Biomedical subjects

W Du

Publications and source records attributed to W Du.

At least 91 records · Page 5Linked to original sources

PubMed1998

Antiproliferative effect of elevated glucose in human microvascular endothelial cells.

Diabetic microangiopathy has been implicated as a fundamental feature of the pathological complications of diabetes including retinopathy, neuropathy, and diabetic foot ulceration. However, previous studies devoted to examining the deleterious effects of elevated glucose on the endothelium have been performed largely in primary cultured cells of macrovessel origin. Difficulty in the harvesting and maintenance of microvascular endothelial cells in culture have hindered the study of this relevant population. Therefore, the objective of this study was to characterize the effect of elevated glucose on the proliferation and involved signaling pathways of an immortalized human dermal microvascular endothelial cell line (HMEC-1) that possess similar characteristics to their in vivo counterparts. Human dermal microvascular endothelial cells (HMEC-1) were grown in the presence of normal (5 mM) or high D-glucose (20 mM) for 14 days. The proliferative response of HMEC-1 was compared under these conditions as well as the cAMP and PKC pathways by in vitro assays. Elevated glucose significantly inhibited (P < 0.05) HMEC-1 proliferation after 7, 10, and 14 days. This effect was not mimicked by 20 mM mannitol. The antiproliferative effect was more pronounced with longer exposure (1-14 days) to elevated glucose and was irreversible 4 days after a 10-day exposure. The antiproliferative effect was partially reversed in the presence of a PKA inhibitor, Rp-cAMP (10-50 microM), and/or a PKC inhibitor, Calphostin C (10 nM). HMEC-1 exposed to elevated glucose (20 mM) for 14 days caused an increase in cyclic AMP accumulation, PKA, and PKC activity but was not associated with the activation of downstream events such as CRE and AP-1 binding activity. These data support the hypothesis that HMEC-1 is a suitable model to study the deleterious effects of elevated glucose on microvascular endothelial cells. Continued studies with HMEC-1 may prove advantageous in delineation of the molecular pathophysiology associated with diabetic microangiopathy.

Cell Division↗

PubMed1998

Induction of interleukin (IL)-1 alpha and beta gene expression in human keratinocytes exposed to repetitive strain: their role in strain-induced keratinocyte proliferation and morphological change.

Recent studies in our laboratory have demonstrated that mechanical strain alters many facets of keratinocyte biology including proliferation, protein synthesis, and morphology. IL-1 is known to play an important role in the autocrine regulation of these basic cellular properties under basal and stimulated conditions. However, it is not known whether IL-1 plays a role in strain-induced alteration of keratinocyte biology. Thus, the objective of this study was to test the hypothesis that cyclic strain stimulates IL-1 expression and that strain-induced changes in keratinocyte function is regulated by IL-1. To test this hypothesis, we examined the effect of cyclic strain (10% average deformation) on keratinocyte IL-1 gene expression and the effect of neutralizing antibodies of IL-1 alpha and IL-1 beta on strain-induced changes in keratinocyte proliferation, morphology, and orientation. Northern blot analyses demonstrated that steady state levels of IL-1 alpha and beta mRNA were elevated by 4 h, peaked at 1 2 h of cyclic strain (IL-1 alpha, 304+/-14.2%; IL-1 beta, 212+/-5.6% increase vs. static controls) and decreased gradually by 24 h. IL-1 antibodies (IL-1 alpha, 0.01 microg/ml; IL-1 beta, 0.01 microg/ml) significantly blocked strain-induced keratinocyte proliferation as well as the basal rate of proliferation. In contrast, IL-1 antibodies (IL-1 alpha, 0.01 microg/ml; IL-1 beta, 0.1 microg/ml) had no effect on strain-induced morphological changes such as elongation and alignment. We conclude that mechanical strain induces IL-1 mRNA expression in keratinocytes. The role of IL-1 in mediating strain-induced changes in keratinocyte biology remains to be determined but appears to be independent of morphological changes.

Antibodies↗

PubMed1998

Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer.

Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3-4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.

