H. T. Hutchison

In vitro demonstration of an endothelial proliferative factor produced by neural cell lines.

Cultured endothelial cells exhibit a six- to tenfold increase in thymidine labeling index in response to a soluble factor elaborated by clonal cell lines of neural origin. This factor, endothelial proliferation factor, appears to be a unique property of tumor cells and may mediate the vascularization of these neoplasms.

High-affinity transport of glutamate in rat brain microvessels

The maintenance of low extracellular concentrations of glutamate in the brain is a complex process in which the role of capillary transport is poorly understood. We examined the kinetics and substrate specificity of glutamate uptake by isolated rat brain microvessels. We showed that these microvessels take up glutamate by an energy- and temperature-dependent, concentrative, high-affinity active transport system with Km of about 2 microM. The presence of this active transport system, coupled with the known slow inward transport of glutamate across the blood-brain barrier, allows us to suggest that this capillary transport system may function in vivo in the unidirectional outward transport of glutamate from brain to blood.

Uptake of biogenic amines by glial cells in culture I. A neuronal-like transport system for serotonin

Abstract Rat C6 astrocytoma cells take up serotonin (5HT) via a high affinity carrier mediated system with Km of 1 micromolar, and a second component of lower affinity. This high affinity 5HT transport system is rapid, concentrative, and highly sodium and temperature dependent. Chlorimipramine and Lilly 110140 preferentially block the glial 5HT but not NE uptake. This preferential inhibition has previously been shown for synaptosomes and brain slices. Norepinerphrine (NE) and to a lesser extent dopamine (DA) block the glial 5HT uptake, suggesting a partial overlap between the catecholamine and indoleamine glial carrier systems. 5-Hydroxy but not 6-hydroxy dopamine inhibits the high affinity 5HT transport in glia. A variety of ring hydroxylated indoleamine analogs block this glial 5HT transport; of the compounds tested, 5, 7 dihydroxytryptamine is the least effective inhibitor. Phenylethylamine (PEA) and its 0-methylated derivatives block synaptosomal and glial 5HT transport equally well. These observations suggest that cultured C6 cells used as models of glia possess a 5HT transport system which kinetically and pharmacologically resembles a neuronal 5HT transport system.

Subacute sclerosing panencephalitis in the differential diagnosis of encephalitis

The authors describe five cases of subacute sclerosing panencephalitis (SSPE) identified through the California Encephalitis Project that emphasize the importance of considering SSPE in the differential diagnosis of encephalitis, particularly among pediatric patients. SSPE was not suspected in the differential diagnosis of three of the cases until results of measles testing were known. The diagnosis of SSPE is often not considered by clinicians because of its rarity in the United States and the nonspecific clinical manifestations at onset.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD‐like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X‐linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Uptake of neurotransmitters and precursors by clonal cell lines of neural origin.

Intercellular communication is a fundamental process underlying behavior. The importance of communication between neurons in determining behavior is undisputed, but recent evidence suggests that communication between glia and neurons and between glia and other cell types may be of significance in the modulation of behavior. It is well established that the principal mode of inactivation of neurotransmitters, other than acetylcholine, is by reuptake into presynaptic terminals1. However, the close spatial relationships, of neurons and glia, and the glial ensheathment of axons and synapses, suggest that glia, as well as neurons, may participate in the uptake of synaptically released neurotransmitters2, 3 In so far as synaptic transmission depends in part on levels of the transmitter in the cleft, rapid removal of transmitter, either by neurons or glia, will influence or modulate efficacy of transmission. To demonstrate a significant glial role in the modulation of synaptic transmission, it is first necessary to show that glial cells possess mechanisms for the accumulation of transmitter which are comparable in substrate affinity to the pumps present in the specific nerve endings using that transmitter.

Estimation of parameters in double uptake systems

Abstract A method is presented for estimating the kinetic parameters describing the cellular uptake of a single molecular species mediated by two independent transport processes. Two cases are considered: first, uptake by two carrier-mediated transport systems, and second, uptake by a single carrier-mediated system and diffusion. Unweighted and weighted least-squares estimations are described; the unweighted estimation is noniterative and provides excellent first approximations for the iterative weighted estimation procedure.

Uptake of neurotransmitters and precursors by clonal lines of astrocytoma and neuroblastoma: III. Transport of choline

Clonal lines of glial, neuronal, and nonneural origin accumulate choline via a high-affinity carrier-mediated transport system withKm in the range of 10–14 μM. These cell lines also accumulate choline by a second system that is not saturable at 10 mM choline, and that may represent diffusion. The transport of choline in glial cells differs from that seen in neuronal cells with respect to its Na+ requirement. The omission of Na+ from the incubation medium reduces high-affinity choline transport in neuronal cells and enhances it in glial cells. Kinetic analysis of the data indicates that reversible cholinesterase inhibitors and hemicholinium-3 (HC-3) inhibit the high-affinity transport system for choline. On the other hand, the diffusional or low-affinity component of choline transport in either cell type appears to have no Na+ requirement and is unaffected by either cholinesterase inhibitors or 10−4 M HC-3. The neuronal-glial differences in the Na+ requirement of choline transport may be related to the coupling of transport to choline metabolism, which differs in the two cell types. The presence of a high-affinity transport system for choline in clonal glial lines used as models of normal glia suggest that glia may modulate the availability of choline for acetylcholine synthesis at cholinergic synapses.

Pyruvate carboxylase activity in subacute necrotizing encephalopathy (Leigh's disease)

Leighs disease is a heterogeneous group of disorders, in which clinical and biochemical features suggest abnormal pyruvate metabolism. In two patients with Leighs disease, diagnosed according to rigorous clinical, radiographic, and histologic criteria, we tested the hypothesis that pyruvate carboxylase deficiency might be the primary etiology. Pyruvate carboxylase specific activities in extracts of cultured skin fibroblasts from both patients were in the normal range. These results, together with other evidence, suggest that isolated pyruvate carboxylase deficiency does not cause the Leighs disease phenotype.

Endothelial Proliferation Factor

The viability of the brain is predicated upon its blood supply. Nowhere is the process of vascularization of the brain more dramatically visualized than in the expansion of the capillary bed within and around tumors of the CNS (6). Recent evidence suggests that this endothelial proliferation (or neovascularization as it is often called) is mediated by a soluble factor (12) released by the growing tumor cells as proposed earlier by Algire (1). The new vessels are recruited by the tumor from the already existent host vasculature in the region of the tumor (1, 26).