Biomedical subjects

J Chang

Publications and source records attributed to J Chang.

At least 181 records · Page 10Linked to original sources

PubMed1999

Structure of the human Lanosterol synthase gene and its analysis as a candidate for holoprosencephaly (HPE1).

Holoprosencephaly (HPE) is the most common birth defect of the brain in humans. It involves various degrees of incomplete separation of the cerebrum into distinct left and right halves, and it is frequently accompanied by craniofacial anomalies. The HPE1 locus in human chromosome 21q22.3 is one of a dozen putative genetic loci implicated in causing HPE. Here, we report the complete gene structure of the human lanosterol synthase (LS) gene, which is located in this interval, and present its mutational analysis in HPE patients. We considered LS an excellent candidate HPE gene because of the requirement for cholesterol modification of the Sonic Hedgehog protein for the correct patterning activity of this HPE-associated protein. Despite extensive pedigree analysis of numerous polymorphisms, as well as complementation studies in yeast on one of the missense mutations, we find no evidence that the LS gene is in fact HPE1, implicating another gene located in this chromosomal region in HPE pathogenesis.

Base Sequence↗

PubMed1999

Transforming growth factor-beta type II receptor confers tumor suppressor activity in murine renal carcinoma (Renca) cells.

OBJECTIVES: To demonstrate that the introduction of the transforming growth factor-beta (TGF-beta) type II receptor (TbetaR-II) decreases tumorigenicity in an aggressive murine renal carcinoma line, Renca. These cells do not express TbetaR-II. Because the presence of TbetaR-II in benign epithelial cells is ubiquitous, the ability to restore tumor suppressor activity in the Renca cell line with its introduction would elucidate the role of TbetaR-II as a tumor suppressor gene. METHODS: Renca cells were stably transfected with a retrovirus-mediated TbetaR-II expression vector. In vitro sensitivity to growth inhibitory effect of TGF-beta was assessed by the 3H-thymidine incorporation assay. For in vivo testing, xenograft tumors were produced by subcutaneous injection of tumor cells into immunodeficient nude mice. The tumorigenicity of these TbetaR-II transfected cells was tested. Wild-type Renca cells and cells transfected with the control vector were also tested for comparison. RESULTS: Expression of TbetaR-II mRNA was evident in Renca cells after transfection with the TbetaR-II construct. In vitro sensitivity to the growth inhibitory effect of TGF-beta was restored. This effect of TGF-beta was reversible with a neutralizing antibody specific for the extracellular domain of TbetaR-II. Xenografts grown from TbetaR-II transfected cells were significantly smaller, weighed less, and developed tumors later than those developed from wild-type Renca cells and those transfected with the control vector. CONCLUSIONS: We conclude that TbetaR-II is a central mediator of tumorigenicity in Renca cells. As with other tumor suppressor genes, the loss of TbetaR-II expression allows for the development of an aggressive phenotype.

Animals↗

PubMed1999

Characterization of patocytosis: endocytosis into macrophage surface-connected compartments.

Previously, we described a unique macrophage endocytosis pathway in which aggregated low density lipoproteins and microcrystalline cholesterol induce and enter a labyrinth of membrane-bound compartments that remain connected to the cell surface. We now show that certain types of non-lipid particles such as polystyrene microspheres and colloidal gold also induce and enter macrophage surface-connected compartments (SCC), a process we call patocytosis. A common property among particles that stimulate patocytosis is their hydrophobic nature. Both aggregated LDL and microcrystalline cholesterol that we showed previously to stimulate patocytosis are hydrophobic. We now show that hydrophobic polystyrene microspheres and gold particles but not their hydrophilic counterparts triggered patocytosis. Uptake by patocytosis was limited to hydrophobic polystyrene microsphere particles less than 0.5 micron in diameter. Hydrophobic polystyrene microspheres greater than this size entered macrophages by phagocytosis. Actin-independent capping of hydrophobic polystyrene microspheres on the plasma membrane preceded actin-dependent uptake of the microspheres into SCC. Sequential rounds of microsphere uptake into SCC over two successive days could occur. There was some mixing of initial and subsequently accumulated microspheres in SCC. SCC formed from plasma membrane invaginations that connected with spaces created by unfolding of stacks of internal microvilli. Microsphere transport from plasma membrane invaginations into these spaces was inhibited by primaquine. Patocytosis is a unique endocytic process in macrophages triggered by small hydrophobic particles that provides a mechanism to sequester large amounts of these materials within a labyrinth of SCC.

Actins↗

PubMed1999

Diprosopus (partially duplicated head) associated with anencephaly: a case report.

Craniofacial duplication (diprosopus) is a rare form of conjoined twin. A 16 year old mother with a twin pregnancy delivered one normally formed baby boy and one diprosopus male. The malformed baby was 33 weeks of gestation with a single trunk, normal limbs and various degrees of facial duplication. Of the following structures there were two of each: noses, eyes, ears (and one dimple), mouths, tongues and, with bilateral central cleft lips and cleft palates. This was associated with holoprosencephaly and craniorachischisis. Internal organs showed no duplication. There were multiple congenital anomalies including diaphragmatic hernia, small lungs, two lobes of the right lung, ventricular septal defect, small adrenal gland and small left kidney with short ureter. The body also had a short neck, small chest cavities and kyphosis. X-ray revealed duplication of the vertebral column. The case presented here represents a type II of diprosopia of Rating (1933) and is the least common type reported. We also reviewed 22 recently reported cases of diprosopus. In addition to facial duplication, anencephaly, neural tube defect and cardiac malformations represent the more common congenital abnormalities associated with diprosopus. The pathogenesis of diprosopus is not well understood. Factors that play a role in diprosopus are probably similar to those factors (genetic, environmental and abnormal placental circulation) which affect monozoygotic twins as observed in this case report. Early ultrasonography diagnosis of diprosopus permits one to consider a vaginal therapeutic abortion.

Abnormalities, Multiple↗

PubMed1999

Functional vision and corneal changes after laser in situ keratomileusis determined by contrast sensitivity, glare testing, and corneal topography.

PURPOSE: To demonstrate the functional vision and corneal changes following laser in situ keratomileusis (LASIK) determined by contrast sensitivity, glare testing, and corneal topography. SETTING: University of Texas Medical School, Houston, Texas, USA. METHODS: Seven patients ranging in age from 20 to 61 years who had bilateral LASIK were evaluated preoperatively and 1 day, 1 week, and 1 and 6 months postoperatively. Visual acuity, using letters on the Baylor Visual Acuity Testor (BVAT) at 98% (standard acuity) and 13% contrast, and the contrast threshold were determined at 3 light levels (darkness, medium brightness acuity testor [BAT], high BAT). Pupil sizes were measured at each level, and corneal topography was performed at each visit. RESULTS: The greatest changes were found 1 day postoperatively: The contrast threshold worsened by a mean of 0.6 lines +/- 1.0 (SD) (P = .05) in darkness, 0.4 +/- 0.7 lines (P = .05) at medium BAT, and 0.8 +/- 0.7 lines (P = .002) at high BAT. The 98% contrast acuity decreased a mean of 1.4 +/- 1.6 lines (P = .01) in darkness, 1.0 +/- 2.0 lines (P = .09) at medium BAT, and 0.8 +/- 2.3 lines (P = .22) at high BAT. The 13% contrast acuity decreased a mean of 2.2 +/- 2.6 lines (P = .01) in darkness, 1.3 +/- 1.9 lines (P = .02) at medium BAT, and 1.4 +/- 2.5 lines (P = .07) at high BAT. The predicted corneal acuity (PCA) obtained from corneal topography decreased by a mean of 3.3 +/- 3.1 lines (P = .002), and the asphericity (Q-value) increased by an average of +0.35 +/- 0.67 (P = .07). All values returned to the preoperative levels by 1 week except PCA, asphericity, visual acuity at 13%, and contrast threshold in darkness, which improved slightly but had not returned to baseline by 6 months. The 98% contrast acuity at medium BAT improved by 0.2 +/- 1.0 lines (P = .34) and 0.3 +/- 0.8 lines (P = .16) at high BAT at 1 month. The 98% contrast acuity values remained 0.3 lines over baseline through 6 months. Corneal topography showed that all corneas became oblate after LASIK to a mean Q-value of +0.47 +/- 0.40 (P = .0001) and PCA was decreased by 1.6 +/- 1.1 lines (P = .0002) at 6 months. CONCLUSIONS: Functional vision changes do occur after LASIK. The optical quality of the cornea is reduced and the asphericity becomes oblate. Changes in functional vision worsen as the target contrast diminishes and the pupil size increases. These findings indicate that the oblate shape of the cornea following LASIK is the predominant factor in the functional vision decrease.