Aged↗

PubMed1998

Successful allogeneic bone marrow transplantation in selected patients over 50 years of age--a single institution's experience.

As allogeneic bone marrow transplantation (BMT) is a procedure with a higher risk of morbidity and mortality in older patients, many institutions place a limit of 50 to 55 years for allogeneic BMT. Consequently, older patients may not be offered potentially curative treatment for otherwise poor prognosis diseases such as AML or myelodysplastic syndrome. We compared the outcome of 59 patients aged over 50, 124 aged 40-50, and 253 aged 18-39 years who underwent allogeneic BMT in our institution between August 1987 and April 1996. Our results show little influence of age on outcome when comparing patients over 50 years with patients 40-50 years. Apart from an initial higher transplant mortality rate, overall survival was not significantly different between the three age groups. The 1-year and 2-year overall survival rates were 57% and 48%, 57% and 48%, and 62% and 58% for the >50 years, 40-50 years, and <40 years patients, respectively. The incidence of GVHD was also comparable. We conclude that allogeneic BMT can be performed in selected patients over the age of 50 years with acceptable morbidity and mortality and that older patients should not be denied this treatment based on age alone.

Adolescent↗

PubMed1998

Regulation of PDGF-B in endothelial cells exposed to cyclic strain.

The present study was designed to examine the regulation by cyclic strain of endothelial cell (EC) platelet-derived growth factor-B chain (PDGF-B) expression. We demonstrate in this study that bovine aortic ECs subjected to 10% (but not 6%) average strain resulted in a 2.6-fold increase in PDGF-B steady state mRNA and immunoreactive protein. Nuclear runoff transcription assays confirmed the induction of PDGF-B transcripts. To address the regulation of PDGF-B gene expression by cyclic strain, we transfected bovine aortic ECs with a construct containing 450 bp of human PDGF-B promoter sequence coupled to chloramphenicol acetyltransferase (CAT), and found that subjecting these cells to 10% average strain resulted in a twofold increase in CAT activity by 4 hours. Analysis of nested 5' deletions of the promoter transfected into ECs demonstrated a 55% drop-off in activity between position -313 and -153, with no induction of activity with the - 101-bp minimal promoter. Since a shear stress response element (SSRE) is located at position -125, we tested the hypothesis that the SSRE site was necessary and/or sufficient for induction of PDGF-B activity with strain. Electromobility shift assays revealed that nuclear proteins from ECs exposed to strain for short intervals (30 minutes) bound to the PDGF-B SSRE. However, transfection of ECs with hybrid promoter constructs containing the SV40 sequence promoter downstream of the SSRE or the -153 PDGF-B promoter sequence bearing a mutation in the SSRE demonstrated that the SSRE was not necessary for inducible reporter gene expression in ECs exposed to cyclic strain.

Animals↗

PubMed1998

Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma.

PURPOSE: Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS: Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS: Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION: The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.

Adult↗

PubMed1997

Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain.

Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.

Animals↗

PubMed1997

The clinical significance of p21(WAF1/CIP-1) and p53 expression in pancreatic adenocarcinoma.

BACKGROUND: Wild-type p53 protein activates the WAF1/CIP-1 (p21) gene, leading to G1 arrest after DNA damage. The authors investigated the relation of p21 and p53 expression in pancreatic adenocarcinomas to disease stage, overall patient survival, and survival when chemotherapy or radiation therapy was given. METHODS: Paraffin embedded tissue sections of 75 ductal adenocarcinomas of the pancreas were immunostained for p53 and p21. Nuclear expression was scored as absent, focal (<10%), moderate (10-50%), or strong or diffuse (>50%). RESULTS: The median survival of patients whose pancreatic tumors expressed the p21 protein (43 of 75 cases, 57%) was better than that for patients whose tumors were p21 negative (32 of 75 cases, 43%) (median survival, 13.5 vs. 9.8 months, respectively; P = 0.23). No difference in survival was found with regard to p53 protein expression (43 of 75 cases, 57%); however, strong p53 expression was significantly associated with advanced disease stage (70% in Stage IV vs. 13-28% in lower stages). Expression of p21 correlated with earlier clinical stage. Stage specific comparisons showed a trend toward increased survival among p21 positive tumor patients diagnosed at clinical Stages I and III but not among those diagnosed at Stage IV. Adjuvant chemotherapy or radiation improved survival significantly if tumors expressed p21 or no p53. CONCLUSIONS: Expression of p21 is significantly associated with earlier clinical stage in pancreatic adenocarcinoma, perhaps accounting for the better survival observed in this patient group than among those whose tumors were p21 negative. Improved survival with either chemotherapy or radiation therapy was observed for patients whose tumors were p21 positive or p53 negative.

