Trends in incidence and treatments of spontaneous subarachnoid hemorrhage- a 10 year hospital based study.

BACKGROUND: Improved endovascular methods make it possible to treat complex ruptured aneurysms, but surgery is still needed in certain cases. We evaluated the effects on the clinical results of the changes in aneurysm treatment. METHODS: The study cohort was 837 patients with spontaneous subarachnoid hemorrhage (SAH) and one or multiple aneurysms, admitted to Dept of Neurosurgery, Uppsala University Hospital from 2012 to 2021. Demography, location and treatment of aneurysms, neurologic condition at admission and discharge, mortality and last tier treatment of high intracranial pressure (ICP) was evaluated. Functional outcome was measured using the Extended Glasgow Outcome Scale (GOSE) Data concerning national incidences of stroke diseases was collected from open Swedish databases. RESULTS: Endovascular methods were used in 666 cases (79.6%). In 111 (13.3%) with stents. Surgery was performed in 115 cases (13.7%) and 56 patients (6.7%) had no aneurysm treatment. The indications for surgery were a hematoma (51 cases, 44.3%), endovascular treatment not considered safe (47 cases, 40.9%), or had been attempted without success (13 cases, 11.3%). Treatment with stent devices increased, and with surgery decreased over time. There was a trend in decrease in hemicraniectomias over time. Both the patient group admitted awake (n = 681) and unconscious (n = 156) improved significantly in consciousness between admission and discharge. Favorable outcome (GOSE 5-8) was seen in 69% for patients admitted in Hunt & Hess I-II and 25% for Hunt & Hess III-V. Mortality at one year was 10.9% and 42.7% for those admitted awake and unconscious, respectively.The number of cases decreased during the study period, which was in line with Swedish national data. CONCLUSIONS: The incidence of patients with SAH gradually decreased in our material, in line with national data. The treatment policy in our unit has been shifting to more use of endovascular methods. During the study period the use of hemicraniectomies decreased.

Cerebrovascular reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury.

PURPOSE: Cerebral perfusion pressure (CPP) guidance by cerebral pressure autoregulation (CPA) status according to PRx (correlation mean arterial blood pressure (MAP) and intracranial pressure (ICP)) and optimal CPP (CPPopt = CPP with lowest PRx) is promising but little is known regarding this approach in elderly. The aim was to analyze PRx and CPPopt in elderly TBI patients. METHODS: A total of 129 old (≥ 65 years) and 342 young (16-64 years) patients were studied using monitoring data for MAP and ICP. CPP, PRx, CPPopt, and ΔCPPopt (difference between actual CPP and CPPopt) were calculated. Logistic regression analyses with PRx and ΔCPPopt as explanatory variables for outcome. The combined effects of PRx/CPP and PRx/ΔCPPopt on outcome were visualized as heatmaps. RESULTS: The elderly had higher PRx (worse CPA), higher CPPopt, and different temporal patterns. High PRx influenced outcome negatively in the elderly but less so than in younger patients. CPP close to CPPopt correlated to favorable outcome in younger, in contrast to elderly patients. Heatmap interaction analysis of PRx/ΔCPPopt in the elderly showed that the region for favorable outcome was centered around PRx 0 and ranging between both functioning and impaired CPA (PRx range - 0.5-0.5), and the center of ΔCPPopt was - 10 (range - 20-0), while in younger the center of PRx was around - 0.5 and ΔCPPopt closer to zero. CONCLUSIONS: The elderly exhibit higher PRx and CPPopt. High PRx influences outcome negatively in the elderly but less than in younger patients. The elderly do not show better outcome when CPP is close to CPPopt in contrast to younger patients.

Expanded range of indications for Neuroform Atlas stent in the treatment of very small, wide-necked cerebral aneurysms.

The purpose of this study was to investigate the range of indications for using the Neuroform Atlas stent. Between 2016 and 2020, we treated 20 females and 5 males for aneurysms with a diameter of less than 3 mm and an aspect ratio less than 1.5. The diameter of the parent arteries varied from 1.1 mm to 4.5 mm. There were 13 ruptured and 12 unruptured aneurysms. Double stent-assisted coiling was performed in 14 cases, and single stent-assisted coiling was performed in 11 cases. After deployment, the morphology of the Neuroform Atlas stents was analyzed in tapered or Y-shaped silicone tubes that simulated parent arteries. Radiological results were assessed 7 months and 2 years after the intervention using the Raymond-Roy scale. Clinical outcome was assessed 1 year after the intervention using the modified Rankin score. There were three fatal outcomes. One aneurysm was recoiled. The rate of class I aneurysm occlusion was registered in 21 patients at the last follow-up. At the end of the clinical follow-up period, a favorable outcome (modified Rankin scale 0 -1) was registered in nine patients with ruptured aneurysms. An analysis of the morphology of the stents deployed in the silicone tubes provided an explanation for the stability of the coil mass in the treated aneurysms. Our results suggest that the range of indications for use of the Neuroform Atlas stent can be expanded beyond the present range with regard to the diameter of the parent vessels and size of the aneurysms.

Prognosis in moderate-severe traumatic brain injury in a Swedish cohort and external validation of the IMPACT models.

BACKGROUND: A major challenge in management of traumatic brain injury (TBI) is to assess the heterogeneity of TBI pathology and outcome prediction. A reliable outcome prediction would have both great value for the healthcare provider, but also for the patients and their relatives. A well-known prediction model is the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic calculator. The aim of this study was to externally validate all three modules of the IMPACT calculator on TBI patients admitted to Uppsala University hospital (UUH). METHOD: TBI patients admitted to UUH are continuously enrolled into the Uppsala neurointensive care unit (NICU) TBI Uppsala Clinical Research (UCR) quality register. The register contains both clinical and demographic data, radiological evaluations, and outcome assessments based on the extended Glasgow outcome scale extended (GOSE) performed at 6 months to 1 year. In this study, we included 635 patients with severe TBI admitted during 2008-2020. We used IMPACT core parameters: age, motor score, and pupillary reaction. RESULTS: The patients had a median age of 56 (range 18-93), 142 female and 478 male. Using the IMPACT Core model to predict outcome resulted in an AUC of 0.85 for mortality and 0.79 for unfavorable outcome. The CT module did not increase AUC for mortality and slightly decreased AUC for unfavorable outcome to 0.78. However, the lab module increased AUC for mortality to 0.89 but slightly decreased for unfavorable outcome to 0.76. Comparing the predicted risk to actual outcomes, we found that all three models correctly predicted low risk of mortality in the surviving group of GOSE 2-8. However, it produced a greater variance of predicted risk in the GOSE 1 group, denoting general underprediction of risk. Regarding unfavorable outcome, all models once again underestimated the risk in the GOSE 3-4 groups, but correctly predicts low risk in GOSE 5-8. CONCLUSIONS: The results of our study are in line with previous findings from centers with modern TBI care using the IMPACT model, in that the model provides adequate prediction for mortality and unfavorable outcome. However, it should be noted that the prediction is limited to 6 months outcome and not longer time interval.

Neurointensive care of traumatic brain injury in the elderly-age-specific secondary insult levels and optimal physiological levels to target need to be defined.

BACKGROUND: Elderly patients with traumatic brain injury increase. Current targets and secondary insult definitions during neurointensive care (NIC) are mostly based on younger patients. The aim was therefore to study the occurrence of predefined secondary insults and the impact on outcome in different ages with particular focus on elderly. METHODS: Patients admitted to Uppsala 2008-2014 were included. Patient characteristics, NIC management, monitoring data, and outcome were analyzed. The percentage of monitoring time for ICP, CPP, MAP, and SBP above-/below-predefined thresholds was calculated. RESULTS: Five hundred seventy patients were included, 151 elderly ≥ 65 years and 419 younger 16-64 years. Age ≥ 65 had significantly higher percentage of CPP > 100, MAP > 120, and SBP > 180 and age 16-64 had higher percentage of ICP ≥ 20, CPP ≤ 60, and MAP ≤ 80. Age ≥ 65 contributed independently to the different secondary insult patterens. When patients in all ages were analyzed, low percentage of CPP > 100 and SBP > 180, respectively, was significant predictors of favorable outcome and high percentage of ICP ≥ 20, CPP > 100, SBP ≤ 100, and SBP > 180, respectively, was predictors of death. Analysis of age interaction showed that patients ≥ 65 differed and had a higher odds for favorable outcome with large proportion of good monitoring time with SBP > 180. CONCLUSIONS: Elderly ≥ 65 have different patterns of secondary insults/physiological variables, which is independently associated to age. The finding that SBP > 180 increased the odds of favorable outcome in the elderly but decreased the odds in younger patients may indicate that blood pressure should be treated differently depending on age.

Use of Distal Intracranial Catheters for Better Working View of Cerebral Aneurysms Hidden by Parent Artery or Its Branches: A Technical Note.

A good working view is critical for safe and successful endovascular treatment of cerebral aneurysms. In a few cases, endovascular treatment of cerebral aneurysms may be challenging due to difficulty in obtaining a proper working view. In this report of 6 cases, we described the advantage of using a distal intracranial catheter (DIC) to achieve better visualization of cerebral aneurysms hidden by a parent artery or its branches. Between September 2017 and January 2021, we treated 390 aneurysms with endovascular techniques. In 6 cases in which it was difficult to obtain a proper working view, the DIC was placed distally close to the aneurysm in order to remove the parent artery projection from the working view and obtain better visualization of the aneurysm. Clinical and procedural outcomes and complications were evaluated. The position of the DIC was above the internal carotid artery siphon in the 6 cases. All aneurysms were successfully embolized. Raymond-Roy class 1 occlusion was achieved in all 4 unruptured aneurysms, while the result was class 2 in the 2 ruptured aneurysms. Placement of the DIC was atraumatic without dissections or significant catheter-induced vasospasm in all patients. Transient dysphasia was seen in 2 cases and transient aphasia in 1. Using this technique, we have found it possible to better visualize the aneurysm sac or neck and thereby treat cases we otherwise would have considered untreatable.

Pre-injury antithrombotic agents predict intracranial hemorrhagic progression, but not worse clinical outcome in severe traumatic brain injury.

BACKGROUND: The incidence of traumatic brain injury (TBI) patients of older age with comorbidities, who are pre-injury treated with antithrombotic agents (antiplatelets and/or anticoagulants), has increased. In this study, our aim was to investigate if pre-injury antithrombotic treatment was associated with worse intracranial hemorrhagic/injury progression and clinical outcome in patients with severe TBI. METHODS: In this retrospective study, including 844 TBI patients treated at our neurointensive care at Uppsala University Hospital, Sweden, 2008-2018, 159 (19%) were pre-injury treated with antithrombotic agents. Demography, admission status, radiology, treatment, and outcome variables were evaluated. Significant intracranial hemorrhagic/injury evolution was defined as hemorrhagic progression seen on the second computed tomography (CT), emergency neurosurgery after the initial CT, or death following the initial CT. RESULTS: Patients with pre-injury antithrombotics were significantly older and with a higher Charlson comorbidity index. They were more often injured by falls and more frequently developed acute subdural hematomas. Sixty-eight (8%) patients were pre-injury treated with monotherapy of antiplatelets, 67 (8%) patients with anticoagulants, and 24 (3%) patients with a combination of antithrombotics. Pre-injury anticoagulants, but not antiplatelets, were independently associated with significant intracranial hemorrhagic/injury evolution in a multiple regression analysis. However, neither anticoagulants nor antiplatelets were associated with mortality and unfavorable outcome in multiple regression analyses. CONCLUSIONS: Only anticoagulants were associated with intracranial hemorrhagic/injury progression, but no antithrombotic agent correlated with worse clinical outcome. Management, including early anticoagulant reversal, availability of emergency neurosurgery, and neurointensive care, may be important aspects for reducing the adverse effects of pre-injury antithrombotics.

Decompressive Craniectomy in Traumatic Brain Injury-Craniectomy-Related and Cranioplasty-Related Complications in a Single Center.

OBJECTIVE: Decompressive craniectomy (DC) relieves intracranial hypertension after severe traumatic brain injury (TBI), but it has been associated with poor clinical outcome in 2 recent randomized controlled trials. In this study, we investigated the incidence and explanatory variables for DC-related and cranioplasty (CP)-related complications after TBI. METHODS: In this retrospective study, we identified 61 patients with TBI who were treated with DC in the neurointensive care unit, Uppsala University Hospital, Sweden, between 2008 and 2018. Demography, admission status, radiology, and clinical outcome were analyzed. RESULTS: Eleven patients (18%) were reoperated because of postoperative hemorrhage after DC. Six (10%) developed postoperative infection during neurointensive care. Twenty-eight (46%) developed subdural hygromas and 10 (16%) received a permanent cerebrospinal fluid shunt. Sixteen patients (26%) died before CP. Median time to CP was 7 months (range, 2-19 months) and 32 (71%) were operated on with autologous bone and 13 (29%) with synthetic material primarily. In 9 patients with autologous bone (29%), the CP had to be replaced because of bone resorption/infection, whereas this did not occur after synthetic material (P = 0.04). However, all 4 postoperative hemorrhages after CP occurred when synthetic material was used (P = 0.005). CONCLUSIONS: DC and CP surgery have a high risk for complications, leading to additional neurosurgery in about one third of cases. Synthetic CP materials may decrease the risk of reoperation, but special care with hemostasis is required because of increased risk of postoperative hemorrhage. Future trials need to address these topics to further improve the outcome for these patients.

Endovascular treatment of type 1 and type 4 non-saccular aneurysms of cerebral arteries - a single-Centre experience.

AIM OF THE STUDY: The aim of this study was to evaluate our results regarding treatment options, complications, and outcomes in patients with non-saccular aneurysms of cerebral arteries belonging to type 1 and type 4 according to Mizutani's classification. METHODS: A total of 26 aneurysms in 26 patients were treated between 2014 and 2019. There were 13 males (mean age 42.77 ± 11.73 years) and 13 females (mean age 50.84 ± 9.37 years). In 23 cases the onset was haemorrhagic and in three cases non-haemorrhagic. A combination of conventional stents and coils was used in 10 cases, conventional stents and flow diverters in three cases, flow diverters and coils in five cases, and flow diverters only were used in eight cases. Radiological results of treatment were assessed after eight months and clinical after one year. RESULTS: In 24 patients, aneurysms were occluded at the end of the follow-up period. An iatrogenic dissection and two haemorrhagic complications were registered. In three cases, parent arteries were occluded due to re-growth of the aneurysm, which caused middle cerebral artery infarction in one case. A favourable clinical outcome was registered in 19, patients, and non-favourable in five. Two patients died in the early postoperative period due to extensive damage to the brain parenchyma caused by initial bleeding. CONCLUSION: Our results indicate that treatment of type 1 and type 4 non-saccular aneurysms with various combination of stents and flow diverters, with or without coils, is promising, although very challenging and technically demanding.

Arterial Oxygenation in Traumatic Brain Injury-Relation to Cerebral Energy Metabolism, Autoregulation, and Clinical Outcome.

BACKGROUND: Ischemic and hypoxic secondary brain insults are common and detrimental in traumatic brain injury (TBI). Treatment aims to maintain an adequate cerebral blood flow with sufficient arterial oxygen content. It has been suggested that arterial hyperoxia may be beneficial to the injured brain to compensate for cerebral ischemia, overcome diffusion barriers, and improve mitochondrial function. In this study, we investigated the relation between arterial oxygen levels and cerebral energy metabolism, pressure autoregulation, and clinical outcome. METHODS: This retrospective study was based on 115 patients with severe TBI treated in the neurointensive care unit, Uppsala university hospital, Sweden, 2008 to 2018. Data from cerebral microdialysis (MD), arterial blood gases, hemodynamics, and intracranial pressure were analyzed the first 10 days post-injury. The first day post-injury was studied in particular. RESULTS: Arterial oxygen levels were higher and with greater variability on the first day post-injury, whereas it was more stable the following 9 days. Normal-to-high mean pO2 was significantly associated with better pressure autoregulation/lower pressure reactivity index (P = .02) and lower cerebral MD-lactate (P = .04) on day 1. Patients with limited cerebral energy metabolic substrate supply (MD-pyruvate below 120 µM) and metabolic disturbances with MD-lactate-/pyruvate ratio (LPR) above 25 had significantly lower arterial oxygen levels than those with limited MD-pyruvate supply and normal MD-LPR (P = .001) this day. Arterial oxygenation was not associated with clinical outcome. CONCLUSIONS: Maintaining a pO2 above 12 kPa and higher may improve oxidative cerebral energy metabolism and pressure autoregulation, particularly in cases of limited energy substrate supply in the early phase of TBI. Evaluating the cerebral energy metabolic profile could yield a better patient selection for hyperoxic treatment in future trials.

Systemic Hyperthermia in Traumatic Brain Injury-Relation to Intracranial Pressure Dynamics, Cerebral Energy Metabolism, and Clinical Outcome.

BACKGROUND: Systemic hyperthermia is common after traumatic brain injury (TBI) and may induce secondary brain injury, although the pathophysiology is not fully understood. In this study, our aim was to determine the incidence and temporal course of hyperthermia after TBI and its relation to intracranial pressure dynamics, cerebral metabolism, and clinical outcomes. MATERIALS AND METHODS: This retrospective study included 115 TBI patients. Data from systemic physiology (body temperature, blood pressure, and arterial glucose), intracranial pressure dynamics (intracranial pressure, cerebral perfusion pressure, compliance, and pressure reactivity), and cerebral microdialysis (glucose, pyruvate, lactate, glycerol, glutamate, and urea) were analyzed during the first 10 days after injury. RESULTS: Overall, 6% of patients did not have hyperthermia (T>38°C) during the first 10 days after injury, whereas 20% had hyperthermia for >50% of the time. Hyperthermia increased from 21% (±27%) of monitoring time on day 1 to 36% (±29%) on days 6 to 10 after injury. In univariate analyses, higher body temperature was not associated with higher intracranial pressure nor lower cerebral perfusion pressure, but was associated with lower cerebral glucose concentration (P=0.001) and higher percentage of lactate-pyruvate ratio>25 (P=0.02) on days 6 to 10 after injury. Higher body temperature and lower arterial glucose concentration were associated with lower cerebral glucose in a multiple linear regression analysis (P=0.02 for both). There was no association between hyperthermia and worse clinical outcomes. CONCLUSION: Hyperthermia was most common between days 6 and 10 following TBI, and associated with disturbances in cerebral energy metabolism but not worse clinical outcome.

Clinical outcome and prognostic factors in elderly traumatic brain injury patients receiving neurointensive care.

