Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.     

Continuous measurement of cardiac output by the Fick principle in infants and children: comparison with the thermodilution method

OBJECTIVE: To compare a system that continuously monitors cardiac output by the Fick principle with measurements by the thermodilution technique in pediatric patients. DESIGN: Prospective direct comparison of the above two techniques. SETTING: Pediatric intensive care unit of a university hospital. PATIENTS: 25 infants and children, aged 1 week to 17 years (median 10 months), who had undergone open heart surgery were studied. Only patients without an endotracheal tube leak and without a residual shunt were included. METHODS: The system based on the Fick principle uses measurements of oxygen consumption taken by a metabolic monitor and of arterial and mixed venous oxygen saturation taken by pulse- and fiberoptic oximetry to calculate cardiac output every 20s. INTERVENTIONS: In every patient one pair of measurements was taken. Continuous Fick and thermodilution cardiac output measurements were performed simultaneously, with the examiners remaining ignorant of the results of the other method. RESULTS: Cardiac output measurements ranged from 0.21 to 4.55 l/min. A good correlation coefficient was found: r2 = 0.98; P < 0.001; SEE = 0.41 l/min. The bias is absolute values and in percent of average cardiac output was - 0.05 l/min or - 4.4% with a precision of 0.32 l/min or 21.3% at 2 SD, respectively. The difference was most marked in a neonate with low cardiac output. CONCLUSION: Continuous measurement of cardiac output by the Fick principle offers a convenient method for the hemodynamic monitoring of unstable infants and children.     

A goal-striving life event and the onset of hypomanic and depressive episodes and symptoms: Perspective from the Behavioral Approach System (BAS) dysregulation theory.

On the basis of the behavioral approach system (BAS) dysregulation theory of bipolar disorder, this study examined the relation between occurrence of a BAS activation-relevant life event--goal striving--and onset of hypomanic and depressive episodes and symptoms. In particular, the authors examined the relation between preparing for and completing final exams (a goal-striving event) and onset of bipolar spectrum episodes and symptoms in college students with bipolar II disorder or cyclothymia (i.e., "soft" bipolar spectrum conditions). One hundred fifty-nine individuals with either a bipolar spectrum disorder (n=68) or no major affective psychopathology (controls; n=91) were further classified on the basis of whether they were college students (i.e., completed final exams). Consistent with the BAS dysregulation theory, preparing for and completing final exams was associated with an increase in hypomanic but not depressive episodes and symptoms in individuals with a soft bipolar spectrum diagnosis. Furthermore, self-reported BAS sensitivity moderated the presence of certain hypomanic symptoms during final exams. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors

The skeletal muscle relaxant dantrolene inhibits the release of Ca2+ from the sarcoplasmic reticulum during excitation-contraction coupling and suppresses the uncontrolled Ca2+ release that underlies the skeletal muscle pharmacogenetic disorder malignant hyperthermia; however, the molecular mechanism by which dantrolene selectively affects skeletal muscle Ca2+ regulation remains to be defined. Here we provide evidence of a high-affinity, monophasic inhibition by dantrolene of ryanodine receptor Ca2+ channel function in isolated sarcoplasmic reticulum vesicles prepared from malignant hyperthermia-susceptible and normal pig skeletal muscle. In media simulating resting myoplasm, dantrolene increased the half-time for 45Ca2+ release from both malignant hyperthermia and normal vesicles approximately 3.5-fold and inhibited sarcoplasmic reticulum vesicle [3H]ryanodine binding (Ki approximately 150 nM for both malignant hyperthermia and normal). Inhibition of vesicle [3H]ryanodine binding by dantrolene was associated with a decrease in the extent of activation by both calmodulin and Ca2+. Dantrolene also inhibited [3H]ryanodine binding to purified skeletal muscle ryanodine receptor protein reconstituted into liposomes. In contrast, cardiac sarcoplasmic reticulum vesicle 45Ca2+ release and [3H]ryanodine binding were unaffected by dantrolene. Together, these results demonstrate selective effects of dantrolene on skeletal muscle ryanodine receptors that are consistent with the actions of dantrolene in vivo and suggest a mechanism of action in which dantrolene may act directly at the skeletal muscle ryanodine receptor complex to limit its activation by calmodulin and Ca2+. The potential implications of these results for understanding how dantrolene and malignant hyperthermia mutations may affect the voltage-dependent activation of Ca2+ release in intact skeletal muscle are discussed.     

Control of contact in robots and biological systems

Summary form only given. The consequences of dynamic interaction caused by physical contact with objects is discussed. Robotic experience has demonstrated that contact with objects can result in unstable behavior, yet humans contact and manipulate objects with no evidence of contact instability. It is shown that impedance control may be used in a robot or prosthesis to eliminate contact instability. Evidence that a similar approach may be the basis of human motor behavior in comparable tasks is reviewed. A model based on exploitation of apparent neuromuscular impedance is shown to be remarkably competent to reproduce fine details of multi-joint reaching behavior. The implication of this model is that some of the stability properties associated with posture are preserved during movement and may be used to simplify its execution. Experiments in which human subjects held the handle of a manipulandum and performed simple reaching motions to visually presented targets are described     

Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors

Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of inhaled anaesthetics. The function of GABA(A) and glycine receptors is enhanced by a number of anaesthetics and alcohols, whereas activity of the related GABA rho1 receptor is reduced. We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric receptor constructs, we have identified a region of 45 amino-acid residues that is both necessary and sufficient for the enhancement of receptor function. Within this region, two specific amino-acid residues in transmembrane domains 2 and 3 are critical for allosteric modulation of both GABA(A) and glycine receptors by alcohols and two volatile anaesthetics. These observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetics.