Clara cell secretory protein deficiency alters clara cell secretory apparatus and the protein composition of airway lining fluid

Clara cells represent the predominant secretory cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara cell secretory protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara cell secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara cell ultrastructure revealed dramatic alterations in secretory apparatus between wild-type (WT) and CCSP knockout (CCSP-/-) mice. Secretory granules, which occupy greater than 2% of Clara cell cytoplasmic volume in WT mice, were completely absent among Clara cells of CCSP-/- mice. Moreover, Clara cells of CCSP-/- mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara cells were associated with altered protein composition of airway lining fluid as revealed by two-dimensional gel analysis of bronchoalveolar lavage proteins, but were not associated with altered abundance or secretion of CC26, another Clara cell secretory protein. We conclude that CCSP is required for the appearance of Clara cell secretory granules and that functional changes to Clara cells that result from CCSP deficiency lead to alterations in the composition of epithelial lining fluid.     

Loss of heterozygosity mutations of tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis

The relationship between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is a subject of controversy. Some investigators suggest a causal relationship, whereas others regard the two as only a coincidental occurrence. An additional complicating factor is the presence of atypical nuclei frequently found within lymphoid infiltrates in CLT, which resemble those in PTC. The finding of the RET-PTC translocations in CLT has been reported by two independent groups of investigators, suggesting that the areas of nuclear atypia in CLT are neoplastic rather than reactive. In the present study, we report additional molecular findings that support the hypothesis that the atypical nuclear changes in CLT may be preneoplastic or neoplastic. We microdissected small areas with atypical nuclei in glands with CLT and observed loss-of-heterozygosity mutations of tumor suppressor genes. These genetic mutations are evidence of clonal preneoplastic or neoplastic changes in the follicular cells of CLT. The clinical malignant potential of these minute foci is likely to be very small but remains to be determined.     

Pigments of the Gastrointestinal Tract: A Comparison of Light Microscopic and Electron Microscopic Findings

It is now apparent that light microscopy and histochemistry failed to identify correctly the nature and composition of pigments in various gastrointestinal tract melanoses. In most instances it was thought that the pigment was melanin or a melanin-like substance. Electron microscopy (EM) and electron-probe energy dispersive x-ray analysis have rectified these errors and have shown the following: in melanosis coli the pigment granules contain lipofuscin; in melanoses ilei the pigment granules may contain either silicates and titanium or hemosiderin; and in melanosis duodeni the pigment granules contain iron sulfide. In melanosis esophagi it is not clear what the pigment is; it could be melanin or lipofuscin.     

Classical Noonan syndrome is not associated with deletions of 22q11

Deletions of 22qll cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22qll deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22qll deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22qll deletion. A 2-month-old infant with several findings suggestive of NS did have a 22qll deletion, suggesting that a small number of 22qll deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. © 1995 Wiley-Liss, Inc.     

Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: Prenatal and postnatal late replication studies

We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical break-points and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome. © 1993 Wiley-Liss, Inc.     

Chorioamnionitis and colonization of the newborn infant with genital mycoplasmas.

To study the role of Mycoplasma hominis and T-mycoplasmas (Ureaplasma urealyticum) in chorioamnionitis, we obtained culture from 249 puerperal women and their babies. The placentas were examined histologically. Infants whose placentas showed inflammation (chorioamnionitis) had cultures positive for T-mycoplasmas more frequently (37.5 per cent) than those with normal placentas (19.0 per cent) (P = 0.021). Colonization with M. hominis was found in 16.0 per cent of the babies and was not significantly associated with chorioamnionitis. Material colonization with mycoplasmas was more frequent (73.4 per cent) and was not correlated with placental inflammation. We conclude that a substantial proportion of cases of chorioamnionitis may be caused by prenatal infection with T-mycoplasmas. The fact that these organisms are not highly virulent could explain the frequent finding of inflammed placentas from otherwise normal pregnacies. No adverse clinical effects of the placental lesions or of mycoplasmal colonization could be detected in this small study.     

Human anti-acetylcholine receptor antibodies use variable gene segments analogous to those used in autoantibodies of various specificities

The production of autoantibodies to the nicotinic acetylcholine receptor are responsible for many of the neurological symptoms observed in myasthenia gravis. An understanding of the structural organization of the anti-receptor antibodies may help to define the role of these antibodies in the pathogenesis of this disease. The nucleotide sequences of the heavy and light chains of three human monoclonal anti-receptor antibodies isolated from peripheral blood lymphocytes from two patients with myasthenia gravis were analyzed. In addition, the structure of an anti-idiotypic antibody was studied. The V_H and V_L gene segments used in the anti-receptor antibodies appear to be derived from the same repertoire as gene segments that have been found in other autoantibodies isolated from patients with various autoimmune diseases. The IgM anti-receptor antibodies are direct copies of germline gene segments, while the structures of the IgG anti-receptor antibody and the anti-idiotypic antibody appear to be mutated suggesting that they have undergone antigenic selection.     

Hemagglutination of Human Type O Erythrocytes, Hemolysin Production, and Serogrouping of Escherichia coli Isolates from Patients with Acute Pyelonephritis, Cystitis, and Asymptomatic Bacteriuria

The purpose of this investigation was to study potential virulence factors associated with Escherichia coli urinary pathogens isolated from patients with urinary tract infection. These factors were compared with characteristics of normal-flora E. coli isolated from stool specimens of healthy individuals without a history of urinary tract infection. The potential virulence factor focused on in this study was hemagglutination (HA) of human type O erythrocytes by E. coli urinary pathogens. A total of 265 strains of E. coli isolated from patients with urinary tract infections were tested for their ability to hemagglutinate human type O erythrocytes; of these, 148 (56%) were HA positive. Only 6 of 36 fecal E. coli strains (17%) isolated from healthy controls were HA positive. This significant association of the presence of hemagglutinin on E. coli that causes urinary tract infections indicates the likelihood that HA is a marker of virulence. Only 12% (5 of 43) of Proteus mirabilis and 3% (3 of 104) of Klebsiella pneumoniae urinary isolates were HA positive. There was a trend for HA-positive E. coli to be isolated from patients with kidney infections and positive tests for antibody-coated bacteria rather than bladder infections and negative tests for antibody-coated bacteria, although the difference was not statistically significant. There was a significant correlation (P < 0.025) between hemolysin production and HA; 67% (69 of 103) of the isolates that produced hemolysin also hemagglutinated human type O erythrocytes. There was no significant correlation between HA and motility, although there was a trend for flagellated organisms to be non-hemagglutinators. There was a marked correlation between the presence of hemagglutinin and the serogroup of the E. coli isolate; serogroups O4, O7, and O50 were almost always HA positive (57 of 63; 90%). In contrast, serogroups O8 and O25 were rarely HA positive (2 of 30; 7%).     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.