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Notes: Functional N-methyl-d-aspartate (NMDA) glutamate receptors are composed of heteromeric complexes of NR1, the obligatory subunit for channel activity, and NR2 or NR3 family members, which confer variability in the properties of the receptors. Recent studies have provided evidence for the existence of both binary (containing NR1 and either NR2A or NR2B) and ternary (containing NR1, NR2A, and NR2B) receptor complexes in the adult mammalian brain. However, the mechanisms regulating subunit assembly and receptor localization are not well understood. In the CNS, NMDA subunits are present both at intracellular sites and the post-synaptic membrane of neurons. Using biochemical protein fractionation and co-immunoprecipitation approaches we have found that in rat striatum binary NMDA receptors are widely distributed, and can be identified in the light membrane, synaptosomal membrane, and synaptic vesicle-enriched subcellular compartments. In contrast, ternary receptors are found exclusively in the synaptosomal membranes. When striatal proteins are chemically cross-linked prior to subcellular fractionation, ternary NMDA receptors can be precipitated from the light membrane and synaptic vesicle-enriched fractions where this type of receptor complex is not detectable under normal conditions. These findings suggest differential targeting of distinct types of NMDA receptor assemblies between intracellular and post-synaptic sites based on subunit composition. This targeting may underlie important differences in the regulation of the transport pathways involved in both normal as well as pathological receptor functions.

Notes: Introduction: Survival in patients awaiting cardiac transplantation is poor due to the severity of left ventricular dysfunction and the susceptibility to ventricular arrhythmia. The potential role of implantable cardioverter defibrillators (ICDs) in this group of patients has been the subject of increasing interest. The aims of this study were to ascertain whether ICDs improve the survival rate of patients on the waiting list for cardiac transplantation and whether any improvement is independent of concomitant beta-blocker or amiodarone therapy. Methods and Results: Data comprised findings from 310 consecutive patients at a single center who were evaluated and deemed suitable for cardiac transplantation and placed on the waiting list. Kaplan-Meier actuarial approach was used for survival analysis. Survival analysis censored patients at time of transplantation or death. Of the 310 patients, 111 (35.8%) underwent successful cardiac transplantation and 164 (52.9%) died while waiting; 35 patients remain on the waiting list. Fifty-nine (19%) patients had ICD placement for ventricular arrhythmias prior to or after being listed. Twenty-nine (49.1%) ICD patients survived until cardiac transplantation, 13 (22%) patients died, and 17 (28.8%) remain on the waiting list. Among non-ICD patients, 82 (32.7%) received transplants, 151 (60.2%) died, and 18 (7.2%) remain on the waiting list. Survival rates at 6 months and 1, 2, 3, and 4 years were better for all ICD patients compared to non-ICD patients (log-rank x2, P = 0.0001 ). By multivariate analysis, ICD therapy and beta-blocker treatment were the strongest predictors of survival. Further, ICD treatment was associated with improved survival independent of concomitant treatment with beta-blocker or amiodarone. Among ICD and non-ICD patients treated with a beta-blocker or amiodarone, survivals at the 1 and 4 years were 93% vs 69% and 57% vs 32%, respectively (log-rank x2, P = 0.003 ). Conclusion: ICD therapy is associated with improved survival in high-risk cardiac transplant candidates, and ICD benefit appears to be independent of concomitant treatment. (J Cardiovasc Electrophysiol, Vol. 14, pp. 578-583, June 2003)

Notes: Introduction: Biventricular cardiac pacemakers provide important hemodynamic benefit in selected patients with heart failure and severe left ventricular (LV) dysfunction. Nevertheless, these patients remain at high mortality risk. To address this issue, we examined mortality outcome in patients with heart failure treated with biventricular pacemakers alone and those treated with biventricular implantable cardioverter defibrillators (ICDs). Methods and Results: The study population consisted of 126 consecutive patients with LV dysfunction and heart failure who received either a biventricular ICD (n = 62) or a biventricular pacemaker (n = 64) between January 1998 and December 2002. A minimum 12 months of follow-up was obtained in all survivors. ICD indications were conventional in all patients. Kaplan-Meier actuarial method and log rank statistics were used to calculate and compare survival rates in both groups. Comparison of mortality rates utilized Chi-square test. The two groups had similar clinical and demographic features, LV ejection fraction, and medication use. Average follow-up times were 13 ± 11.8 months (range 4–60) and 18 ± 13.2 months (range 0.5–53) for biventricular ICD and pacemaker groups, respectively. Overall mortality rate was significantly lower in the biventricular ICD group (13%, 8 deaths) compared to the pacemaker group (41%, 26 deaths) (P = 0.01). Further, the predominant survival benefit for ICD-treated patients becomes evident after the first 12 months of follow-up. Conclusion: The findings in this study, although necessarily limited in their interpretation by the absence of treatment randomization, suggest that biventricular ICDs offer a survival benefit compared to biventricular pacing alone. Furthermore, this benefit may be most apparent if other clinical factors do not preclude patient survival 〉1 year postimplant.

Notes: Background: Female offenders incarcerated in Washington State have demonstrated higher rates of mental health needs than boys. Linehan's (1993a, b) Dialectical Behavioural Therapy (DBT) is an effective treatment for adult women with Borderline Personality Disorder. DBT utilises a combination of skills training, problem solving, and validation to enable patients to reduce self-destructive, impulsive and aggressive behaviours. The prevalence of similar emotional problems among female juvenile offenders suggests that DBT may be an effective strategy for this population. The State of Washington Governor's Juvenile Justice Advisory Committee sponsored a collaborative project conducted by a research team from the University of Washington and the staff at the Juvenile Rehabilitation Administration's Echo Glen Children's Center to evaluate the effectiveness of a DBT intervention.Method: Pre-post intervention records were compared for female offenders from a mental health and a general population unit where DBT was implemented. Youth on a third unit served as a comparison group. Youth behaviour problems, staff punitive responses were compared before and after the intervention period.Results: Youth behaviour problems and use of punitive responses by staff decreased compared to the year prior on one cottage (unit) while no behaviour or staff changes were noted on another.Conclusions: The evaluation demonstrated the efficacy of providing DBT to female offenders in a residential setting and yielded mixed results on behaviour change during the study period that may relate to quality of training and prior youth behaviour problems.

Notes: Abstract: Recent data from our laboratory have shown a regionally specific increase in lipid peroxidation in postmortem progressive supranuclear palsy (PSP) brain. To extend this finding, we measured activities of mitochondrial enzymes as well as tissue malondialdehyde (MDA) levels in postmortem superior frontal cortex (Brodmann’s area 9; SFC) from 14 pathologically confirmed cases of PSP and 13 age-matched control brains. Significant decreases (-39%) in α-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected. Together, these results suggest that mitochondrial dysfunction and lipid peroxidation may underlie the frontal metabolic and functional deficits observed in PSP.

Notes: Synaptic vesicles in the nerve terminal play a pivotal role in neurotransmission. Neurotransmitter accumulation into synaptic vesicles is catalyzed by distinct vesicular transporters, harnessing an electrochemical proton gradient generated by V-type proton-pump ATPase. However, little is known about regulation of the transmitter pool size, particularly in regard to amino acid neurotransmitters. We previously provided evidence for the existence of a potent endogenous inhibitory protein factor (IPF), which causes reduction of glutamate and GABA accumulation into isolated, purified synaptic vesicles. In this study we demonstrate that IPF is concentrated most in the synaptosomal cytosol fraction and that, when introduced into the synaptosome, it leads to a decrease in calcium-dependent exocytotic (but not calcium-independent) release of glutamate in a concentration-dependent manner. In contrast, α-fodrin (non-erythroid spectrin), which is structurally related to IPF and thought to serve as the precursor for IPF, is devoid of such inhibitory activity. Intrasynaptosomal IPF also caused reduction in exocytotic release of GABA and the monoamine neurotransmitter serotonin. Whether IPF affects vesicular storage of multiple neurotransmitters in vivo would depend upon the localization of IPF. These results raise the possibility that IPF may modulate synaptic transmission by acting as a quantal size regulator of one or more neurotransmitters.

Notes: Thermal conductivities Λ of amorphous carbon thin films are measured in the temperatures range 80–400 K using the 3ω method. Sample films range from soft a-C:H prepared by remote-plasma deposition (Λ=0.20 W m−1 K−1 at room temperature) to amorphous diamond with a large fraction of sp3 bonded carbon deposited from a filtered-arc source (Λ=2.2 W m−1 K−1). Effective-medium theory provides a phenomenological description of the variation of conductivity with mass density. The thermal conductivities are in good agreement with the minimum thermal conductivity calculated from the measured atomic density and longitudinal speed of sound. © 2000 American Institute of Physics.

Notes: Glutamate uptake by high affinity glutamate transporters is essential for preventing excitotoxicity and maintaining normal synaptic function. We have discovered a novel role for presenilin-1 (PS1) as a regulator of glutamate transport. PS1-deficient neurons showed a decrease in glutamate uptake of approximately 50% compared to wild-type neurons. Gamma-secretase inhibitor treatment mimicked the effects of PS1 deficiency on glutamate uptake. PS1 loss-of-function, accomplished by PS1 deficiency or γ-secretase inhibitor treatment, caused a corresponding decrease in cell surface expression of the neuronal glutamate transporter, EAAC1. PS1 deficiency is known to reduce intracellular calcium stores. To explore the possibility that PS1 influences glutamate uptake via regulation of intracellular calcium stores, we examined the effects of treating neurons with caffeine, thapsigargin, and SKF-96365. These compounds depleted intracellular calcium stores by distinct means. Nonetheless, each treatment mimicked PS1 loss-of-function by impairing glutamate uptake and reducing EAAC1 expression at the cell surface. Blockade of voltage-gated calcium channels, activation and inhibition of protein kinase C (PKC), and protein kinase A (PKA) all had no effect on glutamate uptake in neurons. Taken together, these findings indicate that PS1 and intracellular calcium stores may play a significant role in regulating glutamate uptake and therefore may be important in limiting glutamate toxicity in the brain.