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Biomedical subjects

D Willis

Publications and source records attributed to D Willis.

At least 37 records · Page 2Linked to original sources
PubMed1998

Retrospective analysis of infectious disease in patients who received recombinant human granulocyte-macrophage colony-stimulating factor versus patients not receiving a cytokine who underwent autologous bone marrow transplantation for treatment of lymphoid cancer.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) significantly shortens the number of days required to achieve an absolute neutrophil count of >500/mm3 after autologous bone marrow transplantation (ABMT); however, the ability of rhGM-CSF to enhance neutrophil and macrophage function in vivo has been incompletely characterized. In this retrospective study, the authors compared the incidence of infection from the day of transplantation to 28 days posttransplantation between two groups of previously studied patients who underwent ABMT at the Fred Hutchinson Cancer Research Center. A control group that received no cytokine was compared with a study group that received rhGM-CSF while participating in phase I, II, or III trials. During the posttransplantation period when both study groups had severe neutropenia, 40% (38 of 95) of control patients were found to have an infection, whereas only 13% (6 of 46) of rhGM-CSF patients developed an infection (p = 0.001). Most infections occurred before an absolute neutrophil count of > 100/mm3 was achieved. There was a trend toward fewer fungal infections (14% vs. 4%; p = 0.093); gram-negative bacterial infections (6% vs. 0%; p = 0.083); pulmonary infections (12% vs. 2%; p = 0.062); fewer days of amphotericin B (p = 0.0305); and fewer days of intravenous antibiotics (p = 0.0791) in rhGM-CSF-treated patients. These results support in vivo findings that the function-enhancing effect of rhGM-CSF may reduce infection-related complications.

Adolescent↗
PubMed1998

Recurrent Twiddler's syndrome in a nonthoracotomy ICD system despite a Dacron pouch.

Twiddler's syndrome is a highly recognized yet rare complication of pacemaker and cardioverter defibrillator (i.c.d.) implantation. We present a case in which persistent generator rotation resulted in lead dislodgment and inappropriate shocks in an initial ICD and recurrent lead fracture in a second ICD system. This case is unusual in that even with extensive surgical precautions including use of a Dacron pouch, generator rotation could not be prevented. Submuscular implantation and use of a smaller generator may prevent Twiddler's syndrome.

Aged↗
PubMed1998

Dexamethasone for pulmonary interstitial emphysema in preterm infants.

The efficacy of a 3-day course of dexamethasone (0.5 mg/kg/ day) in 10 preterm infants (< or = 30 weeks gestation) with pulmonary interstitial emphysema (PIE) was studied in a retrospective case review. PIE was diagnosed at a median age of 7.5 days and treatment with dexamethasone began at 8.5 days. Seven of the 10 subjects had at least 2 days of conservative treatment (lowered mean airway pressure) preceding dexamethasone during which the mean airway pressure (MAP), oxygenation index (OI) and mechanical ventilation index (MVI) were not significantly different although within 3 days of dexamethasone each variable improved significantly (p < 0.05). Similarly, for all 10 infants, OI and MAP were significantly lower at 3 and 7 days from baseline (p < 0.005). By day 7, FiO2 (p = 0.022) and MVI (p = 0.011) were significantly lower and PIE had resolved on chest X-ray in 7/9 (78%) and improved in the remaining 2/9 (22%). Nine of the 10 infants survived to term. Three days of dexamethasone was associated with significant clinical improvement in most of these infants. The mechanism may relate to reduced airway oedema and inflammation and reduced airway obstruction.

Dexamethasone↗
PubMed1998

Mortality from lower respiratory infection in nursing home residents. A pilot prospective community-based study.

BACKGROUND: Lower respiratory infections (LRI) are an important cause of morbidity, mortality, and hospitalization of nursing home residents, yet treatment recommendations have primarily been based on the minority who are hospitalized. We sought to prospectively evaluate risk factors for mortality from LRI in community nursing home residents. METHODS: We studied residents of 10 central Missouri nursing homes (910 beds) from January 1994 to September 1994. Attending physicians authorized nurse evaluations of ill residents who showed symptoms of an LRI. Those residents who met the study definition of LRI received a more detailed assessment and follow ups at 30 and 90 days. RESULTS: The 231 evaluations identified 141 LRIs in 121 individuals. Sixteen (11%) residents died within 30 days of evaluation. The most important univariate predictor of 30-day mortality was severe activities of daily living (ADL) dependency (relative risk = 8.8, 95% confidence interval, 2.55-30.1). Several other clinical and laboratory findings were also significant predictors. In multivariable logistic regression, ADL dependency, respiratory rate, and pneumonia on chest radiograph independently predicted mortality; the model showed good discriminating ability (c = .83). CONCLUSIONS: For nursing home residents with LRI, ADL dependency is an important mortality predictor. Further research with a larger sample should lead to a useful prediction rule for outcome from nursing home-acquired LRI.

Activities of Daily Living↗
PubMed1997

Is histological examination of tissue removed by general practitioners always necessary? Before and after comparison of detection rates of serious skin lesions.

OBJECTIVES: To examine whether histological examination of all tissue removed by general practitioners in minor surgery increases the rate of detection of clinically important skin lesions, and to assess the impact of such a policy on pathologists' workload. DESIGN: Before and after comparison. SETTING: Stratified random sample of 257 general practitioner partnerships from the catchment areas of 19 English pathology laboratories. SUBJECTS: Tissue removed in minor surgery by general practitioners during the control period (September 1992 to February 1993) and intervention period (September 1993 to February 1994). INTERVENTION: General practitioners referred to their local pathology laboratory all solid tissue removed in all minor surgery, irrespective of their previous policy. MAIN OUTCOME MEASURES: Numbers of specimens referred for histology by general practitioners during intervention and control periods; numbers of primary malignant melanomas, non-melanoma malignancies, premalignant lesions, and benign lesions. RESULTS: 257/330 partnerships participated (response rate 78%). During the intervention period 5723 specimens were sent, compared with 4430 during the control period. The referral rate increased by an estimated 1.34 specimens per 1000 patient years (95% confidence interval 0.93 to 1.76, P < 0.0001). General practitioners sent 204 specimens that were malignant (including 16 malignant melanomas) in the control period and 188 that were malignant (including 15 malignant melanomas) during the intervention period (change in total number of malignancies, -1.0 per 100,000 patient years (-5.9 to 3.8, non-significant). CONCLUSIONS: The intervention was associated with a substantial increase in laboratory workload, all of which was accounted for by increases in non-serious lesions. This observation should be taken into account when considering the merits of a policy requiring histological examination in every case.

England↗
PubMed1997

The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan.

Topical diclofenac in 2.5% hyaluronan inhibits basal cell carcinoma, actinic keratosis, and murine colon-26 growth in vivo. colon-26 tumor growth was preceded by angiogenesis and reduced apoptotic and mitotic indices. Diclofenac reduced proliferation and viability in vitro, and stimulated apoptosis. Hyaluronan inhibited proliferation and viability at 1 mg/ml but was inactive below this level. Topical application of diclofenac inhibited tumor prostaglandin synthesis and retarded angiogenesis and tumor growth (ratio of treatment:control, 0.174). The mitotic index remained unaltered in vivo, whereas the apoptotic index and necrosis were increased. Topical vehicle exhibited slight antitumor and antiangiogenesis activity. The substantial quantities of diclofenac delivered locally in hyaluronan may exhibit antitumor activity in similar fashion to those seen in vitro and explain its clinical efficacy.

Adenocarcinoma↗
PubMed1997

Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element.

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.

Animals↗
PubMed1996

The role of vascular endothelial growth factor in a murine chronic granulomatous tissue air pouch model of angiogenesis.

Chronic granulomatous inflammation may be considered an angiogenic-dependent process. Recently it has been demonstrated that vascular endothelial growth factor (VEGF) or vascular permeability factor is essential for tumour angiogenesis. Its role in inflammation-mediated angiogenesis has yet to be determined. In this study, the murine chronic granulomatous air pouch model was used to investigate the role of VEGF in angiogenesis. Animals were treated twice weekly with 10 micrograms per animal of neutralizing antibody to rh VEGF and the vascularity and granuloma dry weight were assessed after 7 days. This resulted in significant suppression of both angiogenesis and granuloma dry weight. Western blot analysis demonstrated the presence of VEGF; the levels of protein paralleled the angiogenic response. These results demonstrate for the first time that VEGF may be an important regulator of angiogenesis in inflammation.

Air↗
PubMed1996

Heme oxygenase: a novel target for the modulation of the inflammatory response.

Chronic inflammatory diseases place a heavy social and economic burden on the resources of many nations, but the number of safe and effective treatments is limited. To date, the major research effort has concentrated on those mediators responsible for the initiation and maintenance of the pathological process. In contrast, little attention has been focused on endogenous factors responsible for the resolution of the inflammation. Heme oxygenase ((HO); EC 1.14.99.3) is the rate-limiting enzyme in the catabolism of heme to biliverdin (which is converted to bilirubin by biliverdin reductase), free iron and carbon monoxide (CO). Two isoforms of HO have been characterized, the constitutive isoform, HO-2, which is the major isoform present under physiological conditions, and the stress-induced isoform, HO-1, which has also been classified as heat-shock protein 32K (ref. 1). Increases in HO activity have been implicated in tissue protection against oxidative stress. In this communication, we describe the effects of modulating HO during an acute complement-dependent inflammatory response. Elevation of this enzyme resulted in a striking suppression, whereas inhibition of the enzyme led to a potentiation of the inflammatory response. Such novel enzyme modulation has application on the one hand to the treatment of inflammatory diseases and on the other hand to immnosuppressed states in which the impaired ability to mount an adequate inflammatory response may result in death from opportunistic infections.

