLUSION: We conclude that these changes are not due to alterations of the intrinsic cross-bridge kinetics. The molecular mechanism of sarcomeric diastolic dysfunction in this FHC model is based on the impaired regulatory switch-off kinetics of cTnI, which induces incomplete inhibition of force-generating cross-bridges at low [Ca(2+)] and thereby slows down relaxation of sarcomeres. Ca(2+) sensitization and impairment of the relaxation of sarcomeres induced by this mutation may underlie the enhanced systolic function and diastolic dysfunction at the sarcomeric level.

Doppler sonography enhances rtPA-induced fibrinolysis in an in vitro clot model of spontaneous intracerebral hemorrhages.

BACKGROUND: Transcranial Doppler (TCD) was shown to enhance intravascular fibrinolysis by rtPA in ischemic stroke. Studies revealed that catheter-based administration of rtPA induces lysis of intracerebral hemorrhages (ICH). However, it is unknown whether TCD would be suitable to enhance rtPA-induced fibrinolysis in patients with ICH. The aim of this study was to assess the potential of TCD to enhance rtPA-induced fibrinolysis in an in vitro clot system. METHODS: Reproducible human blood clots of 25 ml were incubated in a water bath at 37°C during treatments. They were weighed before and after 6 different treatments: (I) control (incubation only), (II) rtPA only, (III) one Doppler probe, (IV) two Doppler probes placed vis-à-vis, (V) one probe and rtPA and (VI) two probes and rtPA. To quantify lysis of the blood clots and attenuation of the Doppler through a temporal squama acoustic peak rarefaction pressure (APRP) was measured in the field of the probes. Temperature was assessed to evaluate possible side effects. RESULTS: Clot weight was reduced in all groups. The control group had the highest relative end weight of 70.2%±7.2% compared to all other groups (p<0,0001). Most efficient lysis was achieved using (VI) 2 probes and rtPA 36.3%±4.4% compared to (II, III, IV) (p<0.0001; p = 0.0002; p = 0.048). APRP was above lysis threshold (535.5±7.2 kPa) using 2 probes even through the temporal squama (731.6±32.5 kPa) (p = 0.0043). There was a maximal temperature elevation of 0.17±0.07°C using both probes. CONCLUSIONS: TCD significantly enhances rtPA-induced lysis of blood clots, and the effect is amplified by using multiple probes. Our results indicate that bitemporal TCD insonation of hematomas could be a new and safe approach to enhance fibrinolysis of ICH´s treated with intralesional catheter and rtPA.