Adenocarcinoma↗

PubMed1997

Prenylation of RhoB is required for its cell transforming function but not its ability to activate serum response element-dependent transcription.

Rho regulates cytoskeletal actin structure and integrin-mediated cell adhesion. Rho also has a role in cell growth regulation and is required for cell transformation by oncogenic Ras. Recently, it has been demonstrated that Rho can activate transcription from the c-fos serum response element (SRE). This raised the possibility that functions required for Rho-mediated cell transformation might overlap with those involved in transcriptional regulation. Here we show that RhoB can activate the SRE and can synergize in cell transformation with constitutively activated Raf-CAAX. Significantly, unprenylated forms of RhoB that are biologically inert and unable to transform cells can still activate SRE-dependent transcription. This finding suggests that transcriptional activation by Rho may be separable from its cell transforming functions.

3T3 Cells↗

PubMed1997

Activation of the adenylyl cyclase/cyclic AMP/protein kinase A pathway in endothelial cells exposed to cyclic strain.

The aim of this study was to assess the involvement of the adenylyl cyclase/cyclic AMP/protein kinase A pathway (AC) in endothelial cells (EC) exposed to different levels of mechanical strain. Bovine aortic EC were seeded to confluence on flexible membrane-bottom wells. The membranes were deformed with either 150 mm Hg (average 10% strain) or 37.5 mm Hg (average 6% strain) vacuum at 60 cycles per minute (0.5 s strain; 0.5 s relaxation) for 0-60 min. The results demonstrate that at 10% average strain (but not 6% average strain) there was a 1.5- to 2.2-fold increase in AC, cAMP, and PKA activity by 15 min when compared to unstretched controls. Further studies revealed an increase in cAMP response element binding protein in EC subjected to the 10% average strain (but not 6% average strain). These data support the hypothesis that cyclic strain activates the AC/cAMP/PKA signal transduction pathway in EC which may occur by exceeding a strain threshold and suggest that cyclic strain may stimulate the expression of genes containing cAMP-responsive promoter elements.

Adenylyl Cyclases↗

PubMed1997

Harmaline-induced tremor and impairment of learning are both blocked by dizocilpine in the rabbit.

Harmaline is known to produce tremors and retard acquisition of the rabbit's nictitating membrane response. These actions have been demonstrated to depend on the ability of harmaline to activate the inferior olive which gives rise to climbing fibers that project directly onto Purkinje cells in cerebellar cortex. However, the precise receptor systems involved in harmaline's actions remains unknown. This study examined the role of the NMDA receptor in harmaline's actions. Harmaline (10 mg/kg, s.c.) produced intense tremors and impaired the acquisition of conditioned responses. Both of these effects of harmaline were significantly blocked by the prior administration of the noncompetitive NMDA channel blocker, dizocilpine (0.01 mg/kg, s.c. given 20 min prior to the administration of harmaline). This dose od dizocilpine had no effect on acquisition of conditioned responses when given alone. A higher dose of dizocilpine (0.1 mg/kg s.c.) completely blocked the tremorogenic effects of harmaline (10 mg/kg, s.c.). Dizocilpine had no effect on motor behavior when given alone. It was suggested that the blockade of harmaline's actions by dizocilpine may be occurring at NMDA channels within the inferior olive. Regardless of the site of action, these data demonstrate that harmaline's ability to activate the interior olivary nucleus depends on the normal activity of the NMDA receptor.

Animals↗

PubMed1997

Strain activation of bovine aortic smooth muscle cell proliferation and alignment: study of strain dependency and the role of protein kinase A and C signaling pathways.

Smooth muscle cell (SMC) phenotype can be altered by physical forces as demonstrated by cyclic strain-induced changes in proliferation, orientation, and secretion of macromolecules. However, the magnitude of strain required and the intracellular coupling pathways remain ill defined. To examine the strain requirements for SMC proliferation, we selectively seeded bovine aortic SMC either on the center or periphery of silastic membranes which were deformed with 150 mm Hg vacuum (0-7% center; 7-24% periphery). SMC located in either the center or peripheral regions showed enhanced proliferation compared to cells grown under the absence of cyclic strain. Moreover, SMC located in the center region demonstrated significantly (P < 0.005) greater proliferation as compared to those in the periphery. In contrast, SMC exposed to high strain (7-24%) demonstrated alignment perpendicular to the strain gradient, whereas SMC in the center (0-7%) remained aligned randomly. To determine the mechanisms of these phenomena, we examined the effect of cyclic strain on bovine aortic SMC signaling pathways. We observed strain-induced stimulation of the cyclic AMP pathway including adenylate cyclase activity and cyclic AMP accumulation. In addition, exposure of SMC to cyclic strain caused a significant increase in protein kinase C (PKC) activity and enzyme translocation from the cytosol to a particulate fraction. Further study was conducted to examine the effect of strain magnitude on signaling, particularly protein kinase A (PKA) activity as well as cAMP response element (CRE) binding protein levels. We observed significantly (P < 0.05) greater PKA activity and CRE binding protein levels in SMC located in the center as compared to the peripheral region. However, inhibition of PKA (with 10 microM Rp-cAMP) or PKC (with 5-20 ng/ml staurosporine) failed to alter either the strain-induced increase in SMC proliferation or alignment. These data characterize the strain determinants for activation of SMC proliferation and alignment. Although strain activated both the AC/cAMP/PKA and the PKC pathways in SMC, singular inhibition of PKA and PKC failed to prevent strain-induced alignment and proliferation, suggesting either their lack of involvement or the multifactorial nature of these responses.

Activating Transcription Factor 2↗

PubMed1997

Relationship of family cancer history to the expression of p53, p21WAF-1, HER-2/neu, and K-ras mutation in pancreatic adenocarcinoma.

CONCLUSION: In our series of 81 cases, a history of family cancer was present in 52% of patients (42/81) with pancreatic cancer. Nine percent (7/81)had a family history of pancreatic cancer. Our studies suggest a possible relationship of family cancer history to the expression of p53 and p21WAF in pancreatic tumors, but show no relationship to the expression of HER-2/neu or to the prevalence of K-ras mutations. A lower incidence of p53 expression observed in patients with a family history of cancer suggests normal p53 protein is present in a majority of patients who develop pancreatic tumors related to other--as yet unidentified-inherited or familial risk factors. There was no significant difference in survival of pancreas cancer patients with and without a family history of cancer. However, survival in pancreas cancer patients may be influenced (improved) by p21WAF-1 expression. BACKGROUND: Pancreas cancer is the fifth leading cause of cancer deaths (27,800 deaths/yr) in the United States. Various risk factors, including cigarette smoking, high-fat diet, DDT exposure, chronic pancreatitis, and diabetes mellitus, have been associated with pancreatic carcinoma. A few studies have suggested a genetic predisposition or increased risk for pancreatic cancer within families, but the exact etiology is largely unknown. In a series of 81 patients with pancreatic carcinoma, we analyzed the status of K-ras gene mutations and the expression of P21WAF-1, p53, and HER-2/neu protein to identify possible molecular associations in pancreas cancer cases of these molecular markers to family histories of cancer and pancreas cancer. METHODS: Paraffin-embedded tissue sections from 81 cases of pancreatic adenocarcinoma were used for DNA extraction and immunohistochemical staining. K-ras mutation was studied by single-stranded conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product. Overexpression (aberrant expression) of p53, p21WAF-1, and HER-2/neu was documented by scoring nuclear localized p53, p21WAF-1 protein and cell membrane expression of HER-2/neu after immunostaining with gene product-specific monoclonal antibodies (MAbs). RESULTS: Forty-two (42) of 81 patients studied in this series had a history of cancer in their families (52%). Seven of those 42 had a history of pancreatic carcinoma (17% or 9% of total cases). The incidence of K-ras mutation and the expression of p21WAF-1 and HER-2/neu in patient groups with and without a family history of cancer was not statistically different (83 vs 74%, p = 0.416; 57 vs 41%, p = 0.184; and 83 vs 81%, p = 1.000, respectively). However, the incidence of p53 expression was significantly lower in patients with a family history of cancer (40 vs 72%, p = 0.007). There was no statistical difference in survival of patients with a family history of cancer in relation to either K-ras mutation, p53 expression, p21, or HER-2/neu expression. However, patients lacking a family history of cancer showed improved survival trends in relation to p21 expression (median survival of 16 vs 8 mo, p = 0.029).

