Biomedical subjects

D Lowe

Publications and source records attributed to D Lowe.

At least 73 records · Page 4Linked to original sources

PubMed2000

Apoptosis of malignant cells in Hodgkin's disease is related to expression of the cdk inhibitor p27KIP1.

Previous results from B-cell chronic lymphocytic leukaemia suggest that expression of p27KIP1 might be important in protection from apoptosis. Given the relevance of apoptosis to the pathogenesis of Hodgkin's disease (HD), it was decided to examine the expression of p27KIP1 in relation to apoptosis in these lesions. Paraffin-wax sections from a total of 65 histologically confirmed HD tumours were used to derive apoptotic index (AI) and DNA fragmentation index (DFI) scores, which were compared with the expression of various cell-cycle-regulating proteins, including p27KIP1 (p27), p21WAF1/CIP1 (p21) and cyclin D1, and with Epstein-Barr virus (EBV) status. The DFI was measured by TdT-mediated dUTP-FITC nick end-labelling (TUNEL), and the AI by conventional morphology. Cells showing the typical morphology of apoptosis, together with those resembling so-called 'mummified' Hodgkin/Reed-Sternberg (HRS) cells, were included in AI measurements. Increasing numbers of p27-positive HRS cells were associated with lower levels of apoptosis in these cells, as indicated by significantly lower AI and DFI scores. There was a trend towards poorer survival in those patients with the highest numbers of p27-positive HRS cells and with lower AI and DFI scores, but these differences were not statistically significant. p21-positive HRS cells were significantly more frequent in those cases with lower AI scores. A similar trend was observed for p21 and DFI, although this relationship was not statistically significant. There was also a trend towards higher levels of cyclin D1 protein in HD cases with high AI and DFI values. A tendency for increasing numbers of p27-positive and p21-positive HRS cells in EBV-positive cases was noted, but this relationship was not statistically significant. EBV status did not correlate with either AI or DFI scores. The results of this study suggest that p27, and possibly also p21, may be involved in protection from apoptosis in HD.

Apoptosis↗

PubMed2000

Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy.

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.

Animals↗

PubMed2000

Distinct patient groups in oral cancer: a prospective study of perceived health status following primary surgery.

Health-related quality of life (HRQOL) is an important consideration in the management of patients with cancer. Pre-treatment data can give an indication of the anticipated response following cancer treatment. However, in order to use HRQOL data meaningfully it is essential to have an appreciation of how different patient groups respond. The aim of the study was to identify distinct patient groups at baseline using the University of Washington head and neck cancer questionnaire (UW-QOL). It was also the intention to see how these groups differed in their: (1) clinical and demographic attributes; (2) European Organisation for Research and Treatment of Cancer (EORTC) C30 and SF 36 scores; and (3) longitudinal trends over 6 and 12 months. One-hundred and thirty consecutive patients with previously untreated oral and oro-pharyngeal cancer were recruited. All were treated by primary surgery. Attrition was evident in the study but care was taken to allow for this. There were two distinct groups of patients identified by the cumulative UW-QOL score at presentation. These groups discriminated throughout the EORTC C30 and SF 36, at baseline and longitudinally, with the exception of mental health. This study demonstrates that HRQOL items are interrelated. There are difficulties in using baseline scores for treatment selection, and scores need to be interpreted in the light of clinical and demographic factors.

Adult↗

PubMed2000

Variation in the frequency of Epstein-Barr virus-associated Hodgkin's disease with age.

A number of studies in developed countries have reported variation in the frequency of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) with age. A 'three disease' model for HD that incorporates the EBV association, histological subtype of HD and age has recently been proposed. In this model, Hodgkin's disease of childhood and older adults is commonly EBV-associated and of mixed cellularity type, whereas young adult HD is generally not EBV-associated and is usually characterised by nodular sclerosis disease. A case series of HD diagnosed in the West Midlands between 1981 and 1997, inclusive, was used to investigate the applicability of the 'three disease' model. In situ hybridisation for the EBV early RNAs (EBERs) was used to determine the presence of EBV in the malignant Hodgkin/Reed-Sternberg cells. In contrast to the 'three disease' model, nodular sclerosis was the predominant subtype in each of the age groups within the case series. In addition, overall there was little variation in EBV-positive rates across the age ranges examined. However, when females were analysed separately, older women (45+ years) were significantly more likely to have EBV-positive disease than their younger counterparts (<45 years). In summary our results do not generally support the 'three disease' model.

