A model of the electrophysiological properties of thalamocortical relay neurons.

1. A model of the electrophysiological properties of single thalamocortical relay neurons in the rodent and cat dorsal lateral geniculate nucleus was constructed, based in part on the voltage dependence and kinetics of ionic currents detailed with voltage-clamp techniques. The model made the simplifying assumption of a single uniform compartment and incorporated a fast and transient Na+ current, INa; a persistent, depolarization-activated Na+ current, INap; a low-threshold Ca2+ current, I(T); a high-threshold Ca2+ current, IL; a Ca(2+)-activated K+ current, IC; a transient and depolarization-activated K+ current, IA; a slowly inactivating and depolarization-activated K+ current, IK2; a hyperpolarization-activated cation current, Ih; and K+ and Na+ leak currents IKleak and INaleak. 2. The effects of the various ionic currents on the electrophysiological properties of thalamocortical relay neurons were initially investigated through examining the effect of each current individually on passive membrane responses. The two leak currents, IKleak and INaleak, determined in large part the resting membrane potential and the apparent input resistance of the model neuron. Addition of IA resulted in a delay in the response of the model cell to a depolarizing current pulse, whereas addition of IK2, or IL combined with IC, resulted in a marked and prolonged decrease in the response to depolarization. Addition of Ih resulted in a depolarizing "sag" in response to hyperpolarization, whereas addition of IT resulted in a large rebound Ca2+ spike after hyperpolarization. Finally, addition of INap resulted in enhancement of depolarization. 3. The low-threshold Ca2+ spike of rodent neurons was successfully modeled with the active currents I(T), IL, IA, IC, and IK2. The low-threshold Ca2+ current I(T) generated the low-threshold Ca2+ spike. The transient K+ current IA slowed the rate of rise and reduced the peak amplitude of the low-threshold Ca2+ spike, whereas the slowly inactivating K+ current IK2 contributed greatly to the repolarization of the Ca2+ spike. Activation of IL during the peak of the Ca2+ spike led to activation of IC, which also contributed to the repolarization of the Ca2+ spike. Reduction of any one of the K+ currents resulted in an increase in the other two, thereby resulting in substantially smaller changes in the Ca2+ spike than would be expected on the basis of the amplitude of each ionic current alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Functional properties of a slowly inactivating potassium current in guinea pig dorsal lateral geniculate relay neurons.

1. The time- and voltage-dependent properties of a slowly inactivating and depolarization-activated potassium current and the functional consequences of its activation was investigated with current and single-electrode voltage-clamp techniques applied to guinea pig dorsal lateral geniculate neurons maintained as a slice in vitro. 2. In current clamp, application of a step depolarization to near firing threshold resulted in a slowly rising membrane potential that took up to 10 s to reach steady state and firing threshold. In voltage clamp, step depolarization of the membrane potential to values positive to approximately -65 mV resulted in the rapid activation followed by slow inactivation of an outward current. In both cases the sudden depolarization was associated with a large increase in membrane conductance, which gradually lessened in parallel with the slow depolarization in current clamp or with the decrease in outward current in voltage clamp. 3. The time course of inactivation of the outward current, which we refer to as IAs, was well fitted by a two-exponential function with time constants of 96 and 2,255 ms, suggesting the presence of a fast and slow phase of inactivation. The activation threshold for IAs was about -65 to -60 mV, whereas inactivation was incomplete even at -50 mV, suggesting the presence of a substantial "window" current. The time course of removal of inactivation of IAs at -85 to -100 mV was well fitted by a single exponential function with time constant of 91 ms. 4. IAs appears to be mediated by K+. Increasing [K+]o from 2.5 to 10 mM resulted in a reduction in amplitude of IAs, whereas changing from 10 to 2.5 mM [K+]o enhanced this current. Intracellular injection of Cs+ resulted in an abolition of IAs, whereas extracellular application of Ba2+ resulted in a large decrease in the apparent input conductance but relatively little reduction of IAs. 5. Both phases of inactivation of the transient outward current were completely blocked by low doses (100 microM) of 4-aminopyridine (4-AP), but not by extracellular application of Cs+, tetraethylammonium (TEA), tetrodotoxin (TTX), or after block of transmembrane Ca2+ currents. Local application of 4-AP to neurons depolarized to near firing threshold resulted in depolarization associated with a decrease in apparent input conductance, thereby confirming the presence of a window current.4+ this bias against depolarizing inputs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Kinds and locations of mutations arising spontaneously in the coding region of theHPRT gene of finite-life-span diploid human fibroblasts

Spontaneous thioguanine-resistant mutants were derived from populations of finite-life-span, diploid human fibroblasts by means of a fluctuation analysis. cDNA was prepared from mutantHPRT mRNA and amplified by the polymerase chain reaction, and the sequence of the product was analyzed. Exon deletions, which very likely arose from mutations in the intron splice site consensus sequences, were found in 10 of the 37 mutants examined (27% of the total). Among the 28 mutations in the coding sequence, base pair substitutions predominated (89%). With the exception of one base pair involved in a tandem mutation, all base pair substitutions resulted in alterations in the predicted amino acid sequence of the protein. In addition there were three frameshift mutations, consisting of the deletion of one or two base pairs. Although mutations occurred throughout the coding sequence, 50% (14/28) were found in the 5 portion of exon 3.     

