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Biomedical subjects

S B Morris

Publications and source records attributed to S B Morris.

At least 19 recordsLinked to original sources
PubMed2001

Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice.

We hypothesized that pulmonary granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically involved in determining the functional capabilities of alveolar macrophages (AM) for host defense. To test this hypothesis, cells were collected by lung lavage from GM-CSF mutant mice [GM(-/-)] and C57BL/6 wild-type mice. GM(-/-) mice yielded almost 4-fold more AM than wild-type mice. The percentage of cells positive for the beta(2)-integrins CD11a and CD11c was reduced significantly in GM(-/-) AM compared with wild-type cells, whereas expression of CD11b was similar in the two groups. The phagocytic activity of GM(-/-) AM for FITC-labeled microspheres was impaired significantly compared with that of wild-type AM both in vitro and in vivo (after intratracheal inoculation with FITC-labeled beads). Stimulated secretion of tumor necrosis factor-alpha (TNF-alpha) and leukotrienes by AM from the GM(-/-) mice was greatly reduced compared with wild-type AM, whereas secretion of monocyte chemoattractant protein-1 was increased. Transgenic expression of GM-CSF exclusively in the lungs of GM(-/-) mice resulted in AM with normal or supranormal expression of CD11a and CD11c, phagocytic activity, and TNF-alpha secretion. Thus, in the absence of GM-CSF, AM functional capabilities for host defense were significantly impaired but were restored by lung-specific expression of GM-CSF.

Animals↗
PubMed2000

Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice.

Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-alpha in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.

Animals↗
PubMed2000

The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis.

Angiogenesis is an absolute requirement for tumor growth beyond 2 mm3 in size. The balance in expression between opposing angiogenic and angiostatic factors controls the angiogenic process. The CXC chemokines are a group of chemotactic cytokines that possess disparate activity in the regulation of angiogenesis. Non-small cell lung carcinoma (NSCLC) has an imbalance in expression of ELR+ (angiogenic) compared with ELR- (angiostatic) CXC chemokines that favors angiogenesis and progressive tumor growth. We found that the level of the ELR- CXC chemokine MIG (monokine induced by interferon gamma) in human specimens of NSCLC was not significantly different from that found in normal lung tissue. These results suggested that the increased expression of ELR+ CXC chemokines found in these tumor samples is not counterregulated by a concomitant increase in the expression of the angiostatic ELR-CXC chemokine MIG. This would result in an even more profound imbalance in the expression of regulatory factors of angiogenesis that would favor neovascularization. We hypothesized that MIG might be an endogenous inhibitor of NSCLC tumor growth in vivo and that reconstituion of MIG in the tumor microenvironment would result in the inhibition of tumor growth and metastasis. In support of this hypothesis, we demonstrate here that overexpression of the ELR-CXC chemokine MIG, by three different strategies including gene transfer, results in the inhibition of NSCLC tumor growth and metastasis via a decrease in tumor-derived vessel density. These findings support the importance of the ELR- CXC chemokine MIG in inhibiting NSCLC tumor growth by attenuation of tumor-derived angiogenesis. Furthermore, these findings demonstrate the potential of gene therapy as an alternative means to deliver and overexpress a potent angiostatic CXC chemokine.

Adenoviridae↗
PubMed2000

Distribution of the standardized mean change effect size for meta-analysis on repeated measures.

When conducting a meta-analysis on studies with repeated measures, a useful measure of effect size is Becker's (1988) standardized mean change. This paper examines the distributional properties of the standardized mean change, and discusses potential problems with the variance formulae given in Becker (1988). First, an error in the exact variance formula can lead to severe underestimation of the actual sampling variance. Second, Becker (1988) recommended the use of an approximation which is shown to underestimate the sampling variance when sample size is small. Using the approximation can decrease the accuracy of meta-analysis results; however, the degree of error is generally small.

Humans↗
PubMed1999

Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells.