Adenocarcinoma↗

PubMed1997

Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma.

CONCLUSION: This study could not attribute survival differences to the coincident acquisition of two common genetic alterations, K-ras mutation and p53 overexpression in pancreatic adenocarcinoma patients. Additionally, our data indicate the converse to be true: Those patients lacking both K-ras mutation and aberrant p53 expression showed the shortest survival when compared with cases showing either alteration or both. This study also showed the negative effect of K-ras mutation and p53 expression on pancreas cancer patients' survival after treatment with either radiation therapy or chemotherapy. BACKGROUND: Mutations of the oncogene K-ras at codon 12 are reported to be the most common genetic alteration in pancreatic carcinoma, whereas either overexpression or mutation of the tumor suppressor p53 gene is considered the most common genetic alteration in neoplasia of all types. p53 overexpression has been attributed to survival differences in pancreatic carcinoma, but such association is still controversial. No studies have fully documented the combined incidence of K-ras and p53 alterations in pancreatic adenocarcinoma, or their combined effect on patient survival in a large case series. The influence of radiation or chemotherapy in groups showing both, either, or neither mutation is also undocumented. METHODS: Paraffin-embedded tissue sections from 76 cases of pancreatic adenocarcinoma were cut for DNA extraction for K-ras analysis and immunohistochemical staining for aberrant p53 expression. K-ras mutation was determined by single-strand conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product p53 expression was scored on the basis of percent nuclear staining with the MAb DO7. RESULTS: Sixty-four of 76 cases (84%) showed K-ras mutation, p53 expression, or both, K-ras was mutated in 55 of 76 cases (72%). p53 was expressed in 33 of 76 cases (43%). Twenty-four of 76 cases (31%) showed both K-ras mutation and p53 expression. The presence of both alterations was not related to significant differences in tumor grade, stage, or survival compared to either alteration alone. A sizable subset (16% of cases) lacked either alteration, and surprisingly, this group showed the shortest median survival compared to those with K-ras mutation, p53 expression, or both (p = 0.024). Patients whose tumors were K-ras-negative showed the greatest difference in median survival with radiation therapy (median survival 30.8 mo vs 7.8 mo with no radiation, p = 0.005).

Adenocarcinoma↗

PubMed1997

Effect of pressure ulcers on the survival of long-term care residents.

BACKGROUND: Past studies have emphasized that patients with pressure ulcers are at high risk of dying. However, it remains unclear whether this increased risk is related to the ulcer or to coexisting conditions. In this study we examined the independent effect of pressure ulcers on the survival of long-term care residents. METHODS: We evaluated all 19,981 long-term care residents institutionalized in Department of Veterans Affairs (VA) long-term care facilities as of April 1, 1993. Baseline resident characteristics and survival status were obtained by merging data from five existing VA data bases. Survival experience over a 6-month period was described using a proportional hazards model. RESULTS: Pressure ulcers were present in 1,539 (7.7%) long-term care residents. Residents with pressure ulcers had a relative risk of 2.37 (95% CI = 2.13, 2.64) for dying as compared to those without ulcers. After adjusting for 16 other measures of clinical and functional status, the relative risk associated with pressure ulcers decreased to 1.45 (95% CI = 1.30, 1.65). No increased risk of death was noted for residents with deeper ulcers. CONCLUSIONS: Pressure ulcers are a significant marker for long-term care residents at risk of dying. After adjusting for clinical and functional status, however, the independent risk associated with pressure ulcers declines considerably. The fact that larger ulcers are not associated with greater risk suggests that other unmeasured clinical conditions may also be contributing to the increased mortality associated with pressure ulcers.