Animals↗
PubMed1996

Linkage between reovirus-induced apoptosis and inhibition of cellular DNA synthesis: role of the S1 and M2 genes.

The mammalian reoviruses are capable of inhibiting cellular DNA synthesis and inducing apoptosis. Reovirus strains type 3 Abney (T3A) and type 3 Dearing (T3D) inhibit cellular DNA synthesis and induce apoptosis to a substantially greater extent than strain type 1 Lang (T1L). We used T1L x T3A and T1L x T3D reassortant viruses to identify viral genes associated with differences in the capacities of reovirus strains to elicit these cellular responses to viral infection. We found that the S1 and M2 genome segments determine differences in the capacities of both T1L x T3A and T1L x T3D reassortant viruses to inhibit cellular DNA synthesis and to induce apoptosis. These genes encode viral outer-capsid proteins that play important roles in viral attachment and disassembly. To extend these findings, we used field isolate strains of reovirus to determine whether the strain-specific differences in inhibition of cellular DNA synthesis and induction of apoptosis are also associated with viral serotype, a property determined by the S1 gene. In these experiments, type 3 field isolate strains were found to inhibit cellular DNA synthesis and to induce apoptosis to a greater extent than type 1 field isolate strains. Statistical analysis of these data indicate a significant correlation between the capacity of T1L x T3A and T1L x T3D reassortant viruses and field isolate strains to inhibit cellular DNA synthesis and to induce apoptosis. These findings suggest that reovirus-induced inhibition of cellular DNA synthesis and induction of apoptosis are linked and that both phenomena are induced by early steps in the viral replication cycle.

Animals↗
PubMed1996

Comparison of rehabilitation practice on hospital wards for stroke patients.

BACKGROUND AND PURPOSE: The aim of the study was to observe patients on a stroke unit and to compare their activity with that of patients on conventional hospital wards to identify aspects of rehabilitation practice that might account for differences in outcome. METHODS: Stroke patients admitted to the hospital were observed on three 8-hour shifts over 3 consecutive days. An observer recorded, at 10-minute intervals, where patients were, what they were doing, and whether their positioning was as recommended by rehabilitation therapists. Patients on a stroke unit were compared with those on conventional wards. RESULTS: Stroke unit patients spent less time by their beds and more time in other locations on the ward (P < .001). There were significant differences in the frequency of behaviors observed in the two types of ward (P < .001). Stroke unit patients had significantly more interaction with nurses and therapists (P < .001). They were also more often in the recommended position (P < .001). CONCLUSIONS: The proportion of time in therapeutic activity was low in all locations, with patients spending many hours sitting and doing nothing. Despite this, stroke unit patients had more therapeutic contact with staff and were more often in the recommended position. These two features may account for some of the differences in outcome.

Activities of Daily Living↗
PubMed1996

Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries.

Anovulation in polycystic ovary syndrome (PCOS) is associated with hyperinsulinemia and insulin resistance, but it has been unclear whether the ovary is insulin resistant in women with PCOS. The aims of this study were, firstly, to determine whether human granulosa cells respond to physiological concentrations of insulin and, secondly, to investigate insulin and gonadotropin interactions in vitro in granulosa cells obtained from normal (N) and polycystic ovaries (PCO). Granulosa cells were incubated with insulin with or without gonadotropins for 48 h. Insulin augmented not only basal production of estradiol and progesterone, but also LH-stimulated steroid accumulation in granulosa cell cultures from N and PCO. Insulin enhanced FSH-stimulated progesterone production by granulosa cells from N and PCO, but the effect on FSH-stimulated estradiol production was variable, ranging from no effect for granulosa cells from N to synergistic for granulosa cells from PCO of anovulatory subjects. Preincubation with insulin for 48 h increased subsequent basal and LH-induced, but not FSH-stimulated, steroid production. These data demonstrate that granulosa cells from PCO respond to insulin despite the association, in vivo, of PCOS with peripheral insulin resistance. Insulin preincubation enhances the subsequent response of human granulosa cells to LH. We propose that in anovulatory women with PCOS, elevated levels of insulin interacting with LH may contribute to the mechanism of anovulation.