Prostate cancer is the second leading cause of malignancy-related mortality in males in the United States. As a solid tumor, clinically significant tumor growth and metastasis are dependent on nutrients and oxygen supplied by tumor-associated neovasculature. As such, there is a selective tumorigenic advantage for those neoplasms that can produce angiogenic mediators. We show here that human prostate cancer cell lines can constitutively produce angiogenic CXC chemokines. Tumorigenesis of PC-3 prostate cancer cells was shown to be attributable, in part, to the production of the angiogenic CXC chemokine, interleukin (IL)-8. Neutralizing antisera to IL-8 inhibits PC-3 tumor growth in a human prostate cancer/SCID mouse model. Furthermore, angiogenic activity in PC-3 tumor homogenates was attributable to IL-8. In contrast, the Du145 prostate cancer cell line uses a different angiogenic CXC chemokine, GRO-alpha, to mediate tumorigenicity. Neutralizing antisera to GRO-alpha but not IL-8 reduced tumor growth in vivo and reduced the angiogenic activity in tumor homogenates. Thus, prostate cancer cell lines can use distinct CXC chemokines to mediate their tumorigenicity.

Animals↗
PubMed1998

Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.

We report here the role of the CXC chemokine, epithelial neutrophil activating peptide (ENA-78), as an angiogenic factor in human non-small cell lung cancer (NSCLC). In freshly isolated human specimens of NSCLC, elevated levels of ENA-78 were found that strongly correlated with the vascularity of the tumors. In a SCID mouse model of human NSCLC tumorigenesis, expression of ENA-78 in developing tumors correlated with tumor growth in two different NSCLC cell lines. Furthermore, passive immunization of NSCLC tumor-bearing mice with neutralizing anti-ENA-78 antibodies reduced tumor growth, tumor vascularity, and spontaneous metastases, while having no effect on the proliferation of NSCLC cells either in vitro or in vivo. These findings suggest that ENA-78 is an important angiogenic factor in human NSCLC.

Adenocarcinoma↗
PubMed1997

The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis. We postulated that an imbalance exists in the expression of angiogenic (IL-8) vs angiostatic (IFN-gamma-inducible protein (IP-10)) CXC chemokines, which favors net angiogenesis in IPF. To test this hypothesis, we obtained open lung biopsies either from normal patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) or from patients with IPF. We found that levels of IL-8 were greater from tissue specimens of IPF patients then from those of controls. In contrast, IP-10 levels were higher from tissue specimens obtained from control subjects than from those from IPF patients. When IL-8 or IP-10 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced or enhanced, respectively. Immunolocalization of IL-8 demonstrated that the pulmonary fibroblast (PF) of IPF lung was the predominant cellular source of IL-8. Isolated PF from IPF patients constitutively produced more IL-8 and less IP-10 than control PF. Conditioned media from IPF-PFs demonstrated constitutive angiogenic activity that was attributable, in part, to IL-8. Depletion of IP-10 from IPF-PF CM resulted in an increase in corneal neovascularization. These findings support the notion that IL-8 and IP-10 are important factors that regulate angiogenic activity in IPF.

Aged↗
PubMed1997

Multiple frequent recurrences in superficial transitional cell carcinoma of the bladder: is survival compromised by a conservative management strategy?

OBJECTIVE: To examine whether a strategy of bladder conservation is reasonable in patients with multiple frequent superficial recurrences of transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Fifty-four patients with pTa/pT1. G1/G2 tumours at diagnosis, with five or more recurrences at two or more cystoscopies within 2 years of diagnosis and a minimum follow-up of 4 years were identified. The patients were categorized according to outcome, i.e. disease settled, continuing high-activity disease and disease progression. RESULTS: Forty-four patients did not progress, of whom 16 continued to have high-activity disease and 28 settled to a lower disease activity. One patient had a cystectomy for superficial disease. Nine patients progressed, six with muscle invasion in the bladder and three elsewhere in the urinary tract. Neither grade nor stage were predictive of recurrence. All but one of the patients with progression had both multicentric tumours at diagnosis and a positive cystoscopy at 3 months. Three patients died from their bladder cancer. CONCLUSION: A policy of endoscopic resections and intravesical chemotherapy or bacille-Calmette-Guèrin, with cystectomy reserved until muscle-invasive disease develops, does not significantly compromise survival in patients with high-activity superficial TCC. Cystectomy for superficial disease is rarely necessary.

Administration, Intravesical↗
PubMed1997

High-intensity focused ultrasound ablation of the kidney in a large animal model.

The purpose of this study was to establish the feasibility of noninvasive treatment of small renal tumors with high-intensity focused ultrasound (HIFU). A 1.69-MHz extracorporeal HIFU transducer of 150-mm focal length was used. In vitro experiments with excised porcine kidneys allowed determination of suitable exposure parameters to be tested in vivo. For short exposure times (< 2 seconds), the minimum energy required to produce acute thermal damage was 500 +/- 100 Wcm-2 per second. Porcine kidneys (N = 18) were treated in vivo at a depth of 40 mm from the skin surface, with acute damage detected in 13. Damage was macroscopically and histologically discrete and confined to the target area within the kidney. Skin induration was observed after treatment in nine cases, and there was one skin burn. Transducer developments to prevent this morbidity and to improve energy deposition within the target are discussed.

Animals↗
PubMed1996

Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8.

Obliterative bronchiolitis (OB) is a devastating complication in lung transplantation. We postulated that the pathogenesis of OB is mediated, in part, by neutrophils. We serially collected bronchoalveolar lavage (BAL) fluid from lung transplant recipients. Patients were divided into two groups depending on the presence or absence of OB. Samples from patients who never developed OB were further divided according to whether rejection was present. These samples were labeled healthy or rejection. Samples from patients who developed OB were divided according to whether the sample was obtained before (future OB) or at the time of diagnosis of OB (OB). The OB group, as compared with the healthy and rejection group, had significantly elevated neutrophil counts (3.9 x 10(5) +/- 1.8 x 10(5) vs 0.3 x 10(5) +/- 0.07 x 10(5) and 0.4 x 10(5) +/- 0.1 x 10(5), respectively, p < 0.01 for both) and levels of IL-8 (3131 +/- 1468 pg/ml vs 240 +/- 62 pg/ml and 172 +/- 47 pg/ml, p < 0.01 for both). Furthermore, we demonstrated immunolocalization of IL-8 associated with alpha smooth muscle actin-positive cells in the peribronchial region of OB. To confirm that the IL-8 present in BAL fluid from patients with OB was bioactive, we performed neutrophil chemotaxis experiments that showed that IL-8 accounted for a significant amount of the neutrophil chemotactic activity. We also found a trend toward higher levels of neutrophils and IL-8 in BALs from the future OB as compared with the healthy group (7.1 x 10(4) +/- 4.2 x 10(4) vs 3.4 x 10(4) +/- 0.7 x 10(4) and 500 +/- 306 pg/ml vs 240 +/- 62 pg/ml). In conclusion, we have provided the novel observation that in lung transplant recipients with OB, neutrophilia is present and highly correlated with the presence of IL-8.

Bronchiolitis Obliterans↗
PubMed1996

Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases.

The success of solid tumor growth and metastasis is dependent upon angiogenesis. Neovascularization within the tumor is regulated, in part, by a dual and opposing system of angiogenic and angiostatic factors. We now report that IP-10, a recently described angiostatic factor, as a potent angiostatic factor that regulates non-small cell lung cancer (NSCLC)-derived angiogenesis, tumor growth, and spontaneous metastasis. We initially found significantly elevated levels of IP-10 in freshly isolated human NSCLC samples of squamous cell carcinoma (SCCA). In contrast, levels of IP-10 were equivalent in either normal lung tissue or adenocarcinoma specimens. The neoplastic cells in specimens of SCCA were the predominant cells that appeared to express IP-10 by immunolocalization. Neutralization of IP-10 in SCCA tumor specimens resulted in enhanced tumor-derived angiogenic activity. Using a model of human NSCLC tumorigenesis in SCID mice, we found that NSCLC tumor growth was inversely correlated with levels of plasma or tumor-associated IP-10. IP-10 in vitro functioned as neither an autocrine growth factor nor as an inhibitor of proliferation of the NSCLC cell lines. Reconstitution of intratumor IP-10 for a period of 8 wk resulted in a significant inhibition of tumor growth, tumor-associated angiogenic activity and neovascularization, and spontaneous lung metastases, whereas, neutralization of IP-10 for 10 wk augmented tumor growth. These findings support the notion that tumor-derived IP-10 is an important endogenous angiostatic factor in NSCLC.

Animals↗
PubMed1996

A feasibility study for the non-invasive treatment of superficial bladder tumours with focused ultrasound.

OBJECTIVE: To determine whether high-intensity focused ultrasound can be used to ablate bladder wall tissue using a transabdominal approach in a large animal model, and whether it can be developed as a non-invasive treatment for superficial bladder tumours. MATERIALS AND METHODS: The bladder wall of 25 large white pigs was treated with a 1.7 MHz extracorporeal focused-bowl ultrasonic transducer. Animals were killed either 2 h, 3 days or 4 weeks after treatment and the bladder wall examined macroscopically and histologically. RESULTS: Acute bladder wall damage was detected in 15 of 16 animals at 2 h and in all six animals examined after 3 days. Areas of healing were seen in 10 of 12 animals at 4 weeks. Histological analysis of the treated areas revealed that the urothelium was denuded within 2 h and was associated with an acute inflammatory response in the bladder wall. At 4 weeks, the urothelium had regenerated over a maturing scar. CONCLUSIONS: Focused ultrasound can be used successfully to destroy regions of the bladder wall in a large animal model in vivo.

Animals↗
PubMed1995

Superficial bladder cancer: for how long should a tumour-free patient have check cystoscopies?

OBJECTIVE: To determine the probability of a patient with superficial bladder cancer developing a recurrent tumour after having remained tumour free for 2 or more years. PATIENTS AND METHODS: One-hundred and seventy-nine patients with Ta or T1 tumours at diagnosis, a minimum follow-up of 3 years and a minimum of 2 years remaining tumour free were identified. Thirteen patients had more than one episode that was eligible for inclusion and there were therefore 192 tumour-free episodes for analysis. Survival curves of the probability of being recurrence-free against time were constructed for the whole group, for subgroups of Ta and T1 tumours and for subgroups with characteristics at diagnosis suggesting a good, intermediate and poor prognosis. RESULTS: The probability of a patient developing a recurrence after 2, 5 and 10 years of being tumour free was 43, 22 and 2% respectively. No patient had a recurrence after remaining tumour free for 12 years. No patient who had been tumour free for at least 2 years progressed to muscle invasion or metastases. There was no significant difference in the probability of recurrence between Ta and T1 tumours after 2 years of remaining tumour free. CONCLUSION: The optimum length of cystoscopic follow-up for patients with superficial bladder cancer is unknown, but patients continue to develop recurrences even after many years of being tumour free. If a patient is to discontinue cystoscopic follow-up, then alternative methods of assessment should be applied.

Adult↗
PubMed1995

Shared care for benign prostatic hyperplasia: a feasibility study.

OBJECTIVE: To determine the proportion of patients with symptoms of urinary outflow obstruction secondary to benign prostatic hyperplasia (BPH) who could be managed in the community after assessment in a shared-care clinic (managed by nursing staff, supervised by a consultant) to which they had direct access. PATIENTS AND METHODS: A total of 127 men were referred to one consultant urologist in a 9-month period for assessment of possible urinary outflow obstruction. All were investigated using urine analysis, serum prostate-specific antigen level, urea and electrolytes, plain abdominal X-ray, renal ultrasonography and urinary flow rate. Additional investigations were undertaken as required. The proportion of men who could have been investigated in a shared-care clinic and then managed in the community was determined. RESULTS: Of 127 men, 88 (69%) were found to have uncomplicated outflow obstruction secondary to BPH; of these 49 (38%) could have been managed in the community after assessment in the shared-care clinic and a further 27 (21%) could have been managed in the community after additional investigation by a specialist. Twelve men (9%) were found to have uncomplicated outflow obstruction and chose to undergo transurethral resection of the prostate. CONCLUSION: Many men with uncomplicated outflow obstruction could be assessed in a shared-care clinic and then managed in the community. A shared-care protocol for the management of these men has now been introduced in this unit.

Adult↗
PubMed1995

Should all patients with ureteric colic be admitted?

A two-part study was undertaken to determine if all patients with uncomplicated ureteric colic require admission. The analgesic requirements and outcome in 31 patients admitted with ureteric colic were assessed; 20/31 (64%) required no further analgesia after admission and 8/31 (26%) required only oral/rectal analgesia. In the second part of the study a protocol was introduced allowing patients with no complicating factors to be discharged directly from the A&E department. Of 58 patients seen in the A&E department, 29 were discharged for outpatient follow-up. Of these patients, 19 required no additional acute hospital treatment, five returned for further parenteral analgesia but outside the time they would have stayed in hospital under our previous protocol (ie beyond 48 h) and three returned within 48 h of their first attendance with pain which had not responded to oral analgesics. No patient discharged from A&E subsequently required intervention for obstruction or infection. We conclude that it is not necessary to admit patients with uncomplicated ureteric colic if the initial colic has been relieved and there is adequate social support.

Adult↗