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Background-Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ).

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Protein kinase A (PKA) phosphorylation of myofibril proteins constitutes an important pathway for β-adrenergic modulation of cardiac contractility and relaxation. PKA targets the N-terminus (Ser-23/24) of cardiac troponin I (cTnI), cardiac myosin-binding protein C (cMyBP-C) and titin. The effect of PKA-mediated phosphorylation on the magnitude of contraction has been studied in some detail, but little is known about how it modulates the kinetics of thin filament activation and myofibril relaxation as Ca(2+) levels vary. Troponin C (cTnC) interaction with cTnI (C-I interaction) is a critical step in contractile activation that can be modulated by cTnI phosphorylation. We tested the hypothesis that altering C-I interactions by PKA, or by cTnI phosphomimetic mutations (S23D/S24D-cTnI), directly affects thin filament activation and myofilament relaxation kinetics. Rat ventricular myofibrils were isolated and endogenous cTn was exchanged with either wild-type cTnI, or S23D/S24D-cTnI recombinant cTn. Contractile mechanics were monitored at maximum and submaximal Ca(2+) concentrations. PKA treatment of wild-type cTn or exchange of cTn containing S23D/S24D-cTnI resulted in an increase in the rate of early, slow phase of relaxation (kREL,slow) and a decrease in its duration (tREL,slow). These effects were greater for submaximal Ca(2+) activated contractions. PKA treatment also reduced the rate of contractile activation (kACT) at maximal, but not submaximal Ca(2+), and reduced the Ca(2+) sensitivity of contraction. Using a fluorescent probe coupled to cTnC (C35S-IANBD), the Ca(2+)-cTn binding affinity and C-I interaction were monitored. Ca(2+) binding to cTn (pCa50) was significantly decreased when cTnI was phosphorylated by PKA (ΔpCa50 = 0.31). PKA phosphorylation of cTnI also weakened C-I interaction in the presence of Ca(2+). These data suggest that weakened C-I interaction, via PKA phosphorylation of cTnI, may slow thin filament activation and result in increased myofilament relaxation kinetics, the latter of which could enhance early phase diastolic relaxation during β-adrenergic stimulation.

Background: R146G and R21C mutations in cardiac TnI are associated with hypertrophic cardiomyopathy. Results: Both mutations blunt PKA-mediated effects on weakening cTnI-cTnC interaction and accelerating myofibril relaxation. Conclusion: Both mutations result in hypercontraction and impaired relaxation, which may contribute to increased risk to traumatic heart failure. Significance: This study increases mechanistic understanding of how single amino acid mutations result in cardiac contractile dysfunction.

During β-adrenergic stimulation, cardiac troponin I (cTnI) is phosphorylated by protein kinase A (PKA) at sites S23/S24, located at the N-terminus of cTnI. This phosphorylation has been shown to decrease KCa and pCa50, and weaken the cTnC-cTnI (C-I) interaction. We recently reported that phosphorylation results in an increase in the rate of early, slow phase of relaxation (kREL,slow) and a decrease in its duration (tREL,slow), which speeds up the overall relaxation. However, as the N-terminus of cTnI (residues 1-40) has not been resolved in the whole cardiac troponin (cTn) structure, little is known about the molecular-level behavior within the whole cTn complex upon phosphorylation of the S23/S24 residues of cTnI that results in these changes in function. In this study, we built up the cTn complex structure (including residues cTnC 1-161, cTnI 1-172, and cTnT 236-285) with the N-terminus of cTnI. We performed molecular-dynamics (MD) simulations to elucidate the structural basis of PKA phosphorylation-induced changes in cTn structure and Ca(2+) binding. We found that introducing two phosphomimic mutations into sites S23/S24 had no significant effect on the coordinating residues of Ca(2+) binding site II. However, the overall fluctuation of cTn was increased and the C-I interaction was altered relative to the wild-type model. The most significant changes involved interactions with the N-terminus of cTnI. Interestingly, the phosphomimic mutations led to the formation of intrasubunit interactions between the N-terminus and the inhibitory peptide of cTnI. This may result in altered interactions with cTnC and could explain the increased rate and decreased duration of slow-phase relaxation seen in myofibrils.

Aggression after traumatic brain injury (TBI) is common but not well defined. Sixty-seven participants with first-time TBI were seen within three months of injury and evaluated for aggression. The prevalence of aggression was found to be 28.4% and to be predominantly verbal aggression. Post-TBI aggression was associated with new-onset major depression (p=0.02), poorer social functioning (p=0.04), and increased dependency on activities of daily living (p=0.03), but not with a history of substance abuse or adult/childhood behavioral problems. Implications of the study include early screening for aggression, evaluation for depression, and consideration of psychosocial support in aggressive patients.

Background Major depression afflicts 20–25% of patients with dementia. Of these, about a third do not improve with antidepressant therapy and may be suitable candidates for electronconvulsive treatment (ECT). However, the use of ECT is dementia patients is concerning due to possible adverse effects on memory and cognition. Outcome studies of ECT in patients with primary dementia and depression are very rare. Objective To determine the effectiveness and complications of ECT treatment for depression in dementia. Method A chart review was conducted of all 31 patients wit ha discharge diagnosis of ‘Dementia with depression’ treated with ECT at the Johns Hopkins Hospital, over a five‐year period. Admission and discharge ratings were made on the Mini‐Mental State Examination (MMSE) and the Montgomery–Asberg Depression Rating Scale (MADRS) as part of the clinical routine. Results All patients suffered from dementia: 55% had vascular dementia, 13% Alzheimer's disease, and 32% degenerative dementia of uncertain etiology. The admission MADRS mean score was 27.5 (SD 8.1) and the MMSE mean score was 18.8 (SD 5.5). The patients received between 1 and 23 ECT treatments (mean 9, SD 5.7). At discharge, there was a statistically significant mean decline on the MADRS of 12.28 points (p<0.01). Forty percent had scores less than 10 (normal) on the MADRS. While 49% of patients developed delirium, by discharge there was also a significant mean increase (improvement) in MMSE of 1.62 points (p<0.02). Conclusions ECT is an effective treatment for depression in dementia, leading to improvements in both mood and cognition. Multiple ECT treatments may be necessary before a significant improvement in mode is achieved. Copyright © 2000 John Wiley & Sons, Ltd.