Positron emission tomography and central neurotransmitter systems in movement disorders

Summary— This article discusses the anatomical and neurochemical structure of the basal ganglia and reviews the Positron Emission Tomographic (PET) ligands available for investigating these pathways. We discuss how clinical PET studies have improved our understanding of the neurochemical changes underlying principal movement disorders.     

Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms

Acute myeloid leukemia (AML) cells respond to exogenous stimulation from myeloid growth factors that may be secreted by cells of the bone marrow (BM) stroma and retained by glycosaminoglycans in the extracellular matrix. We have analyzed the capacity of malignant cells from patients with AML to maintain close proximity to sites of growth factor production and retention by binding to BM stromal elements, including fibroblasts and extracellular matrix proteins. Leukemic cells from all cases of AML adhered to BM fibroblast (BMF) monolayers (mean +/- standard error [SE] percentage binding, 30.9% +/- 2.5%; n = 23) and to fibronectin and laminin (mean +/- SE percentage binding, 28.0% +/- 4.1% [n = 11] and 21.5% +/- 2.3% [n = 8], respectively). Binding to bovine and human collagen type 1, vitronectin, hyaluronic acid, and albumin was minimal. Analysis of binding mechanisms indicated that very late antigen-4 (VLA-4) and VLA-5 were responsible for AML cell binding to fibronectin. Binding to laminin could be inhibited by antibody to the alpha chain of VLA-6. In contrast, AML cell adhesion to BMF monolayers was not impaired by blocking antibodies to either beta 1 or beta 2 integrins used alone, although the combination of anti-CD11/CD18 and anti-VLA-4 inhibited binding in more than 50% of cases. When anti- VLA-5 was added in these cases, mean +/- SE inhibition of binding of 45.5% +/- 9.1% (P < .001) was observed. Binding of AML cells to extracellular matrix proteins fibronectin and laminin is predominantly beta 1-integrin-dependent, but AML cell adhesion to BMF relies on the simultaneous involvement of beta 1 and beta 2 integrins as well as other currently unrecognized ligands.     

Fifteen-year experience with 1678 Hancock porcine bioprosthetic heart valve replacements

The Hancock porcine valve was the first commercially available biologic heart valve and has been in continuous use at the Brigham and Women's Hospital since January 1972. Through December 1987 we implanted 1678 valves in 1533 patients (885 male; 648 female; 17 to 95 years of age, with a mean of 60 years). There were 825 aortic valve replacements (AVR), 562 isolated mitral valve replacements (MVR), and 146 aortic mitral replacements (DVR). Ninety-four per cent of the patients were functional class III or IV. Associated coronary bypass was done in 25% of patients. Four per cent of patients were lost to follow up during a 1- to 16-year period with a mean of 6 years. Morbidity and mortality rates on a actuarial basis were calculated 10 and 15 years after operation for AVR, MVR, and DVR. The data indicates that the probability of reoperation for structural valve failure is quite reasonable as of 10 years, but from 10 to 15 years the numbers sharply fall off so that the probable effective life of the valve is 10 years. However in the elderly age group (equal to or greater than 70 years of age) the incidence of structural valve degeneration is markedly diminished, making this an ideal valve substitute for the elderly. It is also an ideal valve substitute in any patient who has a contraindication to long-term anticoagulation because of current medical or surgical problems.     

Dendritic dynamics in vivo change during neuronal maturation

In vivo imaging of optic tectal neurons in the intact Xenopus tadpole permits direct observation of the structural dynamics that occur during dendritic arbor formation. Based on images of single DiI-labeled neurons collected at daily intervals over a period of 6 d, we divided tectal cell development into three phases according to the total length of the dendritic arbor. During phase 1, the cell differentiates from a neuroepithelial cell type and extends an axon out of the tectum. The total dendritic branch length (TDBL) is <100 micrometers. During phase 2, when TDBL is 100-400 micrometers, the dendritic arbor grows rapidly. During phase 3, when TDBL is >400 micrometers, the dendritic arbor grows slowly and appears stable. Neurons at different positions along the rostrocaudal developmental axis of the tectum were imaged at 2 hr intervals over 6 hr and at 24 hr intervals over several days. Images collected at 2 hr intervals were analyzed to determine rates of branch additions and retractions. Morphologically complex, phase 3 neurons show half the rate of branch additions and retractions as phase 2 neurons. Therefore, rapidly growing neurons have dynamic dendritic arbors, and slower-growing neurons are structurally stable. The change in growth rate and dendritic arbor dynamics from phase 2 to phase 3 correlates with the developmental increase in synaptic strength in neurons located along the rostrocaudal tectal axis. The data are consistent with the idea that strong synaptic inputs stabilize dendritic arbor structures and that weaker synaptic inputs are permissive for a greater degree of dynamic rearrangements and a faster growth rate in the dendritic arbor.     

Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.

The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.     

Hippocampus development and function: role of epigenetic factors and implications for cognitive disease

Lagali PS, Corcoran CP, Picketts DJ. Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. The hippocampus is a primary region of the brain controlling the formation of memories and learned behaviours. The ability to learn or form a memory requires a neuron to translate a transient signal into gene expression changes that have a long‐lasting effect on synapse activity and connectivity. Numerous studies over the past decade have detailed changes in epigenetic modifications under various learning paradigms to support a role for chromatin remodelling in these processes. Moreover, the identification of mutations in epigenetic regulators as the cause of mental retardation or intellectual disability (MR/ID) disorders further strengthens their importance to learning and memory. Animal models for many of these disorders are emerging and advancing our understanding of the molecular mechanisms linking epigenetic regulation and cognitive function. Here, we review how chromatin remodelling proteins implicated in MR/ID contribute to the development of the hippocampus and memory formation.