Enhanced expression of CD44 variants in human atheroma and abdominal aortic aneurysm: possible role for a feedback loop in endothelial cells

CD44, a polymorphic hyaluronate receptor, may participate in chronic inflammation. We hypothesized that CD44 variants contribute to the development of arterial diseases. CD44 levels vary in normal and diseased arterial tissues in the following order: unaffected arteries < fibrous plaques < or = abdominal aortic aneurysm < atheromatous plaques; and correlate with macrophage content. Furthermore, plaque microvessels express CD44, and anti-CD44v3 or anti-CD44v6 treatment reduces endothelial cell proliferation but not apoptosis in vitro, suggesting functionality of these receptors. Endothelial cells express CD44H and CD44v6 after exposure to interleukin-1beta and tumor necrosis factor-alpha. Macrophages, a major source of abundant CD44 in vitro, express not only CD44H but also variants CD44v4/5, CD44v6, and CD44v7/8, isoforms distinctively regulated by proinflammatory cytokines. Several proinflammatory cytokines induce shedding of CD44 from the surface of macrophages and endothelial cells. Soluble CD44 stimulates the expression and release of interleukin-1beta from endothelial cells, suggesting a positive feedback loop of this cytokine. By demonstrating augmented expression of CD44 and variants within human atheroma and in abdominal aortic aneurysm as well as the vascular cell release of sCD44, a process regulated by proinflammatory cytokines, this study provides new insights on the functions of CD44 in arterial diseases.     

Interferon-beta. A potential autocrine regulator of human vascular smooth muscle cell growth.

Positive and negative signals regulate the proliferation in vitro of vascular smooth muscle cells (SMC), a principle cell type in the blood vessel wall. Immune interferon (IFN-gamma, a type II IFN) retards the growth of human SMC, but the effect of type I IFN (IFN-alpha or beta) is unknown. Furthermore, the capacity of SMC to produce IFN is uncharacterized. If type I IFN alters SMC growth and is produced by this cell type, an autocrine inhibitory loop could operate in vascular growth control. To test this possibility, we compared the effects of IFN-alpha, beta, and gamma on the growth of SMC stimulated by platelet-derived growth factor, interleukin-1 or tumor necrosis factor alpha. IFN-beta and IFN-gamma, but not IFN-alpha, consistently retarded growth of SMC cultures (measured by net DNA accumulation and cell number). We investigated whether SMC could produce IFN-beta, a mediator characteristically produced by fibroblasts. Vascular SMC treated with poly(I):poly(C) or tumor necrosis factor-alpha expressed IFN-beta mRNA. SMC treated with poly(I):poly(C) or Newcastle Disease virus elaborated biologically active IFN-beta as well. Our results establish that IFN-beta inhibits human vascular SMC growth and that these cells can express the IFN-beta gene. These findings show that human vascular SMC have the capacity of producing a potential autocrine growth regulator.     

Endocardial cushion defect: Further studies of “isolated” versus “syndromic” occurrence

The isolated occurrence of endocardial cushion defect (ECD) has been suggested to differ from its occurrence within the context of a syndrome, with regard to the nature (complete or partial) of the defect and the associated cardiovascular malformations. Analysis of data derived from the Baltimore-Washington Infant Study of congenital cardiovascular malformations supports the observation that “syndromic” ECD tends to be of the complete atrioventricular canal type and is less frequently associated with left cardiac anomalies than the isolated form. However, each syndrome has a unique impact on the overall cardiovascular “phenotype,” including the ECD. This is especially true for Down and Ivemark syndromes, which are most frequently associated with ECD, but also for other syndromes as well. It is also suggested that isolated ECD is specifically associated with gastrointestinal and urinary tract anomalies. However, in Down syndrome ECD appears to be a specific cardiovascular expression of the trisomic state that is unrelated to other noncardiac malformations. Additional information on the association of ECD with other less common genetic syndromes is needed in order to further investigate the possible genetic basis of this cardiac defect. © 1992 Wiley-Liss, Inc.     

Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS.

Many pathological effects of gram-negative bacteria are produced by their cell wall-derived lipopolysaccharides (LPSs). Differing pathogenicity of gram-negative LPSs, however, may depend on their capacities to induce cytokines. Thus, we studied the lethal toxicity of four nonenterobacterial LPSs and compared it with their capacity to induce mononuclear cell (MNC)-derived interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Unstimulated MNC did not release these cytokines. LPS from the phototrophic strain Rhodobacter capsulatus 37b4 elaborated little toxicity in galactosamine-treated mice (10 micrograms of LPS per mouse was the 100% lethal dose [LD100]) and induced IL-1 and IL-6 release only at high concentrations (10 to 50 micrograms of LPS per ml). R. capsulatus LPS failed to induce TNF activity even at the highest concentration tested (100 micrograms of LPS per ml). In contrast, LPS derived from Pseudomonas diminuta NCTC 8545 or the nodulating species Bradyrhizobium lupini DSM 30140 and Rhizobium meliloti 10406 expressed lethal toxicity (LD100, 1,000, 100, and 10 ng per mouse, respectively) and induced IL-1 or IL-6 (10 to 100, 10, and 1 ng of LPS per ml, respectively) at concentrations 1,000- to 10,000-fold lower than effective levels of R. capsulatus LPS. LPSs from P. diminuta, B. lupini, and R. meliloti also stimulated TNF production and release. MNC accumulated cell-associated IL-1 activities under circumstances in which released activity was readily detected. The cells contained only scant IL-6 activity, indicating release of this mediator rather than intracellular accumulation. Antisera to the respective cytokines inactivated biological activities of the samples selectively. The R. capsulatus LPS inhibited cytokine induction by LPS from P. diminuta, B. lupini, and R. meliloti in coincubation experiments. These results show that the in vivo lethality of the LPSs tested correlates with the induction of monocyte-derived cytokines in vitro. The results of this study suggest that the different lethality of various LPSs from gram-negative bacteria may be due to the differential ability of these LPSs to induce cytokine production.     