BACKGROUND: The probability of favorable outcome after traumatic brain injury (TBI) decreases with age. Elderly, ≥ 60 years, are an increasing part of our population. Recent studies have shown an increase of favorable outcome in elderly over time. However, the optimal patient selection and neurointensive care (NIC) treatments may differ in the elderly and the young. The aims of this study were to examine outcome in a larger group of elderly TBI patients receiving NIC and to identify demographic and treatment related prognostic factors. METHODS: Patients with TBI ≥ 60 years receiving NIC at our department between 2008 and 2014 were included. Demographics, co-morbidity, admission characteristics, and type of treatments were collected. Clinical outcome at around 6 months was assessed. Potential prognostic factors were included in univariate and multivariate regression analysis with favorable outcome as dependent variable. RESULTS: Two hundred twenty patients with mean age 70 years (median 69; range 60-87) were studied. Overall, favorable outcome was 46% (Extended Glasgow Outcome Scale (GOSE) 5-8), unfavorable outcome 27% (GOSE 2-4), and mortality 27% (GOSE 1). Significant independent negative prognostic variables were high age (p < 0.05), multiple injuries (p < 0.05), GCS M ≤ 3 on admission (p < 0.05), and mechanical ventilation (p < 0.001). CONCLUSIONS: Overall, the elderly TBI patients > 60 years receiving modern NIC in this study had a fair chance of favorable outcome without large risks for severe deficits and vegetative state, also in patients over 75 years of age. High age, multiple injuries, GCS M ≤ 3 on admission, and mechanical ventilation proved to be independent negative prognostic factors. The results underline that a selected group of elderly with TBI should have access to NIC.

Decompressive craniectomy in traumatic brain injury: usage and clinical outcome in a single centre.

BACKGROUND: Two randomised controlled trials (RCTs) of decompressive craniectomy (DC) in traumatic brain injury (TBI) have shown poor outcome, but there are considerations of how these protocols relate to real practice. The aims of this study were to evaluate usage and outcome of DC and thiopental in a single centre. METHOD: The study included all TBI patients treated at the neurointensive care unit, Akademiska sjukhuset, Uppsala, Sweden, between 2008 and 2014. Of 609 patients aged 16 years or older, 35 treated with DC and 23 treated with thiopental only were studied in particular. Background variables, intracranial pressure (ICP) measures and global outcome were analysed. RESULTS: Of 35 DC patients, 9 were treated stepwise with thiopental before DC, 9 were treated stepwise with no thiopental before DC and 17 were treated primarily with DC. Six patients received thiopental after DC. For 23 patients, no DC was needed after thiopental. Eighty-eight percent of our DC patients would have qualified for the DECRA study and 38% for the Rescue-ICP trial. Favourable outcome was 44% in patients treated with thiopental before DC, 56% in patients treated with DC without prior thiopental, 29% in patients treated primarily with DC and 52% in patients treated with thiopental with no DC. CONCLUSIONS: The place for DC in TBI management must be evaluated better, and we believe it is important that future RCTs should have clearer and less permissive ICP criteria regarding when thiopental should be followed by DC and DC followed by thiopental.

Promising clinical outcome of elderly with TBI after modern neurointensive care.

BACKGROUND: The increasing number of elderly patients with traumatic brain injury (TBI) leads to specific neurointensive care (NIC) challenges. Therefore, elderly subjects with TBI need to be further studied. In this study we evaluated the demographics, management and outcome of elderly TBI patients receiving modern NIC. METHODS: Patients referred to our NIC unit between 2008 and 2010 were included. Patients were divided in two age groups, elderly (E) ≥65 years and younger (Y) 64-15 years. Parameters studied were the dominant finding on CT scans, neurological motor skills and consciousness, type of monitoring, neurosurgical procedures/treatments and Glasgow Outcome Scale Extended score at 6 months after injury. RESULTS: Sixty-two E (22 %) and 222 Y (78 %) patients were included. Falls were more common in E (81 %) and vehicle accidents were more common in Y patients (37 %). Acute subdural hematoma was significantly more common in E (50 % of cases) compared to Y patients (18 %). Intracranial pressure was monitored in 44 % of E and 57 % of Y patients. Evacuation of significant mass lesions was performed more common in the E group. The NIC mortality was similar in both groups (4-6 %). Favorable outcome was observed in 72 % of Y and 51 % of E patients. At the time of follow-up 25 % of E and 7 % of Y patients had died. CONCLUSIONS: The outcome of elderly patients with TBI was significantly worse than in younger patients, as expected. However, as much as 51 % of the elderly patients showed a favorable outcome after NIC. We believe that these results encourage modern NIC in elderly patients with TBI. We need to study how secondary brain injury mechanisms differ in the older patients and to identify specific outcome predictors for elderly patients with TBI.

Updated periodic evaluation of standardized neurointensive care shows that it is possible to maintain a high level of favorable outcome even with increasing mean age.

BACKGROUND: Periodic evaluation of neurointensive care (NIC) is important. There is a risk that quality of daily care declines and there may also be unrecognized changes in patient characteristics and management. The aim of this work was to investigate the characteristics and outcome for traumatic brain injury (TBI) patients in the period 2008-2009 in comparison with 1996-1997 and to some extent also with earlier periods. METHODS: TBI patients 16-79 years old admitted from 2008 to 2009 were selected for the study. Glasgow Coma Scale Motor score at admission (GCS M), radiology, surgery, and outcome (Glasgow Outcome Extended Scale) were collected from Uppsala Traumatic Brain Injury Register. RESULTS: The study included 148 patients (mean age, 45 years). Patients >60 years old increased from 16 % 1996-1997 to 30 % 2008-2009 (p < 0.01). The proportion of GCS M 4-6 were similar, 92 vs. 93 % (NS). In 1996-1997 patients, 73 % had diffuse injury (Marshall classification) compared to 77 % for the 2008-2009 period (NS). More patients underwent surgery during 2008-2009 (43 %) compared to 1996-1997 (32 %, p < 0.05). Good recovery increased and mortality decreased substantially from 1980-1981 to 1987-1988 and to 1996-1997, but then the results were unchanged in the 2008-2009 period, with 73 % favorable outcome and 11 % mortality. Mortality increased in GCS M 6-4, from 2.8 % in 1996-1997 to 10 % in 2008-2009 (p < 0.05); most of the patients that died had aggravating factors, e.g., high age, malignancy. CONCLUSIONS: A large-proportion favorable outcome was maintained despite that patients >60 years with poorer prognosis doubled, indicating that the quality of NIC has increased or at least is unchanged. More surgery may have contributed to maintaining the large proportion of favorable outcome. For future improvements, more knowledge about TBI management in the elderly is required.

The SHB adapter protein is required for normal maturation of mesoderm during in vitro differentiation of embryonic stem cells.

Definitive mesoderm arises from a bipotent mesendodermal population, and to study processes controlling its development at this stage, embryonic stem (ES) cells can be employed. SHB (Src homology 2 protein in beta-cells) is an adapter protein previously found to be involved in ES cell differentiation to mesoderm. To further study the role of SHB in this context, we have established ES cell lines deficient for one (SHB+/-) or both SHB alleles (SHB-/-). Differentiating embryoid bodies (EBs) derived from these ES cell lines were used for gene expression analysis. Alternatively, EBs were stained for the blood vessel marker CD31. For hematopoietic differentiation, EBs were differentiated in methylcellulose. SHB-/- EBs exhibited delayed down-regulation of the early mesodermal marker Brachyury. Later mesodermal markers relatively specific for the hematopoietic, vascular, and cardiac lineages were expressed at lower levels on day 6 or 8 of differentiation in EBs lacking SHB. The expression of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 was also reduced in SHB-/- EBs. SHB-/- EBs demonstrated impaired blood vessel formation after vascular endothelial growth factor stimulation. In addition, the SHB-/- ES cells formed fewer blood cell colonies than SHB+/+ ES cells. It is concluded that SHB is required for appropriate hematopoietic and vascular differentiation and that delayed down-regulation of Brachyury expression may play a role in this context.