Adult↗

PubMed1999

Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy.

BACKGROUND: Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates. To reduce this risk positive margins are, therefore, usually excised. Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along with radiotherapy. However, no studies to date have examined the correlation between chemoendocrine treatment, together with radiotherapy, and local relapse in patients with unexcised involved resection margins, having had breast conservation treatment. PATIENTS AND METHODS: The histopathology reports were reviewed of 184 patients who were treated from June 1991 to August 1995 within our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate (2M) +/- mitomycin-C (3M) and tamoxifen, used concurrently with radiation following conservation surgical treatment. Histological resection margin was considered positive if ductal carcinoma in situ (DCIS) or invasive carcinoma was present microscopically less than 1 mm from the excision margin. RESULTS: Although 38% of patients had unexcised microscopically involved margins, local relapse rate as first site of relapse was only 1.9% after a median follow up of 57 months. There was no difference in distant relapse (P = 0.2) and survival (P = 0.5) between the positive and negative margins groups. CONCLUSIONS: The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy. Further clinical trials are required.

Adult↗

PubMed1999

Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein.

Chromosomal translocations resulting in the expression of chimaeric transcription factors are frequently observed in tumour cells, and have been suggested to be a common mechanism in human carcinogenesis. Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors (which bind DNA through the conserved ETS domain). It has been shown that transduction of the gene EWSR1-FLI1 (encoding EWS-FLI1 protein) can transform NIH3T3 cells, and that mutants containing a deletion in either the EWS domain or the DNA-binding domain in FLI1 lose this ability. This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown. Because ETS transcription factors regulate expression of TGFBR2 (encoding the TGF-beta type II receptor, TGF-beta RII; Refs 9,14), a putative tumour suppressor gene, we hypothesized that TGFBR2 may be a target of the EWS-FLI1 fusion protein. We show here that Ewing sarcoma [corrected] (ES) cell lines with the EWSR1-FLI1 fusion have reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumours both express low or undetectable levels of TGFBR2 mRNA and protein product. Co-transfection of FLI1 and the TGFBR2 promoter induces promoter activity, whereas EWSR1-FLI1 leads to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppresses TGF-beta RII expression, whereas antisense to EWSR1-FLI1 in ES cell lines positive for this gene fusion restores TGF-beta RII expression. Furthermore, introduction of normal TGF-beta RII into ES cell lines restores TGF-beta sensitivity and blocks tumorigenicity. Our results implicate TGF-beta RII as a direct target of EWS-FLI1.

Animals↗

PubMed1999

Treatment outcome and prognostic factors for relapse after high-dose chemotherapy and peripheral blood stem cell rescue for patients with poor risk high grade non-Hodgkin's lymphoma.

The aim of the study was to determine treatment outcome and identify a particularly high risk group in a consecutive series of 66 patients with poor prognosis high grade lymphoma (NHL) treated with conventional induction chemotherapy followed by high-dose chemotherapy (HDCT) and peripheral blood stem cells (PBSC) rescue. Fifty-one patients with intermediate grade NHL (Kiel) and two or three adverse prognostic features as defined by the age-adjusted International Prognostic Index (IPI) received induction treatment with 7 weeks of doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, prednisolone and methotrexate (VAPEC-B) followed by three cycles of ifosfamide/cytarabine. Fifteen patients with high grade Burkitt's and lymphoblastic NHL received 11 weeks of VAPEC-B followed by three cycles of high-dose methotrexate. HDCT for all 66 patients consisted of busulphan/cyclophosphamide followed by autologous PBSC rescue. Thirty-one patients (47%) received HDCT in first complete remission (CR/CRu) and 34 patients (52%) in first partial remission (PR) after conventional chemotherapy. Following HDCT, 42 patients (64%) were in CR/CRu, 19 patients (29%) in PR and one patient had progressive disease. There were four toxic deaths. After a median follow-up period of 27 months (range 7-73) in 46 surviving patients, the actuarial 3-year estimates of overall survival, event-free survival (EFS) and freedom from progression (FFP) were 67%, 65% and 70%, respectively. In univariate analysis, prognostic factors associated with reduced EFS were mediastinal bulk (P = 0.02), > or = 3 extra-nodal sites (P = 0.02), remission status prior to HDCT (P = 0.05), low albumin (P = 0.08) and raised ESR (P = 0.09). No significant difference was observed between patients with intermediate or high grade NHL or between patients with two or three adverse IPI features. Multivariate analysis identified mediastinal bulk (P = 0.01), > or = 3 extra-nodal sites (P = 0.01) and low albumin (P = 0.03) as joint predictors of poor EFS. Remission status prior to HDCT was not found to be significantly associated with reduced EFS, FFP or survival, suggesting early introduction of HDCT may benefit patients with a PR. Based on these three adverse features, three groups (0, 1 or > or = 2 features) could be identified with differing EFS, survival and freedom from progression (FFP) rates at 3 years; 85%, 63% and 20%, respectively for EFS, 84%, 64% and 25% for survival and 85%, 66% and 33%, respectively for FFP. This prognostic model may identify patients with a particularly poor prognosis despite HDCT, who may benefit from other therapeutic approaches.

