A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.     

Localization of tissue transglutaminase in human carotid and coronary artery atherosclerosis: implications for plaque stability and progression

Although atherosclerosis progresses in an indolent state for decades, the rupture of plaques creates acute ischemic syndromes that may culminate in myocardial infarction and stroke. Mechanical forces and matrix metalloproteinase activity initiate plaque rupture, whereas tissue inhibitors of metalloproteinases have an important (albeit indirect) role in plaque stabilization. In this paper, an enzyme that could directly stabilize the plaque is described. Tissue transglutaminase (TG) catalyzes the formation of epsilon(gamma-glutamyl)lysine isopeptide bonds that are resistant to enzymatic, mechanical, and chemical degradation. We performed immunohistochemistry for TG in atherosclerotic human coronary and carotid arteries. TG was most prominent along the luminal endothelium and in the medium of the vessels with a distribution mirroring that of smooth muscle cells. Variable, often prominent, immunoreactivity for TG was also seen in the intima, especially in regions with significant neovascularization. Additionally, TG was detected in fibrous caps and near the "shoulder regions" of some plaques. A monoclonal antibody to the transglutaminase product epsilon(gamma-glutamyl)lysine isopeptide demonstrated co-localization with TG antigen. Transglutaminase activity was found in 6 of 14 coronary artery atherectomy samples. Cross-linking of TG substrates such as fibrinogen, fibronectin, vitronectin, collagen type I, and protease inhibitors stabilized the plaque. Furthermore, the activation of transforming growth factor-beta-1 by TG might be an additional mechanism for the promotion of plaque stabilization and progression by increasing the synthesis of extracellular matrix components.     

Psychological and neuropsychological aspects of COPD

A review of the literature dealing with the effects of chronic obstructive pulmonary disease (COPD) on psychological and neuropsychological functioning indicates that significant emotional and adaptive deficits characterize this patient population. Psychiatric consultation can provide valuable assistance to the primary care physician by reducing emotional distress and correcting dysfunctional attitudes and beliefs. Neuropsychological assessment can elucidate an individual's neurobehavioral resources and deficits.     

Electrophysiological neurodifferentiation of subventricular zone-derived precursor cells following stroke

Stroke in rodents is associated with increased neurogenesis and the migration of newborn neurons to sites of brain ischemia, where they may participate in repair and recovery. To determine if neurogenesis following stroke yields functional new neurons, we labeled neuronal precursors in the mouse subventricular zone (SVZ) with a lentivirus-green fluorescent protein vector, produced stroke by occluding the middle cerebral artery, and detected newborn neurons 8 weeks later by fluorescence microscopy. Patch-clamp studies on fluorescent neurons in the cortical region surrounding infarction showed tetrodotoxin-sensitive Na⁺ action potentials and spontaneous excitatory post-synaptic currents, suggesting that ischemia led to functional neurogenesis with synaptic integration. These findings support the hypothesis that enhancing endogenous neurogenesis after stroke might have therapeutic benefit.     

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

Human mini-chromosomes in mouse embryonal stem cells

We have introduced human mini-chromosomes of 4 Mb and approximately 15 Mb in size into mouse embryonal stem cells. Although these human mini- chromosomes are stable in hamster and chicken cells, they re-arrange or segregate aberrantly in the embryonal stem cells and are rapidly lost in the absence of selection. However, one of the mini-chromosomes re- arranged, acquired mouse centromeric sequences and was then stably maintained for at least 60 population doublings in culture. This mini- chromosome, which is 4 Mb in size, is a candidate for a mouse germ line chromosome vector.      

Enhancement of antigen incorporation and infectivity of cell cultures by human rotavirus.

Infection of cell cultures with human rotavirus preparations was attempted and the effects of trypsin and low-speed centrifugation on antigen incorporation, as demonstrated by immunofluorescence and radioimmunoassay, were determined. In addition, the effect of viral aggregation on antigen incorporation was investigated by filtering viral preparations. Four strains of human rotavirus were employed, and the results were compared to those obtained with two tissue culture-adapted animal rotaviruses. Centrifugation and trypsin appeared to have little or no effect on infectivity of the tissue culture-adapted (simian rotavirus) or -adaptable (Nebraska calf diarrhea virus) strains, whereas centrifugation and viral aggregation appeared to be essential for the human viruses. In addition, trypsin enhanced antigen incorporation of the human strains to some extent. Infectivity for cell cultures and in vitro human rotavirus protein formation was demonstrated by [35S]methionine incorporation, and the specificity of this human viral protein was established by radio-immunoprecipitation.     

The lung in cystic fibrosis. A quantitative study including prevalence of pathologic findings among different age groups.

The autopsies of 82 patients with cystic fibrosis were reviewed with respect to pathologic changes in the lungs and their respective prevalence among different age groups. Although bronchitis, mucopurulent plugging, and bronchopneumonia were almost universally present among children of all ages, epithelial metaplasia and bronchiectasis were rarer among infants and progressively more prevalent in older age groups. Emphysema was absent in patients under two years of age and affected 11 per cent of the patients two to six years of age and 40 per cent of the patients older than six years, but was never of a severe degree by the point count method. Pulmonary hemorrhage, although uncommon, was usually associated with prominent arterial vessels in walls of bronchiectatic airways. Quantitative assessment of bronchial glands revealed Reid indices significantly higher in patients with cystic fibrosis when compared to noncystic fibrosis patients, but there was no increase in these indices with the age of the patients. Glandular hypertrophy, predominance of mucous acini within glands, and goblet cell hyperplasia of the bronchial mucosa all suggest an explanation for the copious mucous secretion of patients with cystic fibrosis. However, it was not possible to ascertain whether these findings reflect a general exocrine defect of such patients or whether they were merely a response to chronic airway infection, even though the latter is a more plausible assumption.     

Effects of glucocorticoids on the rabbit carotid body

Weekly intramuscular injections of slow-release, depot methyl prednisolone to 15 adult Dutch rabbits did not bring about an increase in the volume of their carotid bodies. However, they caused swelling of chief cells with discrete areas of pallor in the cytoplasm. Factors responsible for these changes appear to be increased storage of catecholamines and an increased number of swollen mitochondria.