Activities of Daily Living↗

PubMed1997

Transplantation in patients with multiple myeloma: a multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant.

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Adult↗

PubMed1997

HER-2/neu expression in pancreatic adenocarcinoma: relation to tumor differentiation and survival.

HER-2/neu expression in pancreatic adenocarcinoma has been inconsistently reported and has not been fully evaluated with respect to histologic grade and tumor grade heterogeneity. We studied HER-2/neu expression in a series of 79 primary pancreatic carcinomas using immunohistochemical methods, with expression scored for each histologic grade represented in each tumor. We found significantly lower expression of HER-2/neu in poorly differentiated (PD) portions of tumors-those areas lacking glandular differentiation-compared to well-differentiated (WD) and moderately differentiated (MD) portions of tumors. Forty-two of 68 (62%) invasive tumors with WD or MD glands showed moderate or strong expression of HER-2/neu in WD/MD areas; only 6 of 32 (19%) invasive tumors with PD areas showed similar expression in PD. In mutually exclusive patient sets, we also found a statistically different prevalence of HER-2/neu expression in patients with PD (6/32 cases; 19%) and without PD (29/47 cases; 62%) tumors (p < 0.001). Twenty-three cases had directly comparable areas of PD versus MD or WD. In 19 of 23 cases HER-2/neu expression was graded comparatively lower (or negative) in areas of PD than in MD or WD. Overall 46 of 79 cases (58%) showed moderate to strong HER-2/neu expression inclusive of all histologic grades, and 63 of 79 (80%) cases were HER-2/neu positive, if including weak or focal staining. There was no significant difference in the survival of patients with HER-2/neu-positive versus-negative tumors or in patients with versus without PD tumors. We have confirmed that although HER-2/neu gene expression is common to many pancreatic carcinomas, it is not common to tumors lacking glandular differentiation. HER-2/neu gene expression could not be related to survival differences--perhaps due to overall poor survival within adenocarcinomas of the pancreas--but the pattern of HER-2/neu expression suggests a relationship to glandular differentiation and early oncogenesis.

Adenocarcinoma↗

PubMed1997

Activation of diacylglycerol in cultured endothelial cells exposed to cyclic strain.

Confluent bovine aortic endothelial cells (EC) were grown on flexible membranes and subjected to 10% average strain at 60 cycles/min for up to 500 s. A biphasic increase in diacylglycerol (DAG) occurred, with an initial transient peak at 10 s followed by sustained elevation to 500 s. The early peak corresponded to the transient formation of inositol 1,4,5-trisphosphate, demonstrating hydrolysis of L-alpha-phosphatidylinositol (PI) by PI-specific phospholipase C. To determine the origin of the sustained DAG phase, we incubated confluent bovine aortic EC with 1 microCi/ml [14C]myristate overnight and subjected them to cyclic strain. There was a decrease in phosphatidylcholine (PC) and a corresponding increase in DAG at 10 s and 250 s, suggesting PC hydrolysis with the generation of DAG at both an early (10 s) and a late (250 s) phase. [14C]phosphatidylethanol, a specific product of phospholipase D (PLD) in the presence of 1% ethanol, was measured in EC preincubated with [14C]myristate. Cyclic strain led to an immediate and sustained activation of PLD. Increased ethanol concentration led to a consistent decrease in DAG. Furthermore, when EC were pretreated with 1% ethanol, the strain-induced proliferative response was attenuated.

Animals↗