All species of Mycobacteria synthesize distinctive cell walls that are rich in phosphatidylinositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). PIM glycolipids, having 2-4 mannose residues, can either be channeled into polar PIM species (with 6 Man residues) or hypermannosylated to form LM and LAM. In this study, we have identified a Mycobacterium smegmatis gene, termed lpqW, that is required for the conversion of PIMs to LAM and is highly conserved in all mycobacteria. A transposon mutant, Myco481, containing an insertion near the 3 end of lpqW exhibited altered colony morphology on complex agar medium. This mutant was unstable and was consistently overgrown by a second mutant, represented by Myco481.1, that had normal growth and colony characteristics. Biochemical analysis and metabolic labeling studies showed that Myco481 synthesized the complete spectrum of apolar and polar PIMs but was unable to make LAM. LAM biosynthesis was restored to near wild type levels in Myco481.1. However, this mutant was unable to synthesize the major polar PIM (AcPIM6) and accumulated a smaller intermediate, AcPIM4. Targeted disruption of the lpqW gene and complementation of the initial Myco481 mutant with the wild type gene confirmed that the phenotype of this mutant was due to loss of LpqW. These studies suggest that LpqW has a role in regulating the flux of early PIM intermediates into polar PIM or LAM biosynthesis. They also suggest that AcPIM4 is the likely branch point intermediate in polar PIM and LAM biosynthesis.Members of the genus Mycobacterium cause important diseases in humans, including tuberculosis and leprosy. Mycobacterium tuberculosis is thought to infect nearly one-third of the world population and to cause two to three million deaths each year (1). This threat to global health is growing as drug-resistant strains emerge and coinfections with human immunodeficiency virus increase the number of individuals with active tuberculosis. All species of mycobacteria synthesize a highly distinctive cell wall that contributes to the ability of pathogenic mycobacteria to survive within the endosomal network of human macrophages and to their innate resistance to many antibiotics. The mycobacterial cell wall has a multilaminate structure, comprising an asymmetric outer membrane and an inner layer of arabinogalactan polysaccharide and peptidoglycan (2, 3). The asymmetric outer membrane has an inner leaflet of tightly packed, long chain (C70 -C90) mycolic acids and an outer leaflet of free (glyco)lipids. This asymmetric outer membrane is responsible for the low permeability properties of the cell wall and also contains lipids that play key roles in the pathogenesis of these organisms.Although the (glyco)lipid composition of the mycobacterial cell wall can vary among mycobacterial species, all species synthesize an abundant class of phosphatidylinositol mannosides (PIMs) 7 and the hypermannosylated PIMs, lipomannan (LM) and lipoarabinomannan (LAM) (4, 5). The PIMs, LM and LAM, may be located in the plasm...
Summary:Purpose: Lateralization of language function is crucial to the planning of surgery in children with frontal or temporal lobe lesions. We examined the utility of functional magnetic resonance imaging (f MRI) as a determinant of lateralization of expressive language in children with cerebral lesions.Methods: f MRI language lateralization was attempted in 35 children (29 with epilepsy) aged 8-18 years with frontal or temporal lobe lesions (28 left hemisphere, five right hemisphere, two bilateral). Axial and coronal f MRI scans through the frontal and temporal lobes were acquired at 1.5 Tesla by using a blockdesign, covert word-generation paradigm. Activation maps were lateralized by blinded visual inspection and quantitative asymmetry indices (hemispheric and inferior frontal regions of interest, at p < 0.001 uncorrected and p < 0.05 Bonferroni corrected).Results: Thirty children showed significant activation in the inferior frontal gyrus. Lateralization by visual inspection was left in 21, right in six, and bilateral in three, and concordant with hemispheric and inferior frontal quantitative lateralization in 93% of cases. Developmental tumors and dysplasias involving the inferior left frontal lobe had activation overlying or abutting the lesion in five of six cases. f MRI language lateralization was corroborated in six children by frontal cortex stimulation or intracarotid amytal testing and indirectly supported by aphasiology in a further six cases. In two children, f MRI language lateralization was bilateral, and corroborative methods of language lateralization were left. Neither lesion lateralization, patient handedness, nor developmental versus acquired nature of the lesion was associated with language lateralization. Involvement of the left inferior or middle frontal gyri increased the likelihood of atypical language lateralization.Conclusions: f MRI lateralizes language in children with cerebral lesions, although caution is needed in interpretation of individual results.
Eight-year-old twins, one with a left frontal tumor and aphasic seizures, the other neurologically normal, underwent serial assessment of expressive language with functional magnetic resonance imaging and neuropsychology. The affected twin showed a significant amount of right hemisphere activation coincident with behavioral deterioration in expressive language and late growth in the tumor. This pattern of language dysfunction and the left language dominance of her co-twin suggested that the affected twin was also left dominant for language, and the significance of her right activation is discussed. We postulate that the right hemisphere activation represents a stabilizing mechanism in the context of a developmental and progressive lesion in language cortex rather than language transfer per se.
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