Pathological changes according to the severity of asthma

BACKGROUND: There have been many studies concerning pathological changes in bronchial mucosa from asthmatics; however, few studies has been carried out to evaluate pathological changes according to the severity of asthma. OBJECTIVE: This study was designed to evaluate the cellular components in bronchoalveolar lavage fluid (BALF) and histological abnormalities in asthmatics according to the severity of asthma. METHODS: Bronchoalveolar lavages, bronchoscopic biopsies and ultrastructural examinations were performed in 13 asthmatics and 11 (BAL) or four (biopsies) non-asthmatic controls. The proportions of epithelial cells and correlations with PC20Meth which reflects bronchial hyperresponsiveness. Light microscopic examination revealed loss of epithelium, inflammatory cell infiltrations and thickening of the basement membrane which also showed significant correlation with PC20Meth. Hypertrophy of airway smooth muscles and hyperplasia of mucous glands were prominent in asthmatics but there was no difference according to the severity of asthma. Ultrastructural examination revealed that basement membrane thickening on light microscopic examination is due to the increased subepithelial collagen deposition with normal thickness of basal lamina. CONCLUSION: These data suggest that loss of epithelial cells, infiltration of inflammatory cells, especially eosinophils, and increased deposition of subepithelial collagen play major roles in determining the severity of asthma and non-specific bronchial hyperresponsiveness.     

Prenatal diagnosis of Apert syndrome

Apert syndrome (AS) is clinically characterized by typical facial features and symmetrical syndactyly of the digits. AS is inherited as an autosomal dominant trait. Recently, a fibroblast growth factor receptors 2 (FGFR2) mutation, either C934G or C937G, was identified in exon IIIa. Our report documents an affected mother and son in whom one of the two mutations in AS had occurred sporadically in the mother. The diagnosed of AS was based on associated abnormal physical features and on molecular genetic analysis. A C-to-G transversion at position 937 of the cDNA resulting in a proline-to-arginine substitution at codon 259 was found in the mother. In her second pregnancy, prenatal diagnosis by both restriction analysis and direct sequencing was undertaken and this showed that the female fetus had not inherited the mutation.     

Effects of midazolam on the differentiation of murine myeloid leukemia cells

The effects of midazolam (MID) on the in vitro growth and differentiation of two murine myeloid leukemia WEHI 3B (JCS) and M1 cells were studied. MID inhibits the proliferation of both M1 and JCS cells in a dose-dependent manner. At the concentration of 10 micrograms/ml, MID was found to induce both monocytic and granulocytic differentiation of the JCS but not M1 cells. Induction of morphological differentiation of the JCS cells was also associated with the enhanced expression of the differentiation antigens Mac-1, F4/80, and Gr-1 for the cells. Results from mRNA phenotyping experiments also indicated that the expression of tumor necrosis factor (TNF-alpha) and neutrophil-specific J11d differentiation marker was significantly upregulated in MID-treated JCS cells. In addition, the phagocytic activity of MID-treated JCS cells was increased towards opsonized yeast cells. Results from this investigation suggested that MID may be used as an inducer for further study on the mechanisms of differentiation in these myeloid leukemia cells.     

Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium

Vascular endothelium is an important transducer and integrator of both humoral and biomechanical stimuli within the cardiovascular system. Utilizing a differential display approach, we have identified two genes, Smad6 and Smad7, encoding members of the MAD-related family of molecules, selectively induced in cultured human vascular endothelial cells by steady laminar shear stress, a physiologic fluid mechanical stimulus. MAD-related proteins are a recently identified family of intracellular proteins that are thought to be essential components in the signaling pathways of the serine/threonine kinase receptors of the transforming growth factor beta superfamily. Smad6 and Smad7 possess unique structural features (compared with previously described MADs), and they can physically interact with each other, and, in the case of Smad6, with other known human MAD species, in endothelial cells. Transient expression of Smad6 or Smad7 in vascular endothelial cells inhibits the activation of a transfected reporter gene in response to both TGF-beta and fluid mechanical stimulation. Both Smad6 and Smad7 exhibit a selective pattern of expression in human vascular endothelium in vivo as detected by immunohistochemistry and in situ hybridization. Thus, Smad6 and Smad7 constitute a novel class of MAD-related proteins, termed vascular MADs, that are induced by fluid mechanical forces and can modulate gene expression in response to both humoral and biomechanical stimulation in vascular endothelium.     

Tumor angiogenesis and metastasis: correlation in invasive renal cell carcinoma

BACKGROUND: Experience suggests that tumor growth is dependent on angiogenesis. The intensity of angiogenesis in human cancer is reported to be predictive of the probability of metastasis in many types of cancer. The aims of this study were 1) to determine the relationship of microvessel density (MVD) in renal cell carcinoma to pathologic stage, and 2) to evaluate the role of MVD in metastasis. METHODS: Paraffin-embedded tumor specimens were reviewed from 34 unselected patients with RCC who had undergone surgery from 1986 to 1990 at Taichung Veterans General Hospital. The pathology findings and clinical records were reviewed to note relationships between pathologic stage and whether or not metastasis had occurred. Specimens were studied from 16 cases (eight Stage I cancers, five Stage II and three Stage III) without metastasis and from 18 cases (two Stage I, six Stage II, six Stage III and four Stage IV) in which metastasis later developed. Microvessels were highlighted by immunostaining endothelial cells for factor VIII-related antigen. Microvessels were counted in a x-400 field (0.1885 mm2/field) in the most active areas of neovascularization. RESULTS: The 16 patients without metastasis have survived for between 65 and 136 months (mean, 94.5 months), up to the present time. Of the 18 patients with metastasis, 15 died and three survived, with mean survivals of 42.8 months (range, 12-99 months). Mean overall MVD was 99.6 vessels; mean MVD was 98.5, 96.2, 109.3 and 90.0 in Stages I, II, III and IV tumors, respectively. Mean MVD was 99.3 in patients without metastasis and 99.9 in patients with metastasis. CONCLUSIONS: MVD does not correlate with pathologic stage and is of no prognostic significance in renal cell carcinoma.     

