Angiogenesis and inflammation in invasive carcinoma of the breast

Transforming growth factor-beta (TGF-beta) plays an important role in the regulation of extracellular matrix (ECM) deposition by stimulating the synthesis of individual matrix proteins like tenascin and fibronectin. Cholesteatoma shows significant changes in the ECM, supporting the view of a disturbed cell-matrix interaction. The purpose of our present study was to evaluate the distribution of TGF-beta in comparison to the deposition of tenascin, fibronectin, and collagen as major components of the ECM in cholesteatoma (n = 12) by means of histochemistry and immunohistochemistry. We found TGF-beta in lymphocytes and fibrohistiocytes in the stroma of 7 cholesteatomas. In corresponding sections, a marked expression of tenascin and fibronectin was seen manifesting as a continuous band along the epidermal-stromal junction, extending to the deeper stroma. In addition, in those cases of TGF-beta expression, beginning collagen fibril formation was seen in adjacent deeper stroma layers, indicating beginning stromal fibrosis. These results suggest that TGF-beta may be involved in the stimulation of the synthesis of tenascin, fibronectin, and collagen. Furthermore, the enhanced expression of tenascin and fibronectin provides evidence for a deregulated cell-matrix interaction in cholesteatoma associated with the enhanced proliferative process of cholesteatoma formation.     

Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex

Cholinergic and serotonergic fiber systems invade the developing visual cortex several weeks before eye opening; both transmitters have been implicated in plasticity of neocortical circuits. These transmitters have been presumed to act predominantly through second messenger-coupled receptors, because fast cholinergic or serotonergic neurotransmission has never been observed in neocortex. However, acetylcholine and serotonin also act on ligand-gated ion channels; the nicotinic acetylcholine receptor and the serotonin 5-HT3 receptor, respectively. Here, using whole-cell patch-clamp techniques in developing ferret visual cortex, we pharmacologically isolated fast, spontaneous, and evoked cholinergic and serotonergic synaptic events in pyramidal cells and interneurons of all cortical layers. The number of cells receiving such inputs increased with the ingrowth of thalamic afferents, and the frequencies of the spontaneous events increased at eye opening. Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections.     

Point mutation flanking a CTL epitope ablates in vitro and in vivo recognition of a full-length viral protein

CD8+ T cells (T(CD8+)) recognize viral Ags as short peptides (epitopes) displayed at the cell surface by MHC class I molecules. Using a panel of recombinant vaccinia viruses, we show that single-point mutations flanking either side of an H-2Kd-restricted epitope, residues 147-155, within full-length influenza nucleoprotein (NP) can impact, even ablate, presentation of that epitope, while having no effect on presentation of distal epitopes. The most severe blocking mutation (Ala to Pro at position 146) did not inhibit NP(147-155) presentation in the context of a truncated minigene, implying that this peptide is not a functional processing intermediate. An amino-terminal proline replacement also significantly reduced presentation of NP(50-57) (H-2Kk restricted), while the same mutation did not affect a third NP epitope. Thus, while trends in processing specificity may exist, the epitope itself contributes to flanking sequence effects. These findings were paralleled by in vivo priming experiments in which, depending on viral dose, subtle in vitro blocking effects were absolute. Proteasome/synthetic peptide coincubation studies support a role for enhanced epitope destruction in preventing presentation, as did the effect of the peptide aldehyde, LLnL, which restored presentation of NP(147-155) from the mutated constructs. This reagent did not inhibit epitope presentation, even from wild-type NP, suggesting that its production may be proteasome independent. These results support the notion that point mutation of epitope flanking sequence can serve as a mechanism for viral immune evasion, shed light on the mechanisms involved, and suggest that in vitro assays may not be sensitive indicators of flanking sequence effects.     

Radial tunnel syndrome: diagnosis and management

PURPOSE: To present the first documentation of iris retraction syndrome in eyes with nonrhegmatogenous retinal detachment. PATIENTS AND METHODS: One patient with age-related macular degeneration and another with panuveitis developed exudative retinal detachment with iris retraction configuration. Ultrasound biomicroscopy was performed to investigate the anatomic relationship of structures in the anterior segment of the eye. RESULTS: Ultrasound biomicroscopy demonstrated a severe backward bowing of the peripheral iris with irido-ciliary body and irido-zonular contact as well as broad iris lens touch. The iris retraction syndrome resolved after pupil dilation and disruption of the pupillary adhesions in both cases. The retinal detachment resolved several months later, without surgery. CONCLUSION: Iris retraction syndrome appears not to be exclusive to rhegmatogenous retinal detachment but can present in eyes with exudative - nonrhegmatogenous retinal detachment. Thus, when the configuration of the iris shows bowing in patients with retinal detachment, iris retraction syndrome should be considered and prompt pupil dilation should be carried out.     

Disturbances of the blood-brain barrier without expression of amyloid precursor protein- containing neuritic clusters or neuronal loss during late stages of thiamine deficiency in guinea pigs

Generalized oxidative deficits associated with experimental thiamine deficiency (TD) lead to selective neurodegeneration. In mouse brain, TD produces region-specific breach of the blood-brain barrier (BBB), neuronal loss and an accumulation of amyloid precursor protein (APP) in abnormal neurites. The APP-laden abnormal neurites within the damaged areas of mouse brain aggregate into neuritic clusters which strikingly resemble the neuritic component of Alzheimer amyloid plaques. However, amyloid beta-peptide (Abeta) immunoreactivity has not been demonstrated in these neuritic clusters, possibly because the Abeta region of APP in mice contains three amino acid substitutions as compared with the amino acid sequence of human Abeta. In contrast, the guinea pig nucleic acid sequence is more related to the human sequence and the Abeta region is identical in sequence to that of human APP. Thus, the current studies tested whether the presence of an authentic Abeta fragment of APP (i.e., identical to that of man) might make guinea pigs more vulnerable to the development of Abeta-containing neuritic clusters following TD. During late stages of TD, BBB abnormalities, manifested by immunoglobulin G (IgG) extravasation and increased NADPH diaphorase reactivity in microvessels, occurred in brain areas known to be damaged by TD in mice. However, despite the prolonged thiamine deprivation and the advanced neurological symptoms of guinea pigs, no significant neuronal loss or altered APP/Abeta immunostaining occurred in any brain region. Microglial activation, another early marker of damage in mice, was not evident in thiamine-deficient guinea pig brain. Ferritin immunoreactivity and iron deposition in oligodendrocytes within areas of BBB abnormalities were either slightly enhanced or unchanged as compared to controls. This is the first report of brain abnormalities in the guinea pig model of dietary and pyrithiamine-induced TD. The results demonstrate species differences in the response to TD-induced damage, and further support the role of BBB and nitric oxide in the initial events in TD pathology.     

Factors associated with women's adherence to mammography screening guidelines

OBJECTIVE: To examine individual and environmental factors associated with adherence to mammography screening guidelines. DATA SOURCES: A unique data set that combines a national probability sample (1992 National Health Interview Survey); a national probability sample of mammography facility characteristics (1992 National Survey of Mammography Facilities); county-level data on 1990 HMO market share; and county-level data on the supply of primary care providers (1991 Area Resource File). STUDY DESIGN: The design was cross-sectional. DATA EXTRACTION/ANALYSIS: Data sets were linked to create an individual-level sample of women ages 50-74 (weighted n = 2,026). We used multipart, sequential logistic regression models to examine the predictors of having ever had mammography, having had recent mammography, and adherence to guidelines. We categorized women as adherent if they reported a lifetime number of exams appropriate for their age (based on screening every two years) and they reported having had an exam in the past two years. PRINCIPAL FINDINGS: Only 27 percent of women had the age-appropriate number of screening exams (range 16 percent-37 percent), while 59 percent of women had been screened within two years. Women were significantly more likely to adhere to screening guidelines if they reported participating with their doctor in the decision to be screened; were younger; had smaller families, higher education and income, and a recent Pap smear; reported breast problems; and lived in an area with a higher percentage of mammography facilities with reminder systems, no shortage of primary care providers, higher HMO market share, and higher screening charges. CONCLUSIONS: A small percentage of women adhere to screening guidelines, suggesting that adherence needs to become a focus of clinical, programmatic, and policy efforts.