Marrow regeneration after mechanical depletion

The origin of marrow regeneration after mechanical depletion was reinvestigated in mouse chimeras. The results were compatible with the local origin of stem cells from remnants of incompletely removed marrow, but not with their origin from a common precursor of both bone and hemopoietic cell lines. In transplanted femurs depleted by a modified technique of in vivo evacuation of marrow, hemopoietic regeneration failed to occur. The presence of hemopoietic stem cells in the Haversian canals was thus excluded. The demonstration of ample hemopoiesis with minimal bone formation in nondepleted controls in which bone marrow initially became necrotic provided new evidence that osteogenesis was not a prerequisite of hemopoietic regeneration.     

Effectiveness of specialized treatment programs for veterans with serious and persistent mental illness: a three-year follow-up

This is the first study to test concurrently the effectiveness of four treatment programs for patients with serious mental illness. Three-year outcome data on utilization and functioning demonstrated important positive changes for seriously mentally ill veterans enrolled in specialized, enhanced inpatient and community case management treatment programs, when compared to patients in an enhanced day treatment program or traditional standard care.     

Complicated stent supported cerebrovascular angioplasty: case analyses and review of literature

BACKGROUND: Hemodynamic lesions of the cervicocerebral vasculature are currently being treated with stent supported percutaneous transluminal angioplasty. These procedures have met with increasing success when compared to the risks and morbidity of more invasive surgical approaches. The versatility of stent-supported angioplasty as a primary therapeutic modality is examined in the following complex cases. CASE DESCRIPTION: We present four cases involving cervical angioplasty with emergent or adjunctive stent placement. Two cases involved the subclavian arteries, whereas the others involved the vertebral and internal carotid arteries. In our experience, complications of cervicocerebral artery angioplasty have been successfully managed by stent placement. CONCLUSION: Our cases demonstrate the emerging role of cervical angioplasty and stent implantation as a successful therapeutic modality, highlighted in these complex cases.     

Evaluation of neurodevelopmental outcome in highrisk infants in Australia

An understanding of the neurodevelopmental outcome of long-term survivors of neonatal intensive care is essential for the informed management of preterm or high risk infants. This annotation looks at the current status of neonatal follow-up services in Australasia and highlights problems in the collection and interpretation of data. It suggests that we should work towards achieving a consensus on standard definitions and test regimes and on national data collection.     

Adult height in patients with childhood onset atopic dermatitis

Cross sectional studies have reported impaired growth in children with atopic dermatitis. If this growth impairment is irreversible, it would be expected to adversely influence final height attainment. The standing heights and other anthropometric parameters were assessed in 35 adults with onset of atopic dermatitis before 5 years of age and a control group of 35 adults with adult onset contact dermatitis or psoriasis. There was no significant difference in the standing height SD score, mid-parental height SD score, sitting height SD score, subischial leg length SD score, nor body mass index between the atopic dermatitis and control groups. The standing height SD score was not significantly different among: (a) patients with atopic dermatitis affecting less than 50% of their body surface area and those with greater than 50% affected; (b) patients using the four different potency topical corticosteroids; and (c) patients with atopic dermatitis without asthma and those with coexisting asthma. It is concluded that short stature is not a feature of our group of adult patients with onset of atopic dermatitis before 5 years of age, continuing into adulthood, and severe enough to require specialist care. This suggests that if growth impairment occurs in childhood, it is likely to be temporary and reversible.     

Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells

Cell to cell communication via gap junctions is essential in the maintenance of the homeostatic balance of multicellular organisms. Aberrant intercellular gap junctional communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis. Oxidative stress has also been implicated in similar pathologies such as cancer. We report a potential link between oxidative stress and GJIC. Hydrogen peroxide, a known tumor promoter, inhibited GJIC in WB-F344 rat liver epithelial cells with an I50 value of 200 microM. Inhibition of GJIC by H2O2 was reversible as indicated by the complete recovery of GJIC with the removal of H2O2 via a change of fresh media. Free radical scavengers, such as t-butyl alcohol, propylgallate, and Trolox, did not prevent the inhibition of GJIC by H2O2, which indicated that the effects of H2O2 on GJIC was probably not a consequence of aqueous free radical damage. The depletion of intracellular GSH reversed the inhibitory effect of H2O2 on GJIC. The treatment of glutathione- sufficient cells with H2O2 resulted in the hyperphosphorylation of connexin43, which is the basic subunit of the hexameric gap junction protein, as determined by Western blot analysis. TPA, a well-known tumor promoter, also inhibits GJIC via hyperphosphorylation of GJIC, which is a result of protein kinase-C activation. However, H2O2 also induced hyperphosphorylation in GSH-deficient cells that had normal rates of GJIC. Therefore, the mechanism of GJIC inhibition must be different from the TPA-pathway and involves GSH.