Vav regulates peptide-specific apoptosis in thymocytes

Homologies between vertebrate forebrain subdivisions are still uncertain. In particular the identification of homologs of the mammalian neocortex or the dorsal ventricular ridge (DVR) of birds and reptiles is still a matter of dispute. To get insight about the organization of the primordia of the main telencephalic subdivisions along the anteroposterior axis of the neural tube, a fate map of the dorsal prosencephalon was obtained in avian chimeras at the 8- to 9-somite stage. At this stage, the primordia of the pallium, DVR and striatum were located on the dorsal aspect of the prosencephalon and ordered caudorostrally along the longitudinal axis of the brain. Expression of homeobox-containing genes of the Emx, Dlx and Pax families were used as markers of anteroposterior developmental subdivisions of the forebrain in mouse, chick, turtle and frog. Their expression domains delineated three main telencephalic subdivisions in all species at the onset of neurogenesis: the pallial, intermediate and striatal neuroepithelial domains. The fate of the intermediate subdivisions diverged, however, between species at later stages of development. Homologies between forebrain subdivisions are proposed based on the conservation and divergence of these gene expression patterns.     

FDA perspective on peptide formulation and stability issues

Traditionally, peptide drugs are prepared as sterile solutions and administered to patients by daily injection. However, this form of drug delivery causes pain and inconvenience to patients and thus has been poorly accepted. In addition to improving patient compliance, many novel delivery systems have been developed to address the need for prolonged, localized (targeted), or pulsatile drug action. Examples include, but are not limited to oral, nasal, or long-acting controlled release injectable dosage forms; a number of them have been approved by FDA recently. The unique characteristics and the relevant regulatory issues with respect to each type of delivery system are presented.     

Substance P induces degranulation of mast cells and leukocyte adhesion to venular endothelium

Substance P (SP), one of the established neurotransmitters, evokes an immunoinflammatory response involving leukocyte adhesion to venular endothelium and the degranulation of mast cells. The pathogenetic relationship between these responses, however, remains unresolved. In this study, we propose to examine the changes associated with the activation of mast cells, as well as leukocyte adhesion to venular endothelium by in vivo observation of the rat mesentery. The use of an in vitro assay for intracellular Ca2+ mobilization and the degranulation of mast cells demonstrated the significant upper shift of concentration response to SP (10(-4)-10(-5) M). In vivo experiments on the mesenteric microcirculation also showed that SP induced a significant increase in the number of degranulated mast cells as well as in the number of leukocytes adherent to the venular wall. Tranilast, a mast cell stabilizer, as well as SP antagonist (CP-96,345) significantly attenuated the extent of mast cell degranulation and leukocyte adhesion elicited by SP. Although an immunoneutralization against CD18 by WT-3 significantly attenuated the leukocyte adhesion, it had no influence on the mast cell degranulation after SP superfusion. These separate in vivo observations show that SP induces leukocyte adhesion to the venular endothelium, possibly through the degranulation of mast cells.     

Epidemiology of falls among the elderly community dwellers in Singapore

AIM: Falling is a serious medical problem for elderly persons. This study was done to look at prevalence and risk factors for falls in community dwelling elderly in Singapore. METHOD: A random sample of 3,000 persons aged 60 years and above was chosen from a database based on the 1990 population census. Letters were sent out to 2,582 subjects who had local and complete addresses. In the letter, they were informed about the purpose of the survey, and invited to participate in a questionnaire and clinical health screening at an appointed date at a polyclinic. Participants were reminded the day before their appointment by telephone, and a new appointment could be given at the subject's convenience. RESULTS: We found a prevalence rate of falls of 17.2%. Two-thirds of these had single falls, while one-third had recurrent falls, defined as having more than one fall within the previous one year. The following factors were found to be significantly associated with increase falling in the elderly: age > or = 75 years (O.R. = 1.82, 95% C.I. 0.95-3.50), female sex (O.R. = 2.5, 95% C.I. 1.40-4.48), Malay race (O.R. = 2.66, 95% C.I. 1.21-5.86), poor vision (O.R. = 1.7, 95% C.I. 0.99-2.90), Barthel's score of less than 20 (O.R. = 1.76, 95% C.I. 0.94-3.28), those taking 2 or more drugs daily (O.R. = 2.1, 95% C.I. 1.22-3.72) and the presence of hypertension (O.R. = 1.78, 95% C.I. 1.06-3.01). Fall rate is also twice as high in women as in men. At the same time, we found that women in the group we studied also tend to exercise less than the men. Fallers also had significantly more mobility and activities of daily living (ADL) disabilities (reflected by a lower Barthel's score) and this is consistent with other results. The only factor that reduced the risk of falling was regular exercise (O.R. = 1.64, 95% C.I. 0.93-2.93). CONCLUSION: In our study, we found differences between the group with single and recurrent falls. In the group with single falls, the fall tend to occur outdoors (O.R. = 2.97, 95% C.I. 1.03-8.60) and during the day (O.R. = 3.47, 95% C.I. 1.20-10.0), tend to be accidental (O.R. = 3.16, 95% C.I. 1.05-9.50) and tend to seek medical attention (O.R. = 3.68, 95% C.I. 1.23-11.0). Overall, 32 persons (46.4%) seek medical treatment after their falls, and of these, 65.6% were women. Risk factors for falls should be screened for all elderly.