White matter microstructure in chronic moderate-to-severe traumatic brain injury: Impact of acute-phase injury-related variables and associations with outcome measures.

This study examines how injury mechanisms and early neuroimaging and clinical measures impact white matter (WM) fractional anisotropy (FA), mean diffusivity (MD), and tract volumes in the chronic phase of traumatic brain injury (TBI) and how WM integrity in the chronic phase is associated with different outcome measures obtained at the same time. Diffusion tensor imaging (DTI) at 3 T was acquired more than 1 year after TBI in 49 moderate-to-severe-TBI survivors and 50 matched controls. DTI data were analyzed with tract-based spatial statistics and automated tractography. Moderate-to-severe TBI led to widespread FA decreases, MD increases, and tract volume reductions. In severe TBI and in acceleration/deceleration injuries, a specific FA loss was detected. A particular loss of FA was also present in the thalamus and the brainstem in all grades of diffuse axonal injury. Acute-phase Glasgow Coma Scale scores, number of microhemorrhages on T2*, lesion volume on fluid-attenuated inversion recovery, and duration of posttraumatic amnesia were associated with more widespread FA loss and MD increases in chronic TBI. Episodes of cerebral perfusion pressure <70 mmHg were specifically associated with reduced MD. Neither episodes of intracranial pressure >20 mmHg nor acute-phase Rotterdam CT scores were associated with WM changes. Glasgow Outcome Scale Extended scores and performance-based cognitive control functioning were associated with FA and MD changes, but self-reported cognitive control functioning was not. In conclusion, FA loss specifically reflects the primary injury severity and mechanism, whereas FA and MD changes are associated with objective measures of general and cognitive control functioning.

Stereoselective synthesis of protectin D1: a potent anti-inflammatory and proresolving lipid mediator.

A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao's chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material.

Intensive care and traumatic brain injury after the introduction of a treatment protocol: a prospective study.

BACKGROUND: Traumatic brain injury (TBI) treatment protocols have been introduced in the intensive care unit (ICU) to avoid secondary brain injury. In this study, we aimed to evaluate the deviations from such a treatment protocol and the frequency of extracranial complications, and relate these findings to outcome. METHODS: During a 5-year period (2004-2009), 133 patients with severe TBI [Glasgow Coma Scale (GCS) score ≤ 8] were prospectively included. The following deviations from treatment goals were studied: intracranial pressure (ICP), blood pressure, haemoglobin, blood glucose, serum sodium, serum albumin, body temperature and extracranial complications during the ICU stay. Outcome was assessed using Glasgow Outcome Scale Extended score at 12 months. RESULTS: The frequencies of deviations from the treatment goals were: episodes of intracranial hypertension 69.5% (of monitored patients), hypotension 20.3%, anaemia 77.4%, hyperglycaemia 42.9%, hyponatremia 34.6%, hypoalbuminemia 30.8% and hyperthermia 54.9%. Pulmonary complications were common (pneumonia 72.2%, acute respiratory distress syndrome/acute lung injury 31.6%). Thrombocytopenia (4.5%), severe sepsis (3.0%), renal failure (0.8%) and liver failure (0.8%) were infrequent. Twenty-six (19.5%) patients died within the first 12 months due to the head injury. Age, GCS score, pupil dilation, Injury Severity Score (ISS), ICP > 25 mmHg, hyperglycaemia and pneumonia predicted a worse outcome. CONCLUSIONS: Deviations from the TBI treatment protocol were frequent. Pneumonia was the most frequent extracranial complication. Age, GCS score, pupil dilation, ISS, high ICP, hyperglycaemia and pneumonia predicted a worse outcome.

Risk factors for aneurysmal subarachnoid hemorrhage - BMI and serum lipids: 11-year follow-up of the HUNT and the Tromsø Study in Norway.

OBJECTIVES: Life-style factors have been associated with the risk for aneurysmal subarachnoid hemorrhage (aSAH), but it is not clear whether body mass index (BMI) and serum lipids are associated with risk. We prospectively assessed these associations in two large population studies. METHODS: A total of 65,526 participants in the Nord-Trøndelag Health Study (1995-1997) and 26,882 participants in the Tromsø Study (1994-1995) were included. Studies included measurements of body weight and height, serum lipids, and self-administered questionnaires. Participants who experienced aSAH were identified, and hazard ratios (HRs) were estimated using Cox regression analysis. RESULTS: During 11 years of follow-up, aSAH was diagnosed in 122 participants. Overweight (BMI 25-29.9) was negatively associated with the risk of aSAH (HR 0.7, 95% CI 0.4-1.0). There was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH, but in participants younger than 50 years, HDL cholesterol was inversely associated with the risk (HR per standard deviation increase 0.6, 95% CI 0.4-0.9). CONCLUSIONS: Overweight may be associated with reduced risk of aSAH, but there was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH in this prospective study.

Bone loss in relation to serum levels of osteoprotegerin and nuclear factor-kappaB ligand: the Tromsø Study.

SUMMARY: In this longitudinal study of 4,137 persons, bone mineral density was negatively associated with osteoprotegerin at baseline in both genders. In postmenopausal women not using hormone replacement therapy (HRT), bone-loss increased with increasing osteoprotegerin levels, whereas no relationship was found in men, premenopausal women, or postmenopausal women taking HRT. INTRODUCTION: In a population-based study of 2,003 men and 2,134 women, the relationship between the osteoprotegerin (OPG)/factor-kappaB ligand (RANKL) system and bone mineral density (BMD) and changes in BMD was examined. METHODS: Baseline measurements included height, weight, BMD of the forearm, OPG, RANKL, vitamin D, and serum parathyroid hormone (PTH) and information about lifestyle, prevalent diseases, and use of medication. BMD was remeasured at follow-up 6 years later. RESULTS: BMD was negatively associated with OPG at baseline in both men and women (p trend over OPG levels = 0.01 and 0.007, respectively, after adjustments for age, and other confounders). In postmenopausal women not on hormone replacement therapy, bone loss increased with increasing OPG (p = 0.005), whereas no relationship was found in men, premenopausal women, or postmenopausal women on HRT (p >or= 0.28). BMD at baseline and BMD changes were not related to RANKL levels in any of the groups (p >or= 0.14). CONCLUSIONS: In postmenopausal women not using HRT, bone loss associated positively with OPG. The results indicate that in women deficient in sex steroids, the OPG/RANKL system may play an important counter regulatory role in order to avoid bone loss and maintain BMD. In men and women replete in sex steroids, the OPG/RANKL system was not associated with BMD.

Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme.

OBJECTIVES: To study overall survival (OS), prognostic factors, and repeated surgery in glioblastoma multiforme (GBM). MATERIAL AND METHODS: Retrospective study of 516 consecutive adult patients who underwent primary surgery for a GBM in year 2003-2008. RESULTS: Median age at primary surgery was 63.7 years (range 18.0-88.0). Median OS was 9.9 months. Age > 60 years, poor preoperative ECOG score, bilateral tumor, biopsy rather than resection, and no temozolomide chemoradiotherapy were negative risk factors. Repeat surgery was performed in 65 patients (13%). Median time between first and second surgery was 7 months. Indications for second surgery were increasing neurological deficits (35.4%), raised ICP (33.8%), asymptomatic but reoperated because of tumor progression verified on MRI (20.0%), and epileptic seizures (11%). Patients who underwent repeated surgery had longer OS; 18.4 months vs 8.6 months (P < 0.001). CONCLUSIONS: OS for adult GBM patients was 9.9 months. Negative prognostic factors were increasing age, poor neurological function, bilateral tumor involvement, biopsy instead of resection, and RT alone compared to temozolomide chemoradiotherapy. Our rate of repeated surgery for GBM was 13% and the main indications for second surgery were raised ICP and increasing neurological deficits. In a carefully selected group of patients, repeat surgery significantly prolongs OS.

Rapid and severe rise in static and pulsatile intracranial pressures during a generalized epileptic seizure.

In a patient with no prior history of seizures we were able to record static (mean) intracranial pressure (ICP) and pulsatile ICP (mean ICP wave amplitude) continuously during a first-time generalized epileptic seizure. The patient experienced episodic headache five months after a subarachnoid haemorrhage. In order to rule out low-pressure hydrocephalus she was admitted for a 24-hour intracranial pressure registration. ICP parameters were normal prior to the seizure. We observed an immediate and enormous rise in both static (mean) ICP and pulsatile ICP (mean ICP wave amplitude). Mean ICP and ICP wave amplitude peaked at 93 mmHg and 22 mmHg, respectively. Pulsatile ICP remained elevated after normalization of static ICP and may indicate impairment of intracranial compliance even after the static ICP was normalized.

Membrane biology: membrane-regulated transcription.

The activation of membrane-bound transcription factors involves release from the membrane by proteolysis. Recent studies show that, for some proteins, cleavage is performed by the proteasome, whereas others require specific proteases.

Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromsø Study.

UNLABELLED: Essentials Registry-based studies indicate a link between arterial- and venous thromboembolism (VTE). We studied this association in a cohort with confounder information and validated outcomes. Myocardial infarction (MI) was associated with a 4.8-fold increased short-term risk of VTE. MI was associated with a transient increased risk of VTE, and pulmonary embolism in particular. SUMMARY: Background Recent studies have demonstrated an association between venous thromboembolism (VTE) and arterial thrombotic diseases. Objectives To study the association between incident myocardial infarction (MI) and VTE in a prospective population-based cohort. Methods Study participants (n = 29 506) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001-2002, and 2007-2008) and followed up to 2010. All incident MI and VTE events during follow-up were recorded. Cox regression models with age as the time scale and MI as a time-dependent variable were used to calculate hazard ratios (HRs) of VTE adjusted for sex, body mass index, blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity, and education level. Results During a median follow-up of 15.7 years, 1853 participants experienced an MI and 699 experienced a VTE. MI was associated with a 51% increased risk of VTE (HR 1.51; 95% confidence interval [CI] 1.08-2.10) and a 72% increased risk of pulmonary embolism (PE) (HR 1.72; 95% CI 1.07-2.75), but not significantly associated with the risk of deep vein thrombosis (DVT) (HR 1.36; 95% CI 0.86-2.15). The highest risk estimates for PE were observed during the first 6 months after the MI (HR 8.49; 95% CI 4.00-18.77). MI explained 6.2% of the PEs in the population (population attributable risk) and 78.5% of the PE risk in MI patients (attributable risk). Conclusions Our findings indicate that MI is associated with a transient increased VTE risk, independently of traditional atherosclerotic risk factors. The risk estimates were particularly high for PE.

Advantages of total androgen blockade in the treatment of advanced prostate cancer.

Total androgen blockade has been proposed as a better therapeutic technique than castration alone for the management of metastatic prostate cancer. This is based on the theory that links adrenal androgens to tumor growth. We have carefully examined the role of adrenal androgens in prostate cancer. Work done in our laboratory, as well as the work of many others, has demonstrated the following in regard to the role of adrenal androgens in prostate cancer: (1) The adrenal cortex secretes significant amounts of adrenal androgens into the blood. (2) Adrenal androgens are converted into dihydrotestosterone (DHT), as indicated by studies of labeled DHT recovered from prostates resected one-half hour after infusion of 3H-androstenedione or 3H-dehydroepiandrosterone sulfate into patients. We have also shown that biopsies of prostates from patients who were previously castrated may contain significant amounts of DHT, which could only be derived from adrenal androgens. (3) We have quantified DHT derived from adrenal androgens by measuring prostate DHT concentrations in castrates and in patients treated with combined gonadal and adrenal blockade. The mean difference between these two groups, 0.32 ng/g of DHT lower with combined blockade, is statistically significant and represents DHT derived from adrenal androgens. (4) We have also demonstrated that the small amounts of DHT derived from adrenal androgens may be biologically significant in stimulating prostatic epithelial cell protein synthesis in humans; others have reported similar findings in animals. (5) A review of patients in relapse after castration, who are treated with adrenal androgen blockade, indicates that approximately one out of three patients will show an objective remission based on National Prostate Cancer Project (NPCP) criteria. Despite data supporting the importance of adrenal androgens in prostate cancer, clinical trials using combined adrenal and gonadal blockade in prostate cancer have shown only modest benefit over castration. The largest and best study to date is the Southwest Oncology Group (SWOG) study, which did show a near-significant (P less than 0.065) difference between patients treated for 20 months with a luteinizing hormone-releasing hormone (LH-RH) plus flutamide compared with LH-RH alone. The difference in median time to progression was approximately 2 months between the groups. However, when one considers the fact that two out of three patients are probably not responding to the total androgen blockade, the 2 month difference may actually represent 6 or more months in a subset of one-third of patients receiving that therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of aminophylline on transpulmonary passage of venous air emboli in pigs.

Aminophylline has been shown to dramatically reduce the filtering capacity of the lung in dogs during venous air embolism. Similarities have been pointed out between the cardiovascular and respiratory systems of the pig and of humans. We therefore wanted to find out whether aminophylline also modifies the transpulmonary spillover of microbubbles to the arterial circulation of the pig. Twenty-eight pigs were anesthetized with pentobarbital sodium and mechanically ventilated. Aminophylline was injected intravenously into 10 of the pigs before the introduction of air bubbles into the right ventricle, while the other 18 pigs served as controls. A transesophageal echocardiographic probe was used to detect eventual air bubbles in the left atrium or in the aorta. Pigs received either air infusion, at rates varying from 0.05 to 0.20 ml.kg-1.min-1, or calibrated microbubbles, 5-300 microns diam. We found that aminophylline-treated pigs did not show any change in spillover incidence compared with controls. Furthermore, in both groups the spillover during continuous air infusion seemed to be a preterminal event, because the pigs had very low arterial pressure when arterial bubbles were observed. Finally, there was an increase in mean pulmonary arterial pressure from 18 +/- 3.4 to 26 +/- 2.2 (SD) mmHg (n = 4, P less than 0.01) in aminophylline-treated pigs after a bolus injection of microbubbles (less than or equal to 50 microns, total volume less than 0.5 ml). Our results suggest that aminophylline does not modify the transpulmonary passage of microbubbles in this porcine model. In addition, it would seem that the pulmonary circulation of the pig is sensitive to very small volumes of air, when injected as microbubbles.

Venous air embolism in swine: transport of gas bubbles through the pulmonary circulation.

The assumption that the lung is an effective filter for gas bubbles is of importance for certain occupations (e.g., divers, astronauts) as well as in the accomplishment of several medical procedures. The filtering capacity was tested in pigs by use of continuous air infusion into the right ventricle and a transesophageal echocardiographic transducer for detection of air in the left atrium. Twenty pigs, anesthetized with pentobarbital sodium and mechanically ventilated, were divided into groups that received air at infusion rates of 0.05 (group 1a, n = 7), 0.10 (group 2, n = 6), and 0.20 (group 3, n = 5) ml.kg-1.min-1. Two pigs served as controls. The breakthrough incidence was 0, 67, and 100%, respectively. Group 1a received a second infusion of 0.10 ml.kg-1.min-1 (group 1b, n = 7), and spillover of bubbles occurred in only 14% of these pigs. Infusion of gas caused a maximum increase in mean pulmonary arterial pressure (PAP) of 129 +/- 9% to 39.2 +/- 1.3 (SE) mmHg, with no significant difference between the groups. Breakthrough was observed only in animals with a dramatic reduction in mean arterial pressure and a PAP that returned to almost-normal values at spillover time. Our results suggest that the threshold value for breakthrough of air bubbles in pigs is reduced compared with that in dogs. The hemodynamic consequences at a given infusion rate are, however, greatly enhanced.

Low-grade non-Hodgkin's lymphoma in northern Norway: treatment, outcome, and prognostic factors.

AIM: All low-grade non-Hodgkin's lymphoma (LG-NHL) patients diagnosed and/or treated at our institution over a 10 year period were investigated with regard to treatment outcome and possible pre-treatment prognostic factors. PATIENTS AND METHODS: During the period 1986-1995, 169 consecutively registered patients with LG-NHL were retrospectively analyzed with regard to personal, treatment, and disease- specific characteristics. The median follow-up time was 52 months (5-132 months). All patients were diagnosed histologically according to the Keil classification system. Median age was 60 years (range 27-87 years), and the male:female ratio was 1.05: 1. RESULTS: The overall response rate was 77%, of which 66% were complete response (CR) and 11% partial response (PR). 5- and 10-year overall survival were 72% and 47%, respectively, and median overall survival was 8.3 years. 10-year overall survival for stage I, II, III, and IV were 86%, 65%, 33%, and 29%, respectively. For follicular lymphoma, 10-year survival was 52% and median survival 12.5 years. In univariate analysis, the following pre-treatment factors indicated a poor prognosis: advanced stage, general symptoms, bone marrow infiltration, poor performance status, tumor > or = 6 cm, low serum albumin, anaemia, and LDH > or = 540 U/l. In multivariate analysis, stage, performance status, tumor size, and anaemia were found to be independent prognostic factors for overall survival. CONCLUSIONS: The treatment strategy has proved successful for most patients with localised disease. Independent prognostic indicators for survival as stage, performance status, tumor size, and anaemia may be useful guides in deciding when and how to treat.

Effects of treatment with Pluronic F-68 during continuous venous air embolism in swine.

Treatment with the surface-active agent Pluronic F-68, shown to modulate the hemodynamic effects of venous air emboli (VAE) in dogs, may be useful for treatment of VAE in divers. We report on the effects of injections of Pluronic F-68 on responses to continuous air infusion in swine. Pretreatment made no significant difference in any hemodynamic or ventilatory variables, but the rise of pulmonary vascular resistance caused by air infusion was greater in surfactant-treated animals; this was also evident after a second treatment during the air infusion. The small effect of surfactant treatment in our study on swine contrasts the effects reported previously in dogs, and could be due to species-specific differences in lung physiology-anatomy, or due to difference in experimental design. We speculate that the minor changes we observed were caused by deeper penetration of the bubbles into the pulmonary arterial tree after surfactant treatment.

Arterial gas bubbles after decompression in pigs with patent foramen ovale.

With patent foramen ovale (PFO), thought to be a risk factor for some forms of DCS, venous bubbles may pass through the patent opening to become arterial bubbles. We exposed 14 anesthetized, spontaneously breathing pigs to air at 5 bar (500 kPa, absolute pressure) for 30 min and then rapidly decompressed at 2 bar/min to 1 bar. We measured intravascular pressures, blood gases, and, with transesophageal echocardiology, bubbles in the pulmonary artery and ascending aorta. Autopsy showed that six of the pigs had a PFO. Arterial bubbles occurred more frequently in the PFO group (in six out of six) than in the non-PFO group (in two out of eight, P < 0.01). When arterial bubbles were detected, the venous bubble count and the pulmonary artery pressure tended to be lower in pigs with PFO than in pigs without a PFO. We conclude that a PFO increases the risk of arterial bubbles after decompression.

Relationship between venous bubbles and hemodynamic responses after decompression in pigs.

We present a new pig model for studying relationships between venous gas bubbles and physiologic effects during and after decompression. Sixteen pigs were anesthetized to allow spontaneous breathing. Eight of them underwent a 30-min exposure to 5 bar (500 kPa) followed by a rapid decompression to 1 bar (2 bar/min); the remaining eight served as controls. The pigs were monitored for intravascular bubbles using a transesophageal echocardiographic transducer, and bubble count in the two-dimensional ultrasound image of the pulmonary artery was used as a measure of the number of venous gas bubbles. Effects on physiologic variables of the pulmonary and the systemic circulations were either measured or estimated. We detected venous bubbles in all pigs after decompression, but the interindividual variation was large. The time course of changes in the mean pulmonary artery pressure, in the pulmonary vascular resistance, in the arterial oxygen tension, and in the pulmonary shunt fraction followed the time course of the bubble count. In contrast, such a relationship to the number of venous gas bubbles was not found for the immediate increase in mean arterial pressure and for the changes in the other variables of the systemic circulation. We conclude that the number of venous gas bubbles, as evaluated by the bubble count in the ultrasound image of the pulmonary artery, is clearly related to changes in the variables of the pulmonary circulation in this pig model.

Serum levels of vitamin D are not associated with future risk of venous thromboembolism. The Tromsø Study.

Previous studies have provided indirect evidence for a possible association between vitamin D status and risk of venous thromboembolism (VTE). However, no study has so far investigated the association between serum levels of 25-hydroxyvitamin D (25(OH)D), the biomarker of vitamin D status, and risk of VTE. The aim of our study was to investigate whether high levels of 25(OH)D were associated with decreased risk of VTE in a prospective population-based study. Serum levels of 25(OH)D were measured in 6,021 men and women, aged 25-84 years, who participated in the Tromsø Study in 1994-1995. Incident VTE-events were registered from date of inclusion through the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) for VTE. There were 201 incident VTE-events during a median of 10.7 years of follow-up. The risk of VTE did not decrease per one standard deviation (SD) (19.8 nmol/l) increase in serum 25(OH)D (multivariable HR 1.02; 95% CI 0.91-1.22). Moreover, subjects with serum 25(OH)D ≥ 70 nmol/l (upper quartile) did not have decreased risk of VTE compared to those ≤ 44 nmol/l (lower quartile) in age- and sex-adjusted analysis (HR 0.91, 95% CI: 0.60-1.37, p for trend across quartiles 0.9) or multivariable analysis adjusted for age, sex, body mass index, smoking, and physical activity (HR 0.76, 95% CI: 0.45-1.28, p for trend across quartiles 0.9). Subgroup analyses showed no associations between serum levels of 25(OH)D and unprovoked or provoked VTE. In conclusion, in our study, normal serum levels of 25(OH)D were not associated with future risk of VTE, suggesting that vitamin D status does not play an important role in the pathogenesis of VTE. However, our findings did not apply to subjects with vitamin D deficiency (< 30 nmol/l) due to lack of statistical power among these subjects.

Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromsø Study.

BACKGROUND: Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis. OBJECTIVE: To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population. PATIENTS/METHODS: OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromsø Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow-up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI). RESULTS: There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of follow-up. Serum OPG (per SD [1.13 ng mL(-1)] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11-1.31), ischemic stroke (1.32; 1.18-1.47), total mortality (1.34; 1.26-1.42), death because of ischemic heart disease, (1.35; 1.18-1.54), stroke (1.44; 1.19-1.75) and non-vascular causes (1.31; 1.22-1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C-reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73-1.43). CONCLUSIONS: Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non-vascular causes independent of traditional cardiovascular risk factors.

Sex differences in risk factors for aneurysmal subarachnoid hemorrhage: a cohort study.

OBJECTIVE: The purpose of this study was to investigate sex differences in the major established risk factors for aneurysmal subarachnoid hemorrhage (aSAH) in a large, population-based cohort. METHODS: Sex differences in the established risk factors for aSAH (smoking, hypertension, and alcohol consumption) were examined in a prospective, population-based cohort consisting of 92,462 participants of the Nord-Trøndelag and the Tromsø Health Studies in Norway. RESULTS: We identified 120 cases of aSAH during 1,002,148 person-years at risk. Compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men (hazard ratio = 8.9, 95% confidence interval [CI] 4.7-17.0 vs hazard ratio = 2.8, 95% CI 1.3-6.1, after adjustment for age and alcohol consumption). The interaction between sex and current smoking was present on an additive scale (relative excess risk due to interaction 3.1, 95% CI 0.5-5.8), indicating a higher risk of aSAH associated with current cigarette smoking in women than in men. No sex differences in the risk of aSAH were observed with respect to hypertension or alcohol consumption. CONCLUSIONS: This prospective, population-based cohort study showed that compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men. This finding may at least partially explain the gender gap in aSAH incidence. A more intensive smoking cessation intervention should be considered in women at risk of aSAH.

Incidence and mortality of aneurysmal subarachnoid hemorrhage in two Norwegian cohorts, 1984-2007.

OBJECTIVE: The incidence of aneurysmal subarachnoid hemorrhage (aSAH) ranges from 4 to 10 per 100,000 person-years in most countries, and 30-day case fatality is high. The aim of this study was to estimate the incidence and case fatality of aSAH and to assess preictal predictors of survival in 2 large Norwegian population-based cohort studies. METHODS: A total of 94,976 adults (≥20 years) in the Nord-Trøndelag Health Study and 31,753 participants (aged ≥20 years) in the Tromsø Study were included. During follow-up, aSAHs were identified, incidence rates were estimated, and predictors of survival were assessed using Cox and Poisson regression analysis. RESULTS: A total of 214 patients with aSAH were identified during 2,077,927 person-years of follow-up from 1984 to 2007. The incidence rate was 10.3 per 100,000 person-years: 13.3 for women and 7.1 for men. The incidence increased by 2% (95% confidence interval [CI] 0-4) per 5-year time period. Case fatality at 3, 7, and 30 days was 20%, 24%, and 36%. Thirty-day case fatality remained stable during follow-up (odds ratio 1.01, 95% CI 0.97-1.06 per year). Never smokers had poorer survival after aSAH than current and former smokers combined (hazard ratio 1.6, 95% CI 0.9-2.9). CONCLUSIONS: The slight increase in incidence of aSAH over time may be explained by differences in diagnostic procedures. Case fatality remained stable during 23 years of follow-up.