Burr-hole drainage with or without irrigation for chronic subdural haematoma (FINISH): a Finnish, nationwide, parallel-group, multicentre, randomised, controlled, non-inferiority trial.

BACKGROUND: Chronic subdural haematoma is a common surgically treated intracranial emergency. Burr-hole drainage surgery, to evacuate chronic subdural haematoma, involves three elements: creation of a burr hole for access, irrigation of the subdural space, and insertion of a subdural drain. Although the subdural drain has been established as beneficial, the therapeutic effect of subdural irrigation has not been addressed. METHODS: The FINISH trial was an investigator-initiated, pragmatic, multicentre, nationwide, randomised, controlled, parallel-group, non-inferiority trial in five neurosurgical units in Finland that enrolled adults aged 18 years or older with a chronic subdural haematoma requiring burr-hole drainage. Patients were randomly assigned (1:1) by computer-generated block randomisation with block sizes of four, six, or eight, stratified by site, to burr-hole drainage either with or without subdural irrigation. All patients and staff were masked to treatment assignment apart from the neurosurgeon and operating room staff. A burr hole was drilled at the site of maximum haematoma thickness in both groups, and the subdural space was either irrigated or not irrigated before inserting a subdural drain, which remained in place for 48 h. Reoperations, functional outcome, mortality, and adverse events were recorded for 6 months after surgery. The primary outcome was the reoperation rate within 6 months. The non-inferiority margin was set at 7·5%. Key secondary outcomes that were also required to conclude non-inferiority were the proportion of participants with unfavourable functional outcomes (ie, modified Rankin Scale score of 4-6, where 0 indicates no symptoms and 6 indicates death) and mortality rate at 6 months. The primary and key secondary analyses were done in both the intention-to-treat and per-protocol populations. The trial was registered with ClinicalTrials.gov (NCT04203550) and is completed. FINDINGS: From Jan 1, 2020, to Aug 17, 2022, we assessed 1644 patients for eligibility and 589 (36%) patients were randomly assigned to a treatment group and treated (294 assigned to drainage with irrigation and 295 assigned to drainage without irrigation; 165 [28%] women and 424 [72%] men). The 6-month follow-up period extended until Feb 14, 2023. In the intention-to-treat analysis, 54 (18·3%) of 295 participants required reoperation in the group assigned to receive no irrigation versus 37 (12·6%) of 294 in the group assigned to receive irrigation (difference of 6·0 percentage points, 95% CI 0·2-11·7; p=0·30; adjusted for study site). There were no significant between-group differences in the proportion of people with modified Rankin Scale score of 4-6 (37 [13·1%] of 283 in the no-irrigation group vs 36 [12·6%] of 285 in the irrigation group; p=0·89) or mortality rate (18 [6·1%] of 295 in the no-irrigation group vs 21 [7·1%] of 294 in the irrigation group; p=0·58). The findings of the primary intention-to-treat analysis were not materially altered in the per-protocol analysis. There were no significant between-group differences in the number of adverse events, and the most frequent severe adverse events were systemic infections (26 [8·8%] of 295 participants who did not receive irrigation vs 22 [7·5%] of 294 participants who received irrigation), intracranial haemorrhage (13 [4·4%] vs seven [2·4%]), and epileptic seizures (five [1·7%] vs nine [3·1%]). INTERPRETATION: We could not conclude non-inferiority of burr-hole drainage without irrigation. The reoperation rate was 6·0 percentage points higher after burr-hole drainage without subdural irrigation than with subdural irrigation. Considering that there were no differences in functional outcome or mortality between the groups, the trial favours the use of subdural irrigation. FUNDING: State Fund for University Level Health Research (Helsinki University Hospital), Finska Läkaresällskapet, Medicinska Understödsföreningen Liv och Hälsa, and Svenska Kulturfonden.

Favourable long-term recovery after decompressive craniectomy: the Northern Finland experience with a predominantly adolescent patient cohort.

PURPOSE: Decompressive craniectomy (DC) is an effective treatment of intracranial hypertension. Correspondingly, the procedure is increasingly utilised worldwide. The number of patients rendered vegetative following surgery has been a concern-a matter especially important in children, due to long anticipated lifetime. Here, we report the long-term outcomes of all paediatric DC patients from an 11-year period in a tertiary-level centre that geographically serves half of Finland. METHODS: We identified all patients younger than 18 years who underwent DC in the Oulu University Hospital between the years 2009 and 2019. Outcomes and clinicoradiological variables were extracted from the patient records. RESULTS: Mean yearly prevalence of brain injury requiring DC was 1.34/100 000 children-twenty-four patients underwent DC during the study period and 21 (88%) survived. The median age of the patients was 16.0 years, and the median preoperative GCS was 5.0 (IQR 5.0). Fifteen patients (63%) had made a good recovery (Extended Glasgow Outcome Scale ≥ 7). Of the surviving patients, two (9.5%) had not returned to school. After traumatic brain injury (n = 20), the Rotterdam CT score (mean 3.0, range 1 to 5) was not associated with mortality, poor recovery or inability to continue school (p = 0.13, p = 0.41, p = 0.43, respectively). Absent basal cisterns were associated with mortality (p = 0.005), but not with poor recovery if the patient survived DC (p = 0.81). Hydrocephalus was associated with poor recovery and inability to continue school (p = 0.01 and p = 0.03, respectively). CONCLUSION: Most of our patients made a favourable recovery and were able to continue school. No late mortality was observed. Thus, even in clinically and radiologically severely brain-injured children, decompressive craniectomy appears to yield favourable outcomes.

Physiological instability is linked to mortality in primary central nervous system lymphoma: A case-control fMRI study.

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREGBOLD ) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age-matched controls (median 63y; 73% females) were scanned for MREGBOLD signal during 2018-2021. Motion effects were removed. Voxel-by-voxel Coefficient of Variation (CV) maps of MREGBOLD signal was calculated to examine the stability of physiological brain pulsations. Group-level differences in CV were examined using nonparametric covariate-adjusted tests. Subject-level CV alterations were examined against control population Z-score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast-enhanced, diffusion-weighted, fluid-attenuated inversion recovery (FLAIR) data]. Whole-brain mean CV was linked to short-term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 105 mm3 ) extended spatially beyond FLAIR lesions (median 0.62 × 105 mm3 ) with differences in volumes (p = .0055).

Cerebrovascular disease at young age is related to mother's health during the pregnancy-The Northern Finland Birth Cohort 1966 study.

BACKGROUND AND PURPOSE: For prevention of cerebrovascular diseases at younger age, it is important to understand the risk factors occurring early in life. We investigated the relationship between mothers' general health during pregnancy and the offspring's risk of cerebrovascular disease in age of 15 to 52 years. METHODS: Within the population-based prospective Northern Finland Birth Cohort 1966, 11,926 persons were followed from antenatal period to 52 years of age. Information on their mother's ill health conditions, i.e., hospitalizations, chronic diseases, medications, vitamin or iron supplement, fever, anemia, mood, and smoking was collected from 24th gestational week onwards. Ischemic and hemorrhagic cerebrovascular diseases of the offspring were identified from national registers in Finland. Cox proportional hazard models were used to estimate the association of mother's health conditions with incidence of cerebrovascular disease in the offspring, with adjustments for potential confounders. RESULTS: During 565,585 person-years of follow-up, 449 (2.8%) of the offspring had a cerebrovascular disease. Hospitalization during pregnancy was associated with an increased risk of cerebrovascular disease in the offspring (hazard ratio (HR) = 1.49; 95% confidence interval (CI) 1.06-2.08) after adjustment for confounders, as was having more than three ill health conditions (HR = 1.89; CI 1.14-3.11). Not using vitamin or iron supplement was associated with increased risk for cerebrovascular disease in the offspring (HR = 1.39; CI 1.01-1.89). CONCLUSIONS: The results suggest that the risk of cerebrovascular disease may start as early as during the antenatal period, and the health characteristics of mothers during pregnancy may play a role in cerebrovascular disease risk of the offspring.

Two-center validation of the Oulu resorption score for bone flap resorption after autologous cranioplasty.

OBJECTIVE: Autologous bone has been the gold standard of cranioplasty materials for decades. Unique to autologous cranioplasty, bone flap resorption is a poorly understood and unclearly defined complication. Even further, it has been unclear, whether the resorption process eventually stabilizes over time. Thus, the sufficient follow-up period after autologous cranioplasty is unknown. The Oulu Resorption Score (ORS) is a straight-forward classification system for the radiological interpretation of bone flap resorption. The aims of the present study were to evaluate the reliability of the ORS using intra-class correlation coefficient (ICC) and to assess the temporal progression of the resorption process. METHODS: We identified 108 consecutive autologous cranioplasty patients treated between 2005 and 2018 in two tertiary referral centers. All 365 head CT scans the patients had undergone were evaluated using the ORS in a blinded, independent two-center setting. Intra- and inter-observer reliabilities were calculated. The ORS was applied to study the temporal progression of the resorption process. RESULTS: The intra-observer reliability of the ORS was excellent (ICC 0.94, 95%CI 0.93-0.95). Inter-observer reliability was good-to-excellent (ICCs 0.87 and 0.89, 95%CIs 0.84-0.89 and 0.87-0.91, respectively). In scatterplot smoothing analyses, the progression of bone flap resorption appeared to stabilize 12-24 months after cranioplasty. CONCLUSIONS: ORS is the only validated radiological tool for the standardized analysis of bone flap resorption after autologous cranioplasty. Evaluated using the ORS, the resorption process seemed to stabilize during the first two postoperative years after cranioplasty, suggesting that the sufficient follow-up time after autologous cranioplasty is two years.

Long-term survival after primary intracerebral hemorrhage: A population-based case-control study spanning a quarter of a century.

BACKGROUND AND PURPOSE: The aim of this study was to determine the differences in life expectancy and causes of death after primary intracerebral hemorrhage (ICH) relative to general population controls. METHODS: In a population-based setting, 963 patients from Northern Ostrobothnia who had their first-ever ICH between 1993 and 2008 were compared with a cohort of 2884 sex- and age-matched controls in terms of dates and causes of death as extracted from the Causes of Death Register kept by Statistics Finland and valid up to the end of 2017. RESULTS: Of our 963 patients, 781 died during the follow-up time (mortality 81.1%). Cerebrovascular disease was the most common cause of death for these patients, 37.3% compared with 8.2% amongst the controls. The most common reasons for cerebrovascular mortality in the ICH patients were late sequelae of ICH in 12.8% (controls 0%) and new bleeding in 10.6% (controls 1.0%). The long-term survivors had a smaller ICH volume (median 12 ml) than those patients who died within 3 months (median 39 ml). The mortality rate of ICH patients during a follow-up between 12 and 24 years was still higher than that of their controls (hazard ratio 2.08, 95% confidence interval 1.58-2.74, p < 0.001). CONCLUSIONS: Very long-term ICH survivors have a constant excess mortality relative to controls even 10 years after the index event. A significantly larger proportion of patients died of cerebrovascular causes and fewer because of cancer relative to the controls.

Increased mortality after post-stroke epilepsy following primary intracerebral hemorrhage.

OBJECTIVES: This study aimed to determine whether post-stroke epilepsy (PSE) predicts mortality, and to describe the most prominent causes of death (COD) in a long-term follow-up after primary intracerebral hemorrhage (ICH). METHODS: We followed 3-month survivors of a population-based cohort of primary ICH patients in Northern Ostrobothnia, Finland, for a median of 8.8 years. Mortality and CODs were compared between those who developed PSE and those who did not. PSE was defined according to the ILAE guidelines. CODs were extracted from death certificates (Statistics Finland). RESULTS: Of 961 patients, 611 survived for 3 months. 409 (66.9%) had died by the end of the follow-up. Pneumonia was the only COD that was significantly more common among the patients with PSE (56% vs. 37% of deaths). In the multivariable models, PSE (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.06-1.87), age (HR 1.07, 95% CI 1.06-1.08), male sex (HR 1.35, 95% CI 1.09-1.67), dependency at 3 months (HR 1.52, 95% CI 1.24-1.88), non-subcortical ICH location (subcortical location HR 0.78, 95% CI 0.61-0.99), diabetes (HR 1.43, 95% CI 1.07-1.90) and cancer (HR 1.45, 95% CI 1.06-1.98) predicted death in the long-term follow-up. CONCLUSION: PSE independently predicted higher late morality of ICH in our cohort. Pneumonia-related deaths were more common among the patients with PSE.

Finnish study of intraoperative irrigation versus drain alone after evacuation of chronic subdural haematoma (FINISH): a study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Chronic subdural haematomas (CSDHs) are one of the most common neurosurgical conditions. The goal of surgery is to alleviate symptoms and minimise the risk of symptomatic recurrences. In the past, reoperation rates as high as 20%-30% were described for CSDH recurrences. However, following the introduction of subdural drainage, reoperation rates dropped to approximately 10%. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and placement of subdural drainage. Yet, the role of intraoperative irrigation has not been established. If there is no difference in recurrence rates between intraoperative irrigation and no irrigation, CSDH surgery could be carried out faster and more safely by omitting the step of irrigation. The aim of this multicentre randomised controlled trial is to study whether no intraoperative irrigation and subdural drainage results in non-inferior outcome compared with intraoperative irrigation and subdural drainage following burr-hole craniostomy of CSDH. METHODS AND ANALYSIS: This is a prospective, randomised, controlled, parallel group, non-inferiority multicentre trial comparing single burr-hole evacuation of CSDH with intraoperative irrigation and evacuation of CSDH without irrigation. In both groups, a passive subdural drain is used for 48 hours as a standard of treatment. The primary outcome is symptomatic CSDH recurrence requiring reoperation within 6 months. The predefined non-inferiority margin for the primary outcome is 7.5%. To achieve a 2.5% level of significance and 80% power, we will randomise 270 patients per group. Secondary outcomes include modified Rankin Scale, rate of mortality, duration of operation, length of hospital stay, adverse events and change in volume of CSDH. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of the Helsinki and Uusimaa Hospital District (HUS/3035/2019 §238) and duly registered at ClinicalTrials.gov. We will disseminate the findings of this study through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04203550.

Predictors of primary autograft cranioplasty survival and resorption after craniectomy.

OBJECTIVECraniectomy is a common neurosurgical procedure that reduces intracranial pressure, but survival necessitates cranioplasty at a later stage, after recovery from the primary insult. Complications such as infection and resorption of the autologous bone flap are common. The risk factors for complications and subsequent bone flap removal are unclear. The aim of this multicenter, retrospective study was to evaluate the factors affecting the outcome of primary autologous cranioplasty, with special emphasis on bone flap resorption.METHODSThe authors identified all patients who underwent primary autologous cranioplasty at 3 tertiary-level university hospitals between 2002 and 2015. Patients underwent follow-up until bone flap removal, death, or December 31, 2015.RESULTSThe cohort comprised 207 patients with a mean follow-up period of 3.7 years (SD 2.7 years). The overall complication rate was 39.6% (82/207), the bone flap removal rate was 19.3% (40/207), and 11 patients (5.3%) died during the follow-up period. Smoking (OR 3.23, 95% CI 1.50-6.95; p = 0.003) and age younger than 45 years (OR 2.29, 95% CI 1.07-4.89; p = 0.032) were found to independently predict subsequent autograft removal, while age younger than 30 years was found to independently predict clinically relevant bone flap resorption (OR 4.59, 95% CI 1.15-18.34; p = 0.03). The interval between craniectomy and cranioplasty was not found to predict either bone flap removal or resorption.CONCLUSIONSIn this large, multicenter cohort of patients with autologous cranioplasty, smoking and younger age predicted complications leading to bone flap removal. Very young age predicted bone flap resorption. The authors recommend that physicians extensively inform their patients of the pronounced risks of smoking before cranioplasty.

Quantitative and qualitative analysis of bone flap resorption in patients undergoing cranioplasty after decompressive craniectomy.

OBJECTIVE: Autologous bone cranioplasty after decompressive craniectomy entails a notable burden of difficult postoperative complications, such as infection and bone flap resorption (BFR), leading to mechanical failure. The prevalence and significance of asymptomatic BFR is currently unclear. The aim of this study was to radiologically monitor the long-term bone flap survival and bone quality change in patients undergoing autologous cranioplasty. METHODS: The authors identified all 45 patients who underwent autologous cranioplasty at Oulu University Hospital, Finland, between January 2004 and December 2014. Using perioperative and follow-up CT scans, the volumes and radiodensities of the intact bone flap prior to surgery and at follow-up were calculated. Relative changes in bone flap volume and radiodensity were then determined to assess cranioplasty survival. Sufficient CT scans were obtainable from 41 (91.1%) of the 45 patients. RESULTS: The 41 patients were followed up for a median duration of 3.79 years (25th and 75th percentiles = 1.55 and 6.66). Thirty-seven (90.2%) of the 41 patients had some degree of BFR and 13 (31.7%) had a remaining bone flap volume of less than 80%. Patients younger than 30 years of age had a mean decrease of 15.8% in bone flap volume compared with the rest of the cohort. Bone flap volume was not found to decrease linearly with the passing of time, however. The effects of lifestyle factors and comorbidities on BFR were nonsignificant. CONCLUSIONS: In this study BFR was a very common phenomenon, occurring at least to some degree in 90% of the patients. Decreases in bone volume were especially prominent in patients younger than 30 years of age. Because the progression of resorption during follow-up was nonlinear, routine follow-up CT scans appear unnecessary in monitoring the progression of BFR; instead, clinical follow-up with mechanical stability assessment is advised. Partial resorption is most likely a normal physiological phenomenon during the bone revitalization process.

Risk for All-cause and Traumatic Death in Head Trauma Subjects: A Prospective Population-based Case-control Follow-up Study.

OBJECTIVE: To investigate long-term mortality for subjects with acute head trauma. BACKGROUND: It is not known why long-term mortality after head trauma without traumatic brain injury is elevated. METHODS: All subjects admitted to Oulu University Hospital emergency room in 1999 with an acute head trauma (n = 737) were followed up until February 2014 and compared with age and sex-matched general population controls (n = 2196). Dates and causes of death were obtained from the official Cause-of-Death Statistics. Cox proportional hazard regression models and Kaplan-Meier survival curves were used to identify predictors for alcohol-related, nonalcohol-related, and all-cause death. RESULTS: Alcohol-related deaths were more frequent among the subjects with head trauma (27.8%) than among the population controls (6.9%). Head trauma with or without traumatic brain injury (TBI) shortened mean life expectancy by 8.7 years and by as much as 13 years if only those without TBI were considered. The risk of alcohol-related death was 7-fold (hazard ratio 6.79; 95% confidence interval, 3.94-11.71) among subjects without TBI as compared with general population. Of all future deaths among these cases 17.1% were because of a new trauma, a significantly higher frequency (P < 0.005) than that observed in the general population (3% of all deaths). Alcohol-related cause of death was significantly more common among the subjects who were under the influence of alcohol at the time of the index trauma than among the sober subjects. CONCLUSIONS: Head trauma subjects without TBI have an elevated risk of alcohol-related death. Alcohol-related traumas are a major cause of death among these subjects.

Immediate, early and late seizures after primary intracerebral hemorrhage.

BACKGROUND: Seizures after primary intracerebral hemorrhage (PICH) are significant and treatable complications, but the factors predicting immediate, early and late seizures are poorly known. We investigated characteristics and outcome with special reference to occurrence and timing of a first seizure among consecutive subjects with PICH. METHODS: A population-based study was conducted in Northern Ostrobothnia, Finland, in 1993-2008 that included all patients with a first-ever primary ICH without any prior diagnosis of epilepsy. Immediate (<24h after admission), early (1-14 days) and late (>2 weeks) seizures were considered separately. RESULTS: Out of a total of 935 ICH patients, 51 had immediate, 21 early and 58 late seizures. The patients with seizures were significantly younger than the others and more often had a subcortical hematoma location (p<0.05). Lifestyle factors did not differ between the groups. The risk factors for immediate seizures in multivariable analysis were a low Glasgow coma scale score (GCS) on admission, subcortical location and age inversely (p<0.01). The only independent risk factor for early seizures was subcortical location (p<0.001), whereas subcortical location (p<0.001), age inversely (p<0.01) and hematoma evacuation (p<0.05) independently predicted late seizures. Immediate and early seizures predicted infectious complications (p<0.05). CONCLUSIONS: Patients with subcortical hematoma and of younger age are at risk for immediate seizures after primary ICH irrespective of hematoma size. Patients with immediate and early seizures more often had infectious complications. Surgery increases the risk of a late seizure after ICH.

A population based study of outcomes after evacuation of primary supratentorial intracerebral hemorrhage.

BACKGROUND AND PURPOSE: The role of surgery after primary intracerebral hemorrhage (ICH) is controversial. To explore whether hematoma evacuation after ICH had improved short-term survival or functional outcome we conducted a retrospective observational population-based study. METHODS: We identified all subjects with primary ICH between 1993 and 2008 among the population of Northern Ostrobothnia, Finland. Hematoma evacuation was carried out by using standard craniotomy or through a burr hole. We compared mortality rates and functional outcomes of patients with hematoma evacuation with those treated conservatively. RESULTS: Of 982 patients with verified ICH during the study period, 127 (13%) underwent hematoma evacuation. Surgically treated patients were significantly younger (mean±SD, 63±11 vs. 70±12 years; p<0.001), had larger hematomas (66±36 vs. 28±40 ml; p<0.001), lower Glasgow Coma Scale scores (median, 11 vs. 14; p<0.001) and more frequently subcortical hematomas (68% vs. 24%; p<0.001) than those treated conservatively. In multivariable analysis, hematoma evacuation independently lowered 3-month mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.43-0.88; p<0.03), particularly among patients aged≤70 years with ≥30 ml supratentorial hematomas (adjusted HR, 0.26; 95% CI, 0.14-0.49; p<0.001). However, poor outcome was not improved by surgery (adjusted odds ratio 0.71; 95% CI 0.29-1.70). CONCLUSIONS: Improved 3-month survival was observed in patients who had undergone hematoma evacuation relative to patients not undergoing evacuation particularly in the subgroup of patients aged≤70 years with ≥30 ml supratentorial hematomas. Surgery might improve outcome if cases could be selected more precisely and if performed before deterioration.

Lack of association between CYP2A5 induction and apoptosis in mouse primary hepatocytes.

Upregulation of mouse hepatic cytochrome P450 2A5 (CYP2A5) is a process closely associated with hepatocellular damage and formation of liver tumours. 2-Aminopurine, a protein kinase inhibitor modulating cell cycle control, was recently shown to strongly induce CYP2A5 in mouse hepatocytes. The objective of this study was to determine the association between CYP2A5 induction and apoptosis in mouse primary hepatocytes. Five well-characterised CYP2A5 inducers were tested for their ability to affect apoptosis rate, determined by immunohistochemical in situ 3'-end-labelling technique, in a primary mouse hepatocyte model. Transforming growth factor beta (TGFbeta) was used as a positive (proapoptotic) control. Phenobarbital, pyrazole and the mitogen-activated protein kinase inhibitor PD98059 did not significantly affect apoptosis rate in hepatocytes. Norcocaine induced apoptosis at 6 hr (1.8-fold) and 2-aminopurine 12 hr (1.4-fold) after treatment, which is considerably earlier than peaks in the amount of CYP2A5 mRNA. TGFbeta reduced CYP2A5 marker activity, coumarin 7-hydroxylase by 74%. These results indicate that in a primary hepatocyte model (a) there is no systematic correlation between apoptosis and CYP2A5 induction; (b) phenobarbital does not significantly affect the rate of apoptosis; and (c) the induction of apoptosis caused by the chemicals tested occurs considerable earlier than elevation of CYP2A5 expression. Thus, no causal link appears to exist between induction of CYP2A5 and apoptotic rate.