Effect of subthreshold voltage-dependent conductances on the transfer function of branched excitable cells and the conduction of synaptic potentials

1. Impulse response functions were determined from complex point impedance and transfer functions from cultured NG-108 cells to simulate the propagation of a synaptic potential in response to the release of transmitter. In general, the flow of synaptic current has a much shorter duration than the normal membrane time constant, thereby making the use of impulse response functions useful approximations to synaptic events. 2. The resonance observed during the activation of the potassium conductance was reflected in the impulse response function as a pronounced damped oscillation. A comparison of the impulse response functions calculated from point impedance and transfer functions showed similar results for current injections in the growth cone. 3. In addition to the resonance effects of the voltage-dependent conductances on transfer and impulse response functions due principally to the activation of conductances for outward currents, transfer functions were measured during the activation of a steady-state negative conductance. Under these conditions the phase function approaches 180 degrees, indicating that the voltage response is out of phase with the current. 4. In the steady state, the effect of a negative conductance is to algebraically add to the positive conductances and generally decrease the absolute conductance unless there is a net negative current. The decreased conductance enhances the impulse response and the DC space constant, thus leading to a better propagation of slow potentials. This effect can be seen as a decrease in the electrotonic length, L, with intermediate depolarizations. At large depolarizations the steady-state activation of the K conductance generally dominates and leads to a greatly increased electrotonic length. 5. Both the net conductances and the associated kinetics play a role in shaping the potential changes during a synaptic current. This is especially critical if there is a net negative steady-state conductance. Under these conditions there is a surprising reduction in the impulse response function. 6. Thus, during a subthreshold activation of the voltage-dependent negative conductances, the observable synaptic potentials would be either large potential responses due to an apparent increase in the impedance (algebraic summation of positive and negative conductances with a net positive conductance) or a minimal response because of the phasic cancellation due to a net negative conductance. The latter condition could exist near the synaptic reversal potential due to a large synaptic drive and would appear experimentally as a form of inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)     

Growth hormone therapy in achondroplasia.

A pilot study was carried out to examine the safety and efficacy of recombinant human growth hormone for growth-promoting therapy of achondroplasia. The data suggest that the agent in doses used to treat non-GH-deficient forms of short stature (0.3 mg/kg/wk) modestly increases overall height velocity in some children with achondroplasia. The effect was seen mainly in children with the lowest growth velocities prior to treatment. No untoward effects were noted. Several questions were raised that require further study.     

Reactivity of microhemagglutination, fluorescent treponemal antibody absorption, Venereal Disease Research Laboratory, and rapid plasma reagin tests in primary syphilis.

Seroreactivity of sera from 109 patients with first-infection primary syphilis was 98.2% in the fluorescent treponemal antibody absorption test, 92.7% in the rapid plasma reagin 18-mm circle card test, 72.5% in the microhemagglutination test (MHA-TP), and 72.5% in the Venereal Disease Research Laboratory test. Seroreactivity of sera from 18 patients with primary syphilis with documented previous infection(s) was 100% in the fluorescent treponemal antibody absorption test, the rapid plasma reagin 18-mm circle card test, and the MHA-TP test and 88.9% in the Venereal Disease Research Laboratory test. The MHA-TP test failed to confirm reactivity in 13 of 79 sera which were reactive in the Venereal Disease Research Laboratory test and in 24 of 101 sera which were reactive in the rapid plasma reagin 18-mm circle card test. Testing another production lot of MHA-TP reagents resulted in even poorer correlation. The reactivity of the MHA-TP test in primary syphilis appeared to vary with the sensitivity of the production lot of reagents.     

Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome?

We report on a boy with congenital scalp and limb defects, consistent with a diagnosis of Adams-Oliver syndrome (aplasia cutis congenita with terminal transverse limb defects). An additional finding present in this child and in his mother was cutis marmorata telangiectatica congenita. Although this boy fits the diagnostic criteria for Adams-Oliver syndrome, his mother does not. We discuss whether this condition is highly variable, or heterogeneous.     

Resonance of spike discharge modulation in neurons of the guinea pig medial vestibular nucleus

The modulation of action potential discharge rates is an important aspect of neuronal information processing. In these experiments, we have attempted to determine how effectively spike discharge modulation reflects changes in the membrane potential in central vestibular neurons. We have measured how their spike discharge rate was modulated by various current inputs to obtain neuronal transfer functions. Differences in the modulation of spiking rates were observed between neurons with a single, prominent after hyperpolarization (AHP, type A neurons) and cells with more complex AHPs (type B neurons). The spike discharge modulation amplitudes increased with the frequency of the current stimulus, which was quantitatively described by a neuronal model that showed a resonance peak >10 Hz. Modeling of the resonance peak required two putative potassium conductances whose properties had to be markedly dependent on the level of the membrane potential. At low frequencies (< or =0.4 Hz), the gain or magnitude functions of type A and B discharge rates were similar relative to the current input. However, resting input resistances obtained from the ratio of the membrane potential and current were lower in type B compared with type A cells, presumably due to a higher level of active potassium conductances at rest. The lower input resistance of type B neurons was compensated by a twofold greater sensitivity of their firing rate to changes in membrane potential, which suggests that synaptic inputs on their dendritic processes would be more efficacious. This increased sensitivity is also reflected in a greater ability of type B neurons to synchronize with low-amplitude sinusoidal current inputs, and in addition, their responses to steep slope ramp stimulation are enhanced over the more linear behavior of type A neurons. This behavior suggests that the type B MVNn are moderately tuned active filters that promote high-frequency responses and that type A neurons are like low-pass filters that are well suited for the resting tonic activity of the vestibular system. However, the more sensitive and phasic type B neurons contribute to both low- and high-frequency control as well as signal detection and would amplify the contribution of both irregular and regular primary afferents at high frequencies.     

The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer

The hepatitis B virus (HBV) genome contains a specific DNA binding site for the glucocorticoid receptor. Using DNase I footprinting, this binding site was localized at HBV map positions 341-370 clockwise from the EcoRI site. The DNA sequence protected in the footprint contains two tandem copies of the GRE core hexanucleotide 5'-TGTTCCT-3'. Deletion analysis and reconstruction experiments in plasmid expression vectors demonstrated that this glucocorticoid receptor binding sequence serves as a signal for augmenting glucocorticoid-dependent activity of the HBV enhancer, which is located approximately 730 nucleotides downstream in the HBV genome. Even though it does not serve as an independent enhancer element, the HBV glucocorticoid receptor domain can therefore be categorized as a functional GRE.     

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.     

Characterization and identification of an iron-oxidizing,Leptospirillum-like bacterium,present in the high sulfate leaching solution of a commercial bioleaching plant

Most copper bioleaching plants operate with a high concentration of sulfate salts, caused by the continuous addition of sulfuric acid and the recycling of the leaching solution. Since the bacteria involved in bioleaching have been generally isolated at low sulfate concentrations, the bacterial population present in the high-sulfate (150 gl(-1)) leaching solution, employed in a copper production plant, was investigated. The iron-oxidizing bacteria able to grow in the leaching solution were enriched by several batch cultivations and, after serial dilution, an abundant bacterial strain was isolated. This strain, called LA, exhibited a relatively constant rate of iron-oxidation in media containing sulfate ions at concentrations ranging from 10 to 150 gl(-1). Culture collection strains of Leptospirillum ferrooxidans and Acidithiobacillus ferrooxidans showed limited abilities to grow at sulfate ion concentrations higher than 70 gl(-1). In spite of its tolerance to high sulfate concentrations, strain LA was as sensitive to NaCl as A. ferrooxidans. Comparative sequence analysis of the 16S rRNA gene of strain LA indicated that it is phylogenetically related to strains described as Leptospirillum ferrooxidans. Bacterial community DNA restriction patterns of 16S rRNA genes suggested that strain LA was a minor component of the bacterial population present in leaching solution, but is abundant in ore leached with this solution.