Targeted gene delivery of BMPR2 attenuates pulmonary hypertension.

Pulmonary arterial hypertension (PAH) remains a fatal disease despite modern pharmacotherapy. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) lead to reduced BMPR2 expression, which is causally linked to PAH. BMPR2 is predominantly expressed on pulmonary endothelium and has complex interactions with transforming growth factor (TGF)-ß signalling mechanisms. Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium. We used two established rat models of PAH: chronic hypoxia and monocrotaline (MCT). In both hypertensive models, those receiving BMPR2 had less right ventricular hypertrophy, less pulmonary vascular resistance, improved cardiac function and reduced vascular remodelling. In the MCT model, there was an increase in TGF-ß, which was prevented by BMPR2 treatment. In vitro, TGF-ß1-induced endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells, which was associated with reduced BMPR2 expression. EndMT was partially ameliorated by stimulating BMPR2 signalling with appropriate ligands even in the ongoing presence of TGF-ß1. Collectively, these results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-ß.

Choline and betaine intake and risk of breast cancer among post-menopausal women.

BACKGROUND: Choline and betaine, similar to folate, are nutrients involved in one-carbon metabolism and hypothesised to reduce breast cancer risk. No prospective study among post-menopausal women has examined choline and betaine intakes in relation to breast cancer risk. METHODS: We examined the intake of choline and betaine and breast cancer risk among 74 584 post-menopausal women in the Nurses' Health Study. Nutrient intake was assessed using a validated food-frequency questionnaire six times since 1984. During 20 years of follow-up from 1984 until 2004, we documented 3990 incident cases of invasive breast cancer. RESULTS: Overall, choline (mean+/-s.d.; 326+/-61 mg per day) and betaine (104+/-33 mg per day) intake was not associated with a reduced risk of post-menopausal breast cancer. Participants in the highest quintile of intakes had multivariate relative risks of 1.10 (95% confidence interval (95% CI): 0.99-1.22; P-value, test for trend=0.14) for choline and 0.98 (95% CI: 0.89-1.09; P-value, test for trend=0.96) for betaine, compared with those in the lowest quintiles of intakes. The results were similar in breast cancer stratified by hormone receptor (oestrogen receptor/progesterone receptor) status. The association between choline intake and breast cancer risk did not differ appreciably by alcohol intake (non-drinker, <15 or 15+ g per day) or several other breast cancer risk factors, including family history of breast cancer, history of benign breast disease, body mass index, post-menopausal hormone use, and folate intake. CONCLUSION: We found no evidence that higher intakes of choline and betaine reduce risk of breast cancer among post-menopausal women.

Burden of depressive symptoms and non-alcohol substance abuse; and their association with alcohol use and partner violence: a cross-sectional study in four sub-Saharan Africa countries.

In sub-Saharan Africa, there are limited data on burden of non-alcohol substance abuse (NAS) and depressive symptoms (DS), yet potential risk factors such as alcohol and intimate partner violence (IPV) are common and NAS abuse may be the rise. The aim of this study was to measure the burden of DS and NAS abuse, and determine whether alcohol use and IPV are associated with DS and/or NAS abuse. We conducted a cross-sectional study at five sites in four countries: Nigeria (nurses), South Africa (teachers), Tanzania (teachers) and two sites in Uganda (rural and peri-urban residents). Participants were selected by simple random sampling from a sampling frame at each of the study sites. We used a standardized tool to collect data on demographics, alcohol use and NAS use, IPV and DS and calculated prevalence ratios (PR). We enrolled 1415 respondents and of these 34.6% were male. DS occurred among 383 (32.3%) and NAS use among 52 (4.3%). In the multivariable analysis, being female (PR  =  1.49, p  =  0.008), NAS abuse (PR  =  2.06, p  =  0.02) and IPV (PR  =  2.93, p < 0.001) were significantly associated with DS. Older age [odds ratio (OR) = 0.31, p < 0.001)], female (OR = 0.48, p  =  0.036) were protective of NAS but current smokers (OR = 2.98, p < 0.001) and those reporting IPV (OR  =  2.16, p  =  0.024) were more likely to use NAS. Longitudinal studies should be done to establish temporal relationships with these risk factors to provide basis for interventions.

Validation of a food frequency questionnaire measurement of selected nutrients using biological markers in African-American men.

OBJECTIVE: To validate selected nutrients assessed by the food frequency questionnaire (FFQ) used in the Harvard cohort studies in an African-American group. DESIGN: Blood aliquots were pooled for each decile of intake of two carotenoids and alpha tocopherol as measured by FFQ. These pooled samples were analyzed for nutrient content, and the resultant blood levels were plotted against the median for each decile of intake. In addition, adipose tissue samples taken from each man were analyzed for content of specific fatty acids. We calculated the Spearman correlations comparing intakes of specific fatty acids as percent of total fat intake, adjusted for energy intake, as measured by FFQ, with the percentage of the corresponding fatty acid in adipose tissue. SUBJECTS AND SETTINGS: African-American men (N=104) with prostate cancer were recruited from a Detroit physician's practice and completed a detailed FFQ. RESULTS: Comparing decile 10 with decile 1 intake of nutrients as measured by FFQ, there was a 32% higher blood level of lycopene, a 288% higher blood level of beta carotene and a 100% higher blood level of alpha tocopherol. The Spearman correlation coefficients between intakes of linoleic acid, alpha linolenic acid, long-chain n-3 fatty acids and trans fatty acid measured by FFQ and the corresponding adipose tissue levels were between 0.10 and 0.47. CONCLUSION: The FFQ was able to distinguish meaningful differences in biochemical measurements of selected nutrients and presumably corresponding differences in the extremes of intake in African-American men with prostate cancer who were likely to be motivated to report accurately. However, the results found are similar to those found in other populations.

Risk of cardiovascular disease among teachers in Cape Town: Findings of the South African PaCT pilot study.

BACKGROUND: The accelerating epidemic of cardiovascular disease (CVD) and other non-communicable diseases (NCDs) highlights the need to establish long-term cohort studies in Africa. OBJECTIVE: The Partnership for Cohort Research and Training (PaCT) seeks to study NCDs in South Africa (SA), Uganda, Tanzania and Nigeria on a long-term basis. Pilot studies at each site have tested feasibility. The SA site additionally studied the prevalence of CVD risk factors and categorised participants' 10-year predicted risk of a cardiovascular event. METHODS: We enrolled teachers from 111 public schools in the Metro South Education District in Cape Town, SA, between January 2011 and May 2012. Participants completed a self-administered questionnaire and biological measurements, and chose post or email for 6-month follow-up. RESULTS: The participation of schools was permitted by 53.2% of principals, and 489 of 1 779 teachers agreed to participate. Of teachers willing to participate in the follow-up, 52% were retained, three-quarters by post and a quarter by email. Their mean age was 46.3 years and 70.3% were female. The prevalence of CVD risk factors was high and featured hypertension (48.5%), hypercholesterolaemia (20.5%), smoking (18.0%), diabetes (10.1%) and chronic kidney disease (10.4%), while 84.7% were overweight or obese. Of the participants, 18.7% were at high risk of a heart attack or stroke within 10 years. CONCLUSION: Establishing a cohort study among teachers has challenges but also opportunities for addressing CVD, which will soon impose a substantial burden on Cape Town's education system.

Dietary fat intake and endogenous sex steroid hormone levels in postmenopausal women.

PURPOSE: To examine the relationship between plasma levels of reproductive sex steroid hormones in postmenopausal women and their reported fat intake. METHODS: We measured plasma sex steroid hormones levels in plasma collected in 1989 and 1990 from 381 healthy postmenopausal women. For each woman, we measured fat intake in 1986 and 1990 by a food-frequency questionnaire. The cross-sectional associations between the percentage of energy from total and specific types of dietary fat intake and plasma hormone levels were assessed by linear regression, controlling for energy intake, obesity, and protein intake. RESULTS: The plasma estradiol level was 4.3% lower (95% confidence limits, -8.3%, -0.2%) for a substitution of 5% of energy from fat intake for an equivalent amount of energy from carbohydrate when adjusted for obesity and other covariates. Estradiol was also inversely associated with all other fat types except trans fat; the inverse associations with vegetable fat and marine omega-3 fats were statistically significant. CONCLUSION: We observed an inverse association between total fat intake averaged over 4 to 5 years and estradiol levels. This result is inconsistent with the hypothesis that fat intake predisposes to breast cancer risk by raising endogenous estrogen levels.

Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women.

BACKGROUND: In metabolic studies, both greater carbohydrate intakes and higher glycemic indexes (GIs) raise fasting triacylglycerol concentrations. In epidemiologic studies, dietary glycemic load (GL) is positively associated with risk of coronary artery disease and type 2 diabetes. OBJECTIVE: We examined both the physiologic relevance of GI and GL and the ability of dietary questionnaires to measure these variables. DESIGN: In the Nurses' Health Study, we measured plasma triacylglycerol concentrations in fasting blood samples from 185 healthy postmenopausal women and HDL-cholesterol concentrations in an additional 95 nonfasting samples. Dietary carbohydrate, GI, and GL were assessed by use of semiquantitative food-frequency questionnaires. The cross-sectional associations between these 3 variables and plasma triacylglycerol and HDL were assessed, with adjustment for potential confounding factors. RESULTS: For the lowest and highest quintiles of GL, the multivariate-adjusted geometric mean triacylglycerol concentrations were 0.98 and 1.75 mmol/L (87 and 155 mg/dL; P for trend < 0.001). Both overall GI (P for trend = 0.03) and carbohydrate (P for trend < 0.01) contributed independently to the strong positive association between GL and fasting triacylglycerol concentrations. GL was also inversely associated with HDL-cholesterol concentrations. For the lowest and highest quintiles of GL, the mean HDL-cholesterol concentrations were 1.50 and 1.34 micromol/L (58 and 52 mg/dL; P for trend = 0.03). The relation between GL and fasting triacylglycerol concentrations differed significantly by body mass index (BMI; in kg/m(2)) categories (P < 0.001 for interaction). For the lowest to the highest quintiles of GL, the mean triacylglycerol concentrations were 0.92 and 2.24 mmol/L (81 and 198 mg/dL) in women with BMIs > 25 (P for trend < 0.001) and 1.02 and 1.42 mmol/L (90 and 126 mg/dL) in women with BMIs < or = 25 (P for trend < 0.001). CONCLUSION: These data support the physiologic relevance of the GL as a potential risk factor for coronary artery disease in free-living women, particularly those prone to insulin resistance. These findings also document the ability of a semiquantitative food-frequency questionnaire to assess dietary GIs and GLs.

Complex partial seizures. Correlation of clinical and metabolic features.

We compared metabolic patterns on 18F-2-deoxyglucose positron emission tomography (PET) with closed circuit television and simultaneous electroencephalographic ictal recordings of complex partial seizures in 48 patients. Closed circuit television and electroencephalographic data and PET scans were scored by "blinded" raters. Of the 48 patients, 26 had unilateral temporal; three, frontal; ten, ipsilateral frontotemporal; one, frontoparietal; and five, temporoparietal hypometabolism; and three had widespread hypometabolism affecting frontal, temporal, and parietal lobes. patients with frontal hypometabolism alone had shorter ictal and postictal durations, but involvement of multiple regions was associated with prolonged seizures. Auras were more likely to be present in patients with temporal hypometabolism alone, but an initial motionless stare did not distinguish this group. However, other metabolic patterns did not predict specific ictal clinical features. Vocalizations (formed or unformed) were not more closely associated with frontal involvement. When hypometabolism is multilobar, it may be difficult to use PET to distinguish between complex partial seizures of frontal and temporal origin.

Unilateral focal preponderance of interictal epileptiform discharges as a predictor of seizure origin.

OBJECTIVE: To test the hypothesis that seizure origin may be predicted from scalp-recorded electroencephalographic interictal epileptiform patterns that occur exclusively or preponderantly over a single focal region. PATIENTS AND METHODS: Fifty-nine of 98 patients (>=16 years old) with intractable epilepsy who underwent sphenoidal/scalp electroencephalographic video monitoring were identified as having interictal epileptiform discharges preponderantly (>=75% of all discharges) or exclusively over a single unilateral region (basal-temporal, midposterior temporal, frontopolar, superior frontal, central). Ictal recordings in 48 patients could be interpreted as demonstrating focal origins, and the ictal findings were compared with the interictal findings. Eleven patients had uninterpretable ictal recordings or no seizures during monitoring and were not further considered. RESULTS: All seizures arose from the expected region in 39 of the 48 patients (Fisher's exact test, P<.001). Interictal discharges occurred exclusively over a single region in 23 of the 48 patients, and all seizures arose from the expected region in 22 of the 23 patients (P<.001). Seventeen patients among this group of 23 had exclusively unilateral basal-temporal discharges, and all seizures arose from the expected side, with the exception of one seizure that arose from the opposite side in one patient, with her other seizure arising from the expected side (P<.001). All seizures arose from the expected region in three patients who exhibited all interictal discharges arising from a single superior frontal region, in two patients with discharges only over a single midposterior temporal region, and in one patient with exclusively unilateral frontopolar discharges. CONCLUSIONS: Interictal discharges that demonstrate a consistent unilateral focal preponderance over a single region, regardless of location, generally predict seizure origin. If the discharges are exclusive to a single region, there is a greater than 95% probability that all recorded seizures will originate from the expected region.

Dietary fat, fat subtypes, and breast cancer risk: lack of an association among postmenopausal women with no history of benign breast disease.

A recent study among 13,707 postmenopausal women without benign breast disease (BBD) from the Breast Cancer Detection Demonstration Project (BCDDP) cohort found breast cancer risk associated with greater total fat, unsaturated fat, and oleic acid intake. We assessed the associations between cumulative averaged dietary intake from 1980, 1984, 1986, and 1990 with breast cancer risk through 1994 among 44,697 postmenopausal participants without BBD in the Nurses' Health Study (NHS). Multivariate Cox proportional hazard models, with age as the time variable, provided the estimated rate ratios (RRs) with 95% confidence intervals (CIs) from the 14 years of follow-up and the 1,071 breast cancer cases. In the Nurses' Health Study, breast cancer rates over the time period from 1980 to 1994 did not increase significantly with greater total fat [quintile (Q) 5 versus Q1 RR, 0.94; 95% CI, 0.77-1.15], saturated fat (RR(Q5 to Q1), 0.88; 95% CI, 0.70-1.12), unsaturated fat (RR(Q5 to Q1), 1.16; 95% CI, 0.92-1.46), oleic acid (RR(Q5 to Q1), 1.13; 95% CI, 0.81-1.57), linoleic acid (RR(Q5 to Q1), 0.93; 95% CI, 0.74-1.16), trans fatty acid (RR(Q5 to Q1), 0.9184; 95% CI, 0.73-1.13), or energy intake (RR(Q5 to Q1), 0.81; 95% CI, 0.67-0.99). A parallel analysis restricted to the same time period as the BCDDP study did not differ substantially. We found no increase in the rate of breast cancer with greater intake of dietary fat and fat subtypes among postmenopausal women without a history of BBD.

Clinical features of meningovascular syphilis.

Meningovascular syphilis presents as a subacute encephalitic syndrome with superimposed cerebrovascular events that may evolve gradually. This picture differs from the more common cases of thrombotic or embolic stroke. Optimal treatment is uncertain, and requires monitoring of spinal fluid abnormalities until they return to normal.

Outcome following surgery in patients with bitemporal interictal epileptiform patterns.

We reviewed outcome at least 1 year after temporal lobectomy in 44 patients with bitemporal, independent, interictal epileptiform patterns on EEG. All 44 underwent preoperative intracranial monitoring. Twenty-two (50%) were seizure-free, 14 (32%) had at a least 75% reduction in seizures, and eight (18%) had less than a 75% reduction in seizures. We analyzed age of seizure onset, duration of epilepsy, gender, side of operation, history and clinical findings, findings on MRI, results of intracranial EEG-video monitoring, presence or absence of lateralizing neuropsychological deficits, and pathology of resected tissue to identify factors associated with outcome. Three factors emerged as independently associated with a good outcome: concordance of MRI abnormality and side of operation (p = 0.01), history of febrile seizures (p = 0.04), and 100% lateralization of intracranially recorded ictal onsets to the side of operation (p = 0.05). A seizure-free outcome was much more likely to occur if more than one of these factors was present: with at least two factors co-existing, 83% (15/18) of patients were seizure-free, while only 35% (7/20) were seizure-free with a single factor present (p = 0.0009). Of the six patients without any of the three factors, none were seizure-free. We conclude that it is possible to predict reasonably which patients with bitemporal epileptiform abnormalities will have a good outcome after surgery.

Singing seizures.

Automatisms are commonly seen in epilepsy, either ictally or postictally. However, most automatisms are simple, with hand movements, mouth smacking, nose-rubbing, repetition of a single word, or coughing, grunting, or screeching. Complex automatisms are less common and striking. The authors report two cases of seizure-associated singing where song expression may be recognizable.

Chlamydia trachomatis cervical infection in women seeking routine gynecologic care: criteria for selective testing.

PURPOSE: Chlamydia trachomatis infection is one of the most common sexually transmitted diseases. Developing methods to identify patients who are at higher risk would enable clinicians to perform selective testing for C. trachomatis infection, which may reduce morbidity, sequelae, and overall costs. Risk factors for C. trachomatis infection of the cervix in women seen for routine gynecologic care were therefore analyzed. PATIENTS AND METHODS: Extensive clinical data and cervical cultures were obtained from 1,141 women between the ages of 18 and 50. Multivariate techniques were used to develop and prospectively test a model to predict infection. RESULTS: In the model development series of 530 patients seen in a hospital-based practice, 24 (4.5%) had a positive culture result. In the validation series of 611 patients seen in private practice, 17 (2.8%) had positive culture results. The majority of infected patients (61%) were asymptomatic. For sexually active women 18 to 35 years of age, the optimal predictive model was based on three factors: level of education (high school or less), a sex partner with other partners during the prior three months, and endocervical bleeding induced by the initial swab. In the validation series, the prevalence of infection for women with one or more of these factors was 5.8% (95% confidence interval, 4.0 to 8.6) compared with 0.9% in patients without these factors (p = 0.005). CONCLUSION: Clinical information can be used in a low-prevalence population to predict a patient's risk for C. trachomatis infection and to select patients for testing.

Unilateral diaphragmatic paralysis following bronchial artery embolization for hemoptysis.

Bronchial artery embolization is an effective treatment for patients with hemoptysis. Serious complications are rare, but may occur if the arterial supply to other structures is compromised. We present a case of unilateral diaphragmatic paralysis following bronchial artery embolization in a patient with cystic fibrosis. We believe that the diaphragmatic paralysis was due to the inadvertent obstruction of the left pericardiacophrenic artery during the embolization procedure, with compromise of the phrenic nerve blood supply. This resulted in a significant loss of lung function in our patient, who did not recover despite the subsequent return of diaphragmatic function.

Spatial spectral analysis of human electrocorticograms including the alpha and gamma bands.

Spatial spectral analysis is essential for deriving spatial patterns from simultaneous recordings of electrocorticograms (ECoG), in order to determine the optimal interval between electrodes in arrays, and to design spatial filters, particularly for extraction of information about the dynamics of human gamma activity. ECoG were recorded from up to 64 electrodes 0.5 mm apart in a linear array 3.2 cm long, which was placed on the exposed superior temporal gyrus or motor cortex of volunteers undergoing diagnostic surgery. Visual displays of multiple traces revealed broad spectrum oscillations in episodic bursts having a common aperiodic wave form with recurring patterns of spatial amplitude modulation (AM patterns) on selected portions of the array. The one-dimensional spatial spectrum of the human ECoG was calculated at successive time samples and averaged over periods of up to 20 s. Log power decreased monotonically with increasing log spatial frequency in cycles/mm (c/mm) to the noise level approximately 2 log units below maximal power at minimal frequency (0.039+/-0.002 c/mm). The inflection point at 0.40+/-0.05 c/mm specified an optimal value for a low pass spatial filter to remove noise, and an optimal interelectrode spacing of 1.25 mm to avoid undersampling and aliasing. An 8 x 8 array with that spacing would be 10 x 10 mm.

Neuronal activity in human right lateral temporal cortex related to visuospatial memory and perception.

Neuronal activity was recorded extracellularly from 22 neurons in the right lateral temporal cortex of 12 patients undergoing awake craniotomy for surgical treatment of epilepsy during tests of visuospatial function. These included: measures of short-term visuospatial memory; face, complex figure and line matching; labeling of facial emotional expressions; and a language task, object naming. Six neurons demonstrated significant changes during one or more of the three 1.3-s epochs following test presentation. All 6 of these neurons demonstrated inhibition during short-term visuospatial memory entry, or retrieval, or both. Four of the neurons also showed significant changes during one or more matching tasks; 8 of 10 of these changes were excitatory. One neuron also demonstrated excitation with labeling of facial emotional expression and another with naming. These data demonstrate in human right lateral temporal cortex a pattern of inhibition of neuronal activity during short-term visuospatial memory that contrasts with excitation during other functions, particularly figure matching.

Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal origin and postsurgical outcome.

OBJECTIVES: To evaluate the significance of exclusively unifocal, unilateral, interictal epileptiform patterns on scalp electroencephalography (EEG) in surgical candidates with medically intractable extratemporal epilepsy. METHODS: We reviewed 126 patients with refractory extratemporal partial seizures who underwent epilepsy surgery at our center. All were followed for at least 2 years after resections. Surgery was based on ictal EEG recordings. We examined ictal onsets and surgical outcome in subjects whose preoperative, interictal scalp EEGs during long-term monitoring (LTM) demonstrated only unilateral, well-defined focal discharges, and outcome in patients whose interictal EEGs during LTM showed bilateral, non-localized, or multifocal epileptiform patterns. RESULTS: We found that 26 subjects exhibited only unilateral, unifocal, interictal epileptiform patterns. In all 26 cases (100%) clinical seizures arose from the regions expected by the interictal findings (P<0.0001, Sign test). At last follow-up 77% (20/26) of these patients were seizure-free, while 23% (6/26) had >75% reduction in seizures. This compares to the remaining patients, of whom 34% (34/100) were seizure-free, 41% (41/100) had >75% reduction in seizures, and 25% (25/100) had <75% reduction in seizures (P=0.0001, Fisher's Exact test). CONCLUSIONS: Strictly unifocal, interictal epileptiform patterns on scalp EEG, though seen in a minority of subjects, may be an important, independent factor in evaluating subjects with intractable extratemporal, localization-related epilepsy for surgical therapy. This finding is highly predictive of both ictal onsets and successful postsurgical outcome.

Scalp-recorded slow EEG responses generated in response to hemodynamic changes in the human brain.

OBJECTIVE: To study whether hemodynamic changes in human brain generate scalp-EEG responses. METHODS: Direct current EEG (DC-EEG) was recorded from 12 subjects during 5 non-invasive manipulations that affect intracranial hemodynamics by different mechanisms: bilateral jugular vein compression (JVC), head-up tilt (HUT), head-down tilt (HDT), Valsalva maneuver (VM), and Mueller maneuver (MM). DC shifts were compared to changes in cerebral blood volume (CBV) measured by near-infrared spectroscopy (NIRS). RESULTS: DC shifts were observed during all manipulations with highest amplitudes (up to 250 microV) at the midline electrodes, and the most pronounced changes (up to 15 microV/cm) in the DC voltage gradient around vertex. In spite of inter-individual variation in both amplitude and polarity, the DC shifts were consistent and reproducible for each subject and they showed a clear temporal correlation with changes in CBV. CONCLUSIONS: Our results indicate that hemodynamic changes in human brain are associated with marked DC shifts that cannot be accounted for by intracortical neuronal or glial currents. Instead, the data are consistent with a non-neuronal generator mechanism that is associated with the blood-brain barrier. SIGNIFICANCE: These findings have direct implications for mechanistic interpretation of slow EEG responses in various experimental paradigms.

Valproate therapy for prevention of posttraumatic seizures: a randomized trial.

OBJECT: Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury. METHODS: The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years. The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7-13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8-2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9-4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients. CONCLUSIONS: Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.