Adult↗
PubMed1995

Modulation of heme oxygenase activity in rat brain and spleen by inhibitors and donors of nitric oxide.

The capacity of nitric oxide to activate or inhibit metalloprotein-containing enzymes underlies many of its biological actions. Heme oxygenase, involved in a variety of biological processes, does not contain heme but utilises it as a substrate. The substrate for nitric oxide, L-arginine (0.1-10mM), but not D-arginine, decreased heme oxygenase activity in rat brain homogenates. The arginine analogue L-NAME (0.1-10mM) increased activity in the same tissue. In spleen homogenates where endogenous nitric oxide activity is lower than in brain, these compounds had no effect. The nitric oxide donor sodium nitroprusside (0.001mM-10mM) reduced heme oxygenase activity in both brain and spleen. These results suggest that biological effects attributed to modulation of nitric oxide synthase may act via heme oxygenase.

Animals↗
PubMed1995

Expression and modulatory effects of heme oxygenase in acute inflammation in the rat.

Heme oxygenase (HO) is the rate limiting enzyme in the catabolism of heme molecules to the bile pigments which have recently been demonstrated to be strong antioxidants. In this study we analyzed the activity of HO in inflammatory cells isolated from a model of carrageenin induced acute inflammation in the rat. HO activity was significantly higher 24 hours after induction of the inflammation, this increase in activity coincided with the appearance of the highly inducible isoform of HO, Heat Shock Protein 32 kDa (HSP32) as detected by Western Blot analysis. Pre-treatment of animals with Tin protoporphyrin, a HO inhibitor, increased cell exudate at 24 hour in this model by 128% as compared to vehicle control. In comparison pre-treatment with a HO inducer, Ferriprotoporphyrin, decreased inflammatory cell number by 50% and cell exudate by 73% at 24 hours compared to control. These results suggest that HO may represent an endogenous protective mechanism against free radicals in acute inflammation and may be involved in the resolution of acute inflammation. The HSP32 isoform of HO may therefore represent a novel therapeutic target for the modulation of the inflammatory response.

Animals↗
PubMed1995

Polyarthritis in the rat: effects of tolerance and sensitization to the bacterial extract OM-89 with a possible mode of action.

The Bacterial Extract OM-89 has been shown to significantly reduce paw swelling in an avridine-induced polyarthritis (AvPA) in female Wistar rats whether given orally for 3 weeks or as a series of i.p. injections. Paw swelling was also markedly reduced in groups of adult rats which had received i.p. injections of OM-89 as neonates. Three separate tolerance-inducing regimes were used and all were equally effective. It is suggested that OM-89 can modulate the undesirable immunological reactions to endogenous antigens and since oral administration has been shown to be clinically effective in the human, that the induction of oral tolerance could be a mechanism of action of OM-89.

Adjuvants, Immunologic↗
PubMed1995

OM-89 modulation of chronic inflammation: relevance to clinical use.

The modulatory effects of a glycoprotein-rich endotoxin-free extract of Escherichia coli (OM-89) have been studied using the cotton pellet model of chronic inflammation in the male Wistar rat. OM-89 had a suppressive effect on the size of granuloma surrounding implanted cotton pellets at both 4 and 40 mg/kg given three times weekly. The lower dosage of 4 mg was effective throughout and there was little to be gained by increasing the dose as further reduction of granuloma size was not obtained. Whether given prior to, at the same time as, or after an inflammatory stimulus, OM-89 had suppressive effects. However, if given before, animals at first went through a phase of 'sensitization' before suppressive effects were seen on further exposure to OM-89 antigens, a phenomenon which might have bearing on clinical findings in rheumatoid arthritis. In animals presensitized to a cotton pellet, OM-89 was statistically as effective as indomethacin in suppressing a second granuloma. OM-89 combined with indomethacin showed additive effects and was highly effective. The results indicate that OM-89 could be efficacious in the treatment of chronic inflammatory conditions and there is the possibility that in appropriate circumstances OM-89 might replace some drugs currently used and in others reduce their dosage.

Adjuvants, Immunologic↗
PubMed1995

Coronary vasoconstriction in vitro in the hearts of polyarthritic rats: effectiveness of in vivo treatment with the endothelin receptor antagonist SB 209670.

Here we demonstrate that perfused hearts removed from polyarthritic rats develop a pronounced coronary vasoconstriction ex vivo. This vasoconstriction is almost entirely blocked by in vivo pretreatment of the rats with the endothelin receptor antagonist, SB 209670. Thus, inflammatory states may be associated with an increased activity of the endothelin system, leading to vascular dysfunction and vasoconstriction.

Animals↗