Adolescent↗

PubMed1999

Characterisation of the differential response of normal and CML haemopoietic progenitor cells to macrophage inflammatory protein-1alpha.

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic colony forming cells (CFC), are resistant to the growth inhibitory effects of the chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha). Here, we tested the hypothesis that MIP-1alpha protects normal, but not CML, CFC from the cytotoxic effects of the cell-cycle active drug cytosine arabinoside (Ara-C). Using a 24-h Ara-C protection assay we showed that MIP-1alpha confers protection to normal CFC but also sensitizes CML CFC to Ara-C. The differential MIP-1alpha responsiveness was not due to a down-regulation of MIP-1alpha receptors on CML CD34+ cells as flow cytometric analysis showed similar binding of a biotinylated MIP-1alpha molecule to normal and CML CD34+ cells. Flow cytometric analysis of the MIP-1alpha receptor subtype CCR-5 revealed comparable CCR-5 expression levels on normal and CML CD34+ cells. Furthermore, culture of CD34+ cells for 10 h in the presence of TNF-alpha resulted in an increased MIP-1alpha receptor expression on both normal and CML CD34+ cells. Our data suggest that the unresponsiveness of CML CFC to the growth inhibitory effect of MIP-1alpha is not caused by a lack of MIP-1alpha receptor or total uncoupling of the MIP-1alpha responsiveness but may be due to an intracellular signalling defect downstream of the receptors.

Adolescent↗

PubMed1999

Content of long-term culture-initiating cells, clonogenic progenitors and CD34 cells in apheresis harvests of normal donors for allogeneic transplantation, and in patients with acute myeloid leukaemia or multiple myeloma.

Using a limiting dilution assay the frequency of long-term culture-initiating cells (LTC-IC) in the apheresis products following mobilization by granulocyte-colony stimulating factor (G-CSP) with or without chemotherapy from 14 normal donors (ND) for allogeneic bone marrow transplantation, 16 patients with multiple myeloma (MM) and 15 patients with acute myeloid leukaemia (AML), where the aphereses were intended for autologous transplantation, were compared. The estimated median incidences of LTC-IC in the first apheresis products from ND, MM and AML were 1/3289, 1/1775 and 1/13075 mononuclear cells (MNC) respectively. The patients with AML had a significantly lower incidence compared with the other two groups (P < 0.0001). There was a positive correlation between the incidence of LTC-IC and the number of CD34+ cells, the number of GM-CFC, and the number of BFU-E. The positive association with GM-CFC or BFU-E was weaker. In these experiments the percentage of CD34+ cells was the best predictor for the frequency of LTC-IC in the peripheral blood progenitor cells (PBPC). In eight cases of MM the LTC-IC assay was performed for both the first and second harvest. All cases had a lower LTC-IC frequency in the second harvest compared with the first, an average of 23% (13-42%, 95% confidence interval) and this reduction was statistically significant (P<0 001); CD34+ cells were also lower (P< 0.001).

Acute Disease↗

PubMed1999

alpha4beta1 integrin-mediated adhesion of CD34+ cells from patients with chronic myeloid leukaemia: influence of IL-3.

