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 demonstration of melt rate control during VAR of “Cracked” electrodes

A particularly challenging problem associated with vacuum arc remelting occurs when trying to maintain accurate control of electrode melt rate as the melt zone passes through a transverse crack in the electrode. As the melt zone approaches the crack, poor heat conduction across the crack drives the local temperature in the electrode tip above its steady-state value, causing the controller to cut back on melting current in response to an increase in melting efficiency. The difficulty arises when the melt zone passes through the crack and encounters the relatively cold metal on the other side, giving rise to an abrupt drop in melt rate. This extremely dynamic melting situation is very difficult to handle using standard load-cell based melt rate control, resulting in large melt rate excursions. We have designed and tested a new generation melt rate controller that is capable of controlling melt rate through crack events. The controller is designed around an accurate dynamic melting model that uses four process variables: electrode tip thermal boundary layer, electrode gap, electrode mass and melting efficiency. Tests, jointly sponsored by the Specialty Metals Processing Consortium and Sandia National Laboratories, were performed at Carpenter Technology Corporation wherein two 0.43 m diameter Pyromet® 718 electrodes were melted into 0.51 m diameter ingots. Each electrode was cut approximately halfway through its diameter with an abrasive saw to simulate an electrode crack. Relatively accurate melt rate control through the cuts was demonstrated despite the observation of severe arc disturbances and loss of electrode gap control. Subsequent to remelting, one ingot was sectioned in the “as cast” condition, whereas the other was forged to 0.20 m diameter billet. Macrostructural characterization showed solidification white spots in regions affected by the cut in the electrode.     

Metastatic parathyroid carcinoma in the MEN2A syndrome

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

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.     

Neural networks,rational functions,and realization theory

The problem of parametrizing single hidden layer scalar neural networks with continuous activation functions is investigated. A connection is drawn between realization theory for linear dynamical systems, rational functions, and neural networks that appears to be new. A result of this connection is a general parametrization of such neural networks in terms of strictly proper rational functions. Some existence and uniqueness results are derived. Jordan decompositions are developed, which show how the general form can be expressed in terms of a sum of canonical second order sections. The parametrization may be useful for studying learning algorithms.This work was supported by the Australian Research Council, the Australian Telecommunications and Electronics Research Board, and the Boeing Commencai Aircraft Company (thanks to John Moore).