Evaluating radiographic parameters for mobile chest computed radiography: phantoms, image quality and effective dose

Conventional chest radiography is technically difficult because of wide variations in tissue attenuations in the chest and limitations of screen-film systems. Mobile chest radiography, performed bedside on hospital inpatients, presents additional difficulties due to geometric and equipment limitations inherent in mobile x-ray procedures and the severity of illness in the patients. Computed radiography (CR) offers a different approach for mobile chest radiography by utilizing a photostimulable phosphor. Photostimulable phosphors overcome some image quality limitations of mobile chest imaging, particularly because of the inherent latitude. Because they are more efficient in absorbing lower-energy x-rays than rare-earth intensifying screens, this study evaluated changes in kVp for improving mobile chest CR. Three commercially available systems were tested, with the goal of implementing the findings clinically. Exposure conditions (kVp and grid use) were assessed with two acrylic-and-aluminum chest phantoms which simulated x-ray attenuation for average-sized and large-sized adult chests. These phantoms contained regions representing the lungs, heart and subdiaphragm to allow proper CR processing. Signal-to-noise ratio (SNR) measurements using different techniques were obtained for acrylic and aluminum disks (1.9 cm diameter) superimposed in the lung and heart regions of the phantoms, where the disk thicknesses (contrast) were determined from disk visibility. Effective doses to the phantoms were also measured for these techniques. The results indicated that using an 8:1, 33 lines/cm antiscatter grid improved the SNR by 60-300 % compared with nongrid images, depending on phantom and region; however, the dose to the phantom also increased by 400-600%. Lowering x-ray tube potential from 80 to 60 kVp improved the SNR by 30-40%, with a corresponding increase in phantom dose of 40-50%. Increasing the potential from 80 to 100 kVp reduced both the SNR and the phantom dose by approximately 10%. The most promising changes in technique for trial in clinical implementation include using an antiscatter grid, especially for large patients, and potentially increasing kVp.     

Development of a dual-color fluorescence in situ hybridization probe set on chromosome 6q to improve cytogenetic diagnosis of lymphoid malignancies

Deletions in the long arm of chromosome 6 are one of the most commonly observed chromosome aberrations in lymphoid malignancies and have been identified as an adverse prognostic factor in subsets of leukemia and lymphoma. Although large deletions can readily be detected with conventional banding methods, subtle rearrangements represent a major diagnostic challenge. To identify and follow up 6q abnormalities that are difficult to detect with conventional banding analysis, we have developed a dual-color fluorescence in situ hybridization probe set on 6q21 and 6q27. We have also demonstrated its potential for clinical applications. While applying this new probe set to clinical cytogenetic studies, we identified a unique t(6;14) translocation in a patient with acute lymphoid leukemia. Because the translocation breakpoint on chromosome 6 is located within a common deletion region in patients with lymphoid malignancies, the determination of this translocation breakpoint will facilitate the identification of a candidate tumor suppressor gene in 6q.     

Progressive bilateral nasal alar collapse: A dominantly inherited trait

We describe a 47-year-old woman with progressive bilateral collapse of the alae nasi first noted at age 16 years. Her dizygotic twin daughters have similar nasal collapse beginning at age 20 years. This condition appears to be inherited as a dominant trait. Although plastic surgical correction has been successful for a phenotypically similar condition due to trauma, surgical correction must be considered cautiously in individuals with an atraumative, possibly inherited, progressive form of the disorder.     

“It’s a Little Different for Men”—Sponsorship and Gender in Academic Medicine: a Qualitative Study

BackgroundWomen remain underrepresented in top leadership positions in academic medicine. In business settings, a person with power and influence actively supporting the career advancement of a junior person is referred to as a sponsor and sponsorship programs have been used to diversify leadership. Little is known about how sponsorship functions in academic medicine.ObjectiveTo explore perceptions of sponsorship and its relationship to gender and career advancement in academic medicine.DesignQualitative study using semi-structured, one-on-one interviews with sponsors and protégés.ParticipantsTwelve sponsors (clinical department chairs) and 11 protégés (participants of a school of medicine executive leadership program [N = 23]) at the Johns Hopkins School of Medicine.Key ResultsAll sponsors were men and all were professors, six of the 11 protégés were women, and four of the 23 participants were underrepresented minorities in medicine. We identified three themes: (1) people (how and who): women seek out and receive sponsorship differently; (2) process (faster and further): sponsorship provides an extra boost, especially for women; and (3) politics and culture (playing favorites and paying it forward): sponsorship and fairness. Informants acknowledge that sponsorship provides an extra boost for career advancement especially for women. Sponsors and protégés differ in their perceptions of how sponsorship happens. Informants describe gender differences in how sponsorship is experienced and specifically noted that women were less likely to actively seek out sponsorship and be identified as protégés compared to men. Informants describe a tension between sponsorship and core academic values such as transparency, fairness, and merit.ConclusionSponsorship is perceived to be critical to high-level advancement and is experienced differently by women. Increased understanding of how sponsorship works in academic medicine may empower individual faculty to utilize this professional relationship for career advancement and provide institutions with a strategy to diversify top leadership positions.KEY WORDS: academic medicine, sponsorship, leadership, gender disparities