Interactions between integrins on haemopoietic progenitor cells and their stromal ligands have an important role in the control of haemopoiesis. Growth factors can modulate these interactions (so-called 'inside-out' signalling) resulting in changes in ligand binding activity. We have studied alpha4beta1 integrin-mediated adhesion to the H120 fragment of fibronectin (which contains the strongest alpha4beta1 binding site) in CD34+ cells from patients with chronic myeloid leukaemia (CML) and have determined the effect of IL-3 on the level of adhesion. Compared to normal CD34+ cells isolated from cord blood and peripheral blood progenitor harvests (mean of 61.4 +/- 14.9% of cells attached) the CML CD34+ cells showed reduced levels of adhesion (mean of 41.9 +/- 14.7%, P < 0.05). The effect of 10 ng/ml of IL-3 resulting in reduced adhesion of normal CD34+ cells at 30 min was absent in 6/7 patients with CML. Abnormalities of adhesion to fibronectin may thus be related to IL-3 pathways affected by BCR-ABL. These findings will have implications for understanding the dysregulation of growth and adhesion in CML.

Adult↗

PubMed1999

Early investigation and initiation of therapy for invasive pulmonary aspergillosis in leukaemic and bone marrow transplant patients.

Invasive fungal infections are an increasingly common problem in cancer patients and in other vulnerable groups. Invasive pulmonary aspergillosis (IPA) in the neutropenic host presents particular challenges in terms of diagnosis and therapy. Against the background of a recognized problem of invasive aspergillosis in haematology/oncology patients treated at the Christie Hospital, we undertook a prospective study in patients at risk for IPA. The aim of the study was to improve outcome by using the linked strategies of first, early diagnosis, and secondly, early aggressive therapy with a lipid-associated formulation of amphotericin B, amphotericin B colloidal dispersion ('Amphocil'). Early investigation comprised the use of high-resolution computerized tomography scanning of the thorax and fibreoptic bronchoscopy to obtain bronchoalveolar lavage specimens, processed using conventional detection and culture methods. Using this approach, the incidence of proven or probable IPA in patients with acute leukaemia was 9%. Prompt initiation of amphotericin B colloidal dispersion therapy led to a successful outcome in 11 of 13 patients, compared with a mortality of 100% in historical controls.

Adolescent↗

PubMed1999

Endobronchial metastasis from stomach cancer.

A young woman presented with a dry cough present during the previous 4 weeks. A chest radiograph demonstrated diffuse interstitial infiltration in both lower lung fields. Fibreoptic bronchoscopic examination revealed multiple 2-3 mm elevated nodules on the bronchial surface and a mucosal biopsy showed extensive subepithelial infiltration of poorly differentiated adenocarcinoma without definite precancerous alteration in the overlying epithelium. Studies for the evaluation of primary tumour focus were performed. Oesophagogastroduodenoscopy showed advanced gastric cancer of Borrmann type III, and mucosal biopsy of the stomach showed poorly differentiated adenocarcinoma. The patient was treated three times with systemic chemotherapy, but her condition deteriorated. Three months after diagnosis, she died of complicated pneumonia. This is a rare case of endobronchial metastasis from stomach cancer. The stomach is an unusual site of endobronchial metastasis from extrathoracic primary malignancy.

Adenocarcinoma↗

PubMed1999

Propofol hemisuccinate protects neuronal cells from oxidative injury.

Oxidative stress contributes to the neuronal death observed in neurodegenerative disorders and neurotrauma. Some antioxidants for CNS injuries, however, have yet to show mitigating effects in clinical trials, possibly due to the impermeability of antioxidants across the blood-brain barrier (BBB). Propofol (2,6-diisopropylphenol), the active ingredient of a commonly used anesthetic, acts as an antioxidant, but it is insoluble in water. Therefore, we synthesized its water-soluble prodrug, propofol hemisuccinate sodium salt (PHS), and tested for its protective efficacy in neuronal death caused by non-receptor-mediated, oxidative glutamate toxicity. Glutamate induces apoptotic death in rat cortical neurons and the mouse hippocampal cell line HT-22 by blocking cystine uptake and causing the depletion of intracellular glutathione, resulting in the accumulation of reactive oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons and HT-22 cells from glutamate. The mechanism of protection is attributable to the antioxidative property of PHS because PHS decreases the ROS accumulation caused by glutamate. Furthermore, PHS protects HT-22 cells from oxidative injury induced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. For comparison, we also tested alpha-tocopherol succinate (TS) and methylprednisolone succinate (MPS) in the glutamate assay. Although TS is protective against glutamate at lower concentrations than PHS, TS is toxic to HT-22 cells. In contrast, MPS is nontoxic but also nonprotective against glutamate. Taken together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat CNS injuries owing to its antioxidative properties, low toxicity, and permeability across the BBB.

Animals↗

PubMed1999

Scientific evaluation of traditional Chinese medicine under DSHEA: a conundrum. Dietary Supplement Health and Education Act.

In the United States, traditional Chinese medicines (TCM) are currently sold as dietary supplements, as defined by The Dietary Supplement Health and Education Act (DSHEA). This legislation is unique to the United States and while "structure and function" claims are allowable under DSHEA, disease claims are not. The narrow definition, however, poses a challenge to designing appropriate clinical studies that can provide data for "structure and function" claim substantiation. The process of melding Chinese herbal medicines into the dietary supplement category is complex and there is a need to define a clinical trial paradigm carefully that addresses "structure and function claims" without sacrificing scientific rigor. It is frequently not recognized that TCM favors an amalgamation of several herbs to generate the putative clinical effect. Because of this historical multiherb approach, the reliance on retrospective data to support the potential health benefits of an herb extract has severe limitations. Notwithstanding the immense value of identifying the pharmacological activity of a TCM herb to a chemical suitable for pharmaceutical development, another approach to safe and efficacious herbal products is to develop a standardized herbal extract. This article highlights issues related to the latter approach and will discuss a research-based strategy that may be suitable for validating, in part, the putative health benefits of TCM.

Consumer Product Safety↗

PubMed1999

Survival after coronary artery bypass graft surgery and community socioeconomic status: clinical and research implications.

OBJECTIVES: Epidemiologic studies have linked adverse health outcomes to lower socioeconomic status (SES). To our knowledge, none have associated post-operative coronary artery bypass graft (CABG) surgery survival to this risk factor. To assess this, we compared post-operative survival among 771 CABG patients from different SES communities in a Southeastern state 36 months after surgery (mean follow-up = 30 months). All patients were admitted to the same tertiary care medical center for surgery in 1994 (mean age = 62; females = 214; African Americans = 13; person years of follow-up = 2,153; 36-month mortality = 8.8%). METHODS: Data were extracted from the medical records of all CABG patients admitted in 1994 using the Society of Thoracic Surgeons' data-collection protocol. The study hypothesis was that patients from "disadvantaged" communities would have lower survival rates after surgery, controlling for the severity of the patient's medical condition. In this study, 181 patients were from an Appalachian county and 437 were from a medically under-served county. Post-discharge mortality was ascertained from state mortality files. Forward and backwards step-wise Cox proportional hazard regression models were used to select the most significant risk factors for mortality from 8 county-level community indicators and 32 clinical risk factor variables potentially associated with post-operative survival. RESULTS: Controlling for traditional risk factors for post-operative CABG survival, patients from counties with the lowest housing values have a significant increased risk of death 36 months after CABG surgery (hazard ratio [HR] = 2.46, 95% CI = 1.26-4.78, P = 0.008). Being an African American also appeared to be a significant and independent risk factor for death 36 months after surgery, as well (HR = 4.55, 95% CI = 1.37-15.11, P = 0.013). CONCLUSION: This study suggests that residence in a poor community and possibly African American status are significant and independent risk factors for mortality 36 months after CABG surgery, although the latter may have included too few cases (n = 13) to assess this effectively. Additional research is needed to determine why these associations exist and to develop specific interventions. In the mean time, closer surveillance is recommended for CABG patients admitted from lower SES communities and possibly for African American patients.

Aged↗

PubMed1999

Proliferative hemangiomas: analysis of cytokine gene expression and angiogenesis.

Hemangiomas are benign vascular tumors of childhood that can lead to disfigurement and/or life-threatening consequences. The pathogenesis of hemangioma formation is likely to involve increased angiogenesis. Basic fibroblast growth factor and vascular endothelial growth factor are cytokines that stimulate angiogenesis in multiple in vivo and in vitro models. Proliferative hemangiomas have been found to have elevated levels of basic fibroblast growth factor and vascular endothelial growth factor protein, but the gene expression of these cytokines in human specimens has not been previously studied. We examined the gene expression and spatial distribution of basic fibroblast growth factor and vascular endothelial growth factor messenger RNA in proliferative versus involuted human hemangioma specimens using nonisotopic in situ hybridization techniques. Thirteen hemangioma specimens were harvested during initial surgical excision. In situ hybridization was performed on frozen sections of both proliferative and involuted hemangioma specimens using genetically engineered antisense probes specific for basic fibroblast growth factor and vascular endothelial growth factor messenger RNA. Controls were an interleukin-6 sense sequence and a transforming growth factor-beta 1 antisense sequence. A large number of cells within the specimens of proliferative hemangiomas revealed localized gene expression of basic fibroblast growth factor and vascular endothelial growth factor messenger RNA (626 +/- 129 and 1660 +/- 371 cells/mm2, respectively). The majority of the cells were endothelial in origin. In contrast, involuted hemangioma specimens revealed significantly lower numbers of cells staining positive for basic fibroblast growth factor and vascular endothelial growth factor messenger RNA (44 +/- 11 and 431 +/- 76 cells/mm2, respectively; p < 0.05). Transforming growth factor-beta 1 messenger RNA was slightly more expressed by involuted hemangiomas (117 +/- 30 cells/mm2). There were very low levels of transforming growth factor-beta 1 gene expression from proliferative hemangiomas (37 +/- 24 cells/mm2; p < 0.02). These data demonstrate that (1) in situ hybridization allows identification and relative quantitation of cells expressing messenger RNA for specific growth factors in human hemangioma specimens; (2) basic fibroblast growth factor and vascular endothelial growth factor messenger RNA are up-regulated in proliferative hemangiomas; and (3) transforming growth factor-beta 1 messenger RNA remains low in both proliferative and involuted hemangiomas. Because basic fibroblast growth factor and vascular endothelial growth factor messenger RNA have been implicated in the pathobiology of human hemangioma formation, biochemical modulation of these angiogenic cytokines may eventually help inhibit proliferation and promote regression of hemangiomas.

Child, Preschool↗

PubMed1999

Basic fibroblast growth factor and transforming growth factor beta-1 expression in the developing dura mater correlates with calvarial bone formation.

Numerous studies have found dura mater-calvarial mesenchyme interactions during calvarial bone induction; however, the exact molecular mechanisms governing these inductive events remain unknown. Recent studies have implicated basic fibroblast growth factor (FGF-2) and transforming growth factor-beta1 (TGF-beta1) in regulating bone formation. The purpose of this study was, therefore, to investigate the expression of FGF-2 and TGF-beta1 during calvarial bone formation in rats. Eight rats were killed on embryonic days 14, 18, and 20 and neonatal day 1 (n = 32). Four animals at each time point were analyzed by in situ hybridization, and the remainder were analyzed by immunohistochemistry. The results indicated that the dura mater underlying the developing calvarial bone strongly expressed FGF-2 and TGF-beta1 mRNA at all time points examined. In contrast, minimal growth factor expression was noted in the overlying calvarial mesenchyme until embryonic day 18, but it increased significantly with increasing age. Importantly, FGF-2 and TGF-beta1 mRNA expression in the dura mater underlying the developing calvarium preceded and was significantly greater than expression in the calvarium mesenchyme (p < 0.05). Interestingly, minimal expression of FGF-2 and TGF-beta1 mRNA was noted for all time points in the dura mater underlying the posterior frontal suture and within the posterior frontal suture connective tissue (p < 0.01 when compared with the dura mater underlying the developing calvarium). Immunohistochemical findings closely paralleled mRNA expression, with intense staining for FGF-2 and TGF-beta1 in the dura mater underlying the developing calvarial mesenchyme. Increasing FGF-2 and TGF-beta1 staining was noted within calvarial osteoblasts with increasing age, particularly in cells located near the endocranial surface (i.e., in contact with the developing dura mater). These findings, together with the known biologic functions of FGF-2 and TGF-beta1, implicate these growth factors in the regulation of calvarial bone growth by the developing dura mater. The possible mechanisms of this interaction are discussed.

Animals↗