Adolescent↗

PubMed2000

Effect of short-term high dose of steroids on the healing of microvascular anastomoses in a rabbit model: pilot study.

Short-term high doses of steroids have been used in head and neck surgery to reduce swelling in free tissue transfers. This study was set up to assess the effect of this treatment on the healing of microvascular anastomoses in a rabbit model. Anastomoses were made in the common carotid artery and anterior facial vein in 40 animals, half of which were given high doses of methylprednisolone (2.5 mg/kg/day) intravenously for 48 h peri-operatively. The patency of the vessels was assessed and they were harvested for histological examination at 1, 3, 7, 14, and 90 days postoperatively. Steroids tended to reduce the swelling in the vessel walls during the early stages of healing (24 h and 3 days), and also to reduce the inflammatory cell count in the lumen of the vessels at 3 days. It seems likely from these initial observations that steroids are more likely to improve than jeopardize the healing of microvascular anastomoses.

Animals↗

PubMed2000

Use of microalbuminuria as a predictor of outcome in critically ill patients.

We have investigated the use of microalbuminuria as a predictor of outcome in a pilot study involving 50 critically ill patients in a six-bed hospital intensive care unit (ICU). Urinary microalbumin:creatinine (M:Cr) ratios measured only 6 h after admission to the ICU demonstrated a significant difference (P = 0.01) between survivors and non-survivors, allowing rapid identification of patients at increased risk of developing organ failure and at greater risk of death. This work suggests that earlier identification of these patients using a rapid, simple, inexpensive biochemical test is possible; if confirmed in a larger study, it may be that clinical interventions can be targeted at those most likely to benefit.

Adult↗

PubMed2000

Expression of the matrix metalloproteinase 9 in Hodgkin's disease is independent of EBV status.

BACKGROUND: In vitro the Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP-1) has been shown to upregulate expression of matrix metalloproteinase 9 (MMP-9), a member of a family of zinc dependent endopeptidases that is believed to facilitate tumour invasion and metastasis by degradation of the extracellular matrix. AIM: To test whether the expression of MMP-9 in Hodgkin's disease correlates with EBV status and survival and to investigate whether LMP-1 expression affects MMP-9 concentrations in the Hodgkin's disease cell line, L428. METHODS: MMP-9 expression was measured by means of immunohistochemistry in a series of Hodgkin's disease tumours and this expression was correlated with EBV status and survival. The influence of LMP-1 on MMP-9 expression was also investigated in the Hodgkin's disease cell line, L428. RESULTS: MMP-9 expression was demonstrated in the malignant Hodgkin and Reed-Sternberg cells of all (n = 86) formalin fixed, paraffin wax embedded Hodgkin's disease tumours examined. Although the intensity of MMP-9 immunostaining varied between cases, there was no correlation between MMP-9 expression and EBV status or survival. MMP-9 expression was also detected in a variety of non-malignant cells, including fibroblasts. MMP-9 was detected by zymography in the L428 and KMH2 Hodgkin's disease cell lines, whereas low or undetectable amounts of MMP-9 were found in the L591 Hodgkin's disease cell line. Induction of LMP-1 expression in the Hodgkin's disease cell line L428 did not result in a detectable increase in the values of MMP-9 as measured by zymography. CONCLUSIONS: These results demonstrate that MMP-9 is consistently expressed by the Hodgkin and Reed-Sternberg cells of Hodgkin's disease tumours and by the Hodgkin's disease cell lines, L428 and KMH2. However, this expression does not appear to be related either to LMP-1 values or to survival.

Biomarkers, Tumor↗

PubMed2000

Artificial neural networks and survival prediction in ovarian carcinoma.

The standard use of known survival predictors for ovarian cancer in clinical practice are primarily based on disease stage. This does not permit a real individualization of a patient's potential outcome. This study assessed the value of neural networks to refine the prediction of survival based only on information gleaned at primary surgery. The possibility exists that such methods may permit further elucidation of outcome and influence management.

England↗

PubMed1999

Comparison of prophylactic oophorectomy specimens from carriers and noncarriers of a BRCA1 or BRCA2 gene mutation. United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group.

BACKGROUND: The natural history of ovarian cancer is not well understood and, to date, there is conflicting evidence as to whether or not there is a demonstrable precursor lesion. Some women at high risk of developing ovarian cancer because of their family history elect to have a prophylactic oophorectomy. To determine whether or not a recognizable premalignant lesion could be defined in familial ovarian carcinogenesis, we reviewed ovarian tissue specimens from women whose ovaries were removed prophylactically before gene testing became available and who were tested subsequently for BRCA1 or BRCA2 gene mutations. METHODS: We analyzed ovarian tissue specimens from 37 women. The specimens were examined for the presence of the following four features: inclusion cysts, clefts and fissures, ovarian epithelial metaplasia, and the presence of papillae on the ovarian surface epithelium. The specimens were also examined closely for the presence of dysplasia and occult neoplasia. Furthermore, the occurrence of endometriosis and benign ovarian tumors was documented in these women. The protein truncation test, nonradioactive single-stranded conformation polymorphism analysis, and heteroduplex analysis, followed by DNA sequencing, were used to identify BRCA1 or BRCA2 mutations in either blood samples or ovarian tissue specimens. RESULTS: Eleven women had inherited a mutated BRCA1 or BRCA2 gene; 26 women had not. There was no difference between these groups for any of the features studied. CONCLUSIONS: Our data suggest that many of the histologic "abnormalities" described in "normal" ovaries are, in fact, variations of the normal and are not associated with the development of cancer.

Adult↗

PubMed1999

The University of Washington head and neck cancer measure as a predictor of outcome following primary surgery for oral cancer.

BACKGROUND: The purpose of this study was to investigate the disease specific functional status of patients with oral cancer treated by primary surgery. The University of Washington head and neck cancer questionnaire (UW-QOL) was used, and outcome was compared against patient's age, sex, T category, site, surgical procedure, and adjuvant radiotherapy. METHODS: In the year 1995, consecutive patients with previously untreated squamous cell carcinoma of the oral region were recruited. Questionnaires were given at four time intervals: preoperatively and at 3, 6, and 12 months. RESULTS: Fifty patients underwent primary surgery for oral cancer between 4 January and 12 December 1995. Of 48 patients recruited, 41 (85%) had microvascular free tissue reconstruction. Patients with T category 3 or 4 tumors tended to report more severe problems than did patients with T category 1 or 2 tumors; this was especially true for increased pain (p <.001). There was a marked fall in cumulative UW-QOL scores by 3 months, with some recovery to 12 months. Of the initial 48 patients, 29 (60%) were alive and disease free at 1 year, and there were 25 completed questionnaires. The trend at 1 year was for better scores in women, T category 1 and 2, anterior oral cavity, primary closure/laser treatments, and patients not requiring adjuvant radiotherapy. CONCLUSIONS: Patients undergoing surgery for oral cancer have a profound fall in quality of life scores by 3 months, and their scores approach pretreatment levels by 12 months. Clinical parameters are useful in predicting trends in UW-QOL outcome at 1 year and are also associated with differences in individual domain scores.

Aged↗

PubMed1999

Measures of total free radical activity in critically ill patients.

OBJECTIVES: To examine the role played by free radicals during the initial phase of critical illness in patients on an Intensive Care Unit (ICU). DESIGN AND METHODS: Serum total antioxidant status (TAS) and uric acid (UA) levels were measured in 50 patients over 18 hours to represent the initial stage of critical illness. Clinical scoring systems (APACHE II and multiple organ dysfunction scores) were used to assess the degree of organ dysfunction. Outcome was assessed according to patient survival (survivors, n = 36; non-survivors, n = 14). RESULTS: Serum TAS was higher in non-survivors; a similar finