Getting to precision psychopharmacology: Combining clinical and genetic information to predict fat gain from aripiprazole.

INTRODUCTION: All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults. MATERIALS AND METHODS: Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation. RESULTS: The value of the combined genetic + clinical multiple moderator (Mcg) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (Mc) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism. DISCUSSION: These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach.

Choice of anaesthesia for category-1 caesarean section in women with anticipated difficult tracheal intubation: the use of decision analysis.

A predicted difficult airway is sometimes considered a contra-indication to rapid sequence induction of general anaesthesia, even in an urgent case such as a category-1 caesarean section for fetal distress. However, formally assessing the risk is difficult because of the rarity and urgency of such cases. We have used decision analysis to quantify the time taken to establish anaesthesia, and probability of failure, of three possible anaesthetic methods, based on a systematic review of the literature. We considered rapid sequence induction of general anaesthesia with videolaryngoscopy, awake fibreoptic intubation and rapid spinal anaesthesia. Our results show a shorter mean (95% CI) time to induction of 100 (87-114) s using rapid sequence induction compared with 9 (7-11) min for awake fibreoptic intubation (p < 0.0001) and 6.3 (5.4-7.2) min for spinal anaesthesia (p < 0.0001). We calculate the risk of ultimate failed airway control after rapid sequence induction to be 21 (0-53) per 100,000 cases, and postulate that some mothers may accept such a risk in order to reduce potential fetal harm from an extended time interval until delivery. Although rapid sequence induction may not be the anaesthetic technique of choice for all cases in the circumstance of a category-1 caesarean section for fetal distress with a predicted difficult airway, we suggest that it is an acceptable option.

Deep brain stimulation: new directions.

The role of deep brain stimulation (DBS) in the treatment of movement disorders is well established, but there has recently been a proliferation of additional indications that have been shown to be amenable to this technology. The combination of innovative approaches to neural interface technology with novel target identification based on previously discovered clinical effects of lesioning procedures has led to a fundamental paradigm for new directions in the application of DBS. The historical use of neurosurgical lesioning procedures in the treatment of psychiatric diseases such as obsessive compulsive disorder provided an initial opportunity to expand the use of DBS. The list is rapidly expanding and now includes major depressive disorder, Tourette's syndrome, addiction disorders, and eating disorders. Keen observations by neurosurgeons using these devices have lead to the incidental discovery of treatments for diseases without previous neurosurgical treatments. These discoveries are breaking new ground in the treatment of disorders of cognition, headache syndromes, disorders of consciousness, and epilepsy. Two features of DBS make it well-suited for treatment of disorders of nervous system function. First, the reversible, non-lesional nature of DBS allows for investigation of new targets without the morbidity of permanent side effects. Second, the programmable nature of DBS allows practitioners to alter stimulation patterns to minimize side effects and potentially improve efficacy through reprogramming. More importantly, proper scientific evaluation of new targets is aided by the ability to turn stimulation on and off with evaluators blinded to the stimulation status. Knowledge of these emerging therapies is important for practitioners, as there are many situations where a single target can effectively treat the symptoms of more than one disease. The intersection of advances in neuromodulation, neurophysiology, neuroimaging, and functional neuroanatomy has created an environment rife with new therapeutic possibilities.

Measurement of the positive muon lifetime and determination of the Fermi constant to part-per-million precision.

We report a measurement of the positive muon lifetime to a precision of 1.0 ppm; it is the most precise particle lifetime ever measured. The experiment used a time-structured, low-energy muon beam and a segmented plastic scintillator array to record more than 2×10(12) decays. Two different stopping target configurations were employed in independent data-taking periods. The combined results give τ(µ(+)) (MuLan)=2 196 980.3(2.2) ps, more than 15 times as precise as any previous experiment. The muon lifetime gives the most precise value for the Fermi constant: G(F) (MuLan)=1.166 378 8(7)×10(-5) GeV(-2) (0.6 ppm). It is also used to extract the µ(-)p singlet capture rate, which determines the proton's weak induced pseudoscalar coupling g(P).

Pre-operative vitamin B infusion and prevention of nitrous oxide-induced homocysteine increase.

SUMMARY: Nitrous oxide inactivates vitamin B(12) with detrimental consequences for folate and methionine metabolism, detectable by an increase in total plasma homocysteine. We hypothesised that a pre-operative vitamin B(12) and folate infusion prevents nitrous oxide-induced homocysteine increase. Sixty-three healthy patients having elective surgery were randomly allocated to receive either B-vitamin plus nitrous oxide; placebo plus nitrous oxide or placebo plus air. Fifty-nine patients completed the study. After intravenous B-vitamin infusion, plasma vitamin B(12) and folate concentrations increased 35-fold and 12-fold, respectively, on the first postoperative measurement. Patients who received B-vitamins developed a similar increase (18%) in homocysteine after nitrous oxide (1.9 micromolxl(-1); 95% CI 0.2-3.6 micromolxl(-1)) as those who did not (22%; 2.7 micromolxl(-1); 95% CI 0.6-4.8 micromolxl(-1)). Patients not receiving nitrous oxide had no homocysteine change (0.5 micromolxl(-1); 95% CI -0.8-1.9 micromolxl(-1)), indicating that pre-operative intravenous B-vitamins may not prevent nitrous oxide-induced hyperhomocysteinaemia.

Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas.

The tumor suppressive activities of the Kip-family of cyclin-dependent kinase (cdk) inhibitors often go beyond their role directly regulating the cell cycle. In this study, we show that p27 enhances Rad51 accumulation during repair of double-strand DNA breaks. Progression of platelet-derived growth factor (PDGF)-induced oligodendrogliomas was accelerated in mice lacking the cyclin-cdk binding activities of p27(kip1). To understand how p27 deficiency contributes, cell lines were developed from RCAS-PDGF infection of nestin-tv-a brain progenitor cells in culture. p27 deficiency did not affect cell proliferation in early passage cell lines; however, the absence of p27 affected chromosomal stability. In p27-deficient cells, the activation of Atm and Chk2 and the accumulation of gamma-H2AX was unaffected when compared with wild-type cells, and the number of phospho-histone H3 staining mitotic cells was decreased, consistent with G2/M checkpoint activation. However, the percentage of Rad51 foci-positive cells was decreased, and the kinase activity that targets the C-terminus of BRCA2, regulating BRCA2/Rad51 interactions, was increased in lysates derived from p27-deficient cells. Increased numbers of chromatid breaks in p27-deficient cells that adapted to the checkpoint were also observed. These findings suggest that Rad51-dependent repair of double-stranded breaks was hindered in p27-deficient cells, leading to chromosomal instability, a hallmark of cancers with poor prognosis.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS): A single-center RCT.

BACKGROUND: Constraint-induced movement therapy (CIMT) is among the most developed training approaches for motor restoration of the upper extremity (UE). METHODS: Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS) was a single-blind phase II trial of CIMT during acute inpatient rehabilitation comparing traditional UE therapy with dose-matched and high-intensity CIMT protocols. Participants were adaptively randomized on rehabilitation admission, and received 2 weeks of study-related treatments. The primary endpoint was the total Action Research Arm Test (ARAT) score on the more affected side at 90 days after stroke onset. A mixed model analysis was performed. RESULTS: A total of 52 participants (mean age 63.9 +/- 14 years) were randomized 9.65 +/- 4.5 days after onset. Mean NIHSS was 5.3 +/- 1.8; mean total ARAT score was 22.5 +/- 15.6; 77% had ischemic stroke. Groups were equivalent at baseline on all randomization variables. As expected, all groups improved with time on the total ARAT score. There was a significant time x group interaction (F = 3.1, p < 0.01), such that the high intensity CIT group had significantly less improvement at day 90. No significant differences were found between the dose-matched CIMT and control groups at day 90. MRI of a subsample showed no evidence of activity-dependent lesion enlargement. CONCLUSION: Constraint-induced movement therapy (CIMT) was equally as effective but not superior to an equal dose of traditional therapy during inpatient stroke rehabilitation. Higher intensity CIMT resulted in less motor improvement at 90 days, indicating an inverse dose-response relationship. Motor intervention trials should control for dose, and higher doses of motor training cannot be assumed to be more beneficial, particularly early after stroke.

Search for Lorentz and CPT violation effects in Muon spin precession.

The spin precession frequency of muons stored in the (g-2) storage ring has been analyzed for evidence of Lorentz and CPT violation. Two Lorentz and CPT violation signatures were searched for a nonzero delta omega a(=omega a mu+ - omega a mu-) and a sidereal variation of omega a mu+/-). No significant effect is found, and the following limits on the standard-model extension parameters are obtained: bZ = -(1.0+/-1.1) x 10(-23) GeV; (m mu dZ0 + HXY)=(1.8+/-6.0) x 10(-23) GeV; and the 95% confidence level limits b perpendicular mu+ <1.4 x 10(-24) GeV and b perpendicular mu- <2.6 x 10(-24) GeV.

Two-generation reproductive toxicity study of inhaled acrylonitrile vapors in Crl:CD(SD) rats.

To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.

Pathology of ilioinguinal neuropathy produced by mesh entrapment: case report and literature review.

Ilioinguinal neuropathy is a well-described complication of mesh inguinal herniorrhaphy. We report the first human case, to our knowledge, of ilioinguinal nerve mesh entrapment with neuropathological changes that suggest an inflammatory cause for this chronic pain syndrome.

Improved measurement of the positive-muon lifetime and determination of the Fermi constant.

The mean life of the positive muon has been measured to a precision of 11 ppm using a low-energy, pulsed muon beam stopped in a ferromagnetic target, which was surrounded by a scintillator detector array. The result, tau(micro)=2.197 013(24) micros, is in excellent agreement with the previous world average. The new world average tau(micro)=2.197 019(21) micros determines the Fermi constant G(F)=1.166 371(6)x10(-5) GeV-2 (5 ppm). Additionally, the precision measurement of the positive-muon lifetime is needed to determine the nucleon pseudoscalar coupling g(P).

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. PATIENTS AND METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.

PM2.5 constituents and related air quality variables as predictors of survival in a cohort of U.S. military veterans.

Air quality data on trace metals, other constituents of PM2.5, and criteria air pollutants were used to examine relationships with long-term mortality in a cohort of male U.S. military veterans, along with data on vehicular traffic density (annual vehicle-miles traveled per unit of land area). The analysis used county-level environmental data for the period 1997-2002 and cohort mortality for 1997-2001. The proportional hazards model included individual data on age, race, smoking, body mass index, height, blood pressure, and selected interactions; contextual variables also controlled for climate, education, and income. In single-pollutant models, traffic density appears to be the most important predictor of survival, but potential contributions are also seen for NO2, NO3-, elemental carbon, nickel, and vanadium. The effects of the other main constituents of PM2.5, of crustal particles, and of peak levels of CO, O3, or SO2 appear to be less important. Traffic density is also consistently the most important environmental predictor in multiple-pollutant models, with combined relative risks up to about 1.2. However, from these findings it is not possible to discern which aspects of traffic (pollution, noise, stress) may be the most relevant to public health or whether an area-based predictor such as traffic density may have an inherent advantage over localized measures of ambient air quality. It is also possible that traffic density could be a marker for unmeasured pollutants or for geographic gradients per se. Pending resolution of these issues, including replication in other cohorts, it will be difficult to formulate additional cost-effective pollution control strategies that are likely to benefit public health.

Angle- and velocity-specific alterations in torque and semg activity of the quadriceps and hamstrings during isokinetic extension-flexion movements.

The purpose of this study was to investigate the effect of movement velocity (100 degrees, 200 degrees , 300 degrees s(-1), and 400 degrees s(-1)) and joint position (0 degrees - 15 degrees [L0], 25 degrees - 40 degees [L25], 55 degrees - 70 degrees [L55], and 75 degrees - 90 degrees [L75]) on peak torque (PT) parameters and surface electromyography (SEMG) of the knee-joint muscles during reciprocal isokinetic extension and flexion movements. Thirteen subjects (age = 22.7 +/- 2.1 years, mean height = 161.1 +/- 6.6 cm, mean weight = 63.5 +/- 5.8 kg) participated in the study. Bipolar surface electrodes were placed over the vastus medialis, vastus lateralis, biceps femoris, and medial hamstrings for determination of the root mean square (SEMGrms) and median frequency (SEMGmf) of the SEMG. Peak torque, angle of peak torque (PTang), percentage of peak torque (PTper), SEMGrms, and SEMGmf were analyzed using separate repeated measures analysis of variance (ANOVA). The following main results, significant at p < or = 0.05 or better, were found: The PTang was influenced by movement velocity (in extension there was a decrease in PTang moving from 300 degrees x s(-1) to 400 degrees x s(-1) and inflexion there was an increase in PTang moving from 300 degrees x s(-1) to 400 degrees x s(-1)). Secondly, a greater percentage of peak torque (PTper) was maintained during knee flexion than knee extension. And thirdly, both the quadriceps and hamstrings exhibited changing amplitudes and spectral frequencies based on joint position and movement velocity. There was a trend of decreasing SEMGrms for the quadriceps as the knee moved into extension, and a lower SEMGmf during early (L75) and end stages of knee extension (L0). For the hamstrings, SEMGrms was lowest at the more shortened position (L75) and highest near the mid-position (L25); the lowest SEMGmf occurred at the more lengthened position (L0) and the highest occurred at the more shortened position (L75). Finally, velocity influenced hamstrings and quadriceps muscle amplitude such that SEMGrms was highest at the slower velocities and lowest at the higher velocities. Velocity had no impact on quadriceps spectral properties (p > 0.05), but had a cyclic effect on hamstrings spectral properties. Changes in amplitude and frequency spectrum in tested muscles could be explained, in part, by neural drive to these muscles. Data support the hypothesis of lower activation levels of the quadriceps muscle in the extended position espoused by several authors as a way to protect the knee-joint in the knee-extended position.

Coactivation patterns of the medial and lateral hamstrings based on joint position and movement velocity during isokinetic movements.

The purpose of this investigation was to determine the effect of movement velocity (100 degrees x s(-1), 200 degrees x s(-1), 300 degees x s(-1), and 400 degrees x s(-1)) and joint position (0 degrees - 20 degrees [L0] 30 degrees - 50 degrees [L30], and 70 degrees - 90 degrees [L70] knee flexion) on reciprocal coactivation patterns of the medial and lateral hamstrings as determined by the amplitude and frequency spectrum of surface electromyography (SEMG). Thirteen female subjects (age = 22.7 +/- 2.1 years, mean height = 161.1 +/- 6.6 cm, mean weight = 63.5 +/- 5.8 kg) participated in the study. Bipolar surface electrodes were placed over the biceps femoris (BF) and medial hamstrings (MH) for determination of the root mean square (SEMGrms) and median frequency (SEMGmf) of the SEMG. Normalized SEMGrms values for the MH and BF were determined as a percentage of agonist SEMGrms activity for the same muscle during its agonist phase. Data were analyzed using separate 2 x 3 x 4 (muscle x position x angular velocity) repeated measures analysis of variance (ANOVA). For SEMGrms, there were significant muscle (p < 0.01) and position (p < or = 0.0001) main effects. Post-hoc analyses indicated the BF displayed greater muscle amplitude than the MH and that there was greater muscle amplitude at the L0 position (as the knee approached terminal extension). No velocity effect was noted (p > 0.05). For SEMGmf there were muscle x position (p < or = 0.05) and muscle x position x velocity (p < or = 0.01) interaction effects. Post-hoc analyses indicated the BF displayed a higher frequency spectrum than the MH at the L0 position. Secondly, velocity affected the BF and MH frequency spectrum such that values for both the MH and BF were lowest at 200 degrees x s(-1) and highest at 300 degrees x s(-1) (BF) and 400 degrees x s(-1) (MH). Velocity had little impact on the frequency spectrum in the midrange of the ROM (L30 position). Higher SEMGrms and SEMGmf values for the BF could be explained by the locking or screw home mechanism of the knee, and a way in which the human motor control system provides the limb with a dynamic braking system to control both extension and lateral rotational forces during the final stage of knee extension. It would appear that the way in which the body performs this function is not only to increase the amplitude of BF muscle firing but also to shift toward the recruitment of more fast-twitch motor units.

Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin.

Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (dV/dt(max)) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents (I(Na)) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of I(Na). All of these treatments rescued I(Na) to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of I(Na). To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice.

Ultrastructural analysis of a murine model of congenital hydrocephalus produced by overexpression of transforming growth factor-beta1 in the central nervous system.

The purpose of this study was to elucidate using transmission electron microscopy (TEM) the ultrastructural changes that occur within the cortical gray matter of a novel reproducible model of congenital hydrocephalus in mice created to overexpress the cytokine transforming growth factor-beta1 (TGF-beta1) in the central nervous system. Brain tissue was obtained from mice from a colony engineered to overexpress TGF-beta1 at two days postpartum and compared to a wild-type aged-matched control. This tissue was fixed using a solution containing 1.25% paraformaldehyde and 1.25% glutaraldehyde in phosphate buffer at least 3-4 h and then cut into 40-50 microm sections. Randomly selected thin sections were stained with uranyl acetate and lead citrate, and then analyzed using a JEOL-100CX or 1200EX transmission electron microscope at accelerating voltage 80 kV. Dramatic neuronal and glial pathology was observed throughout the cortical neuropil in TGF-beta1 mice. The most striking change in the hydrocephalic mice was severe edema with extracellular fluid, possibly due to cerebrospinal fluid (CSF) penetration into the cortex. In addition, severe disruption of the cytoplasmic matrix was seen throughout the cortex, with damage to cellular organelles and particularly severe damage to mitochondria. Our results suggest that congenital hydrocephalus may be associated with significant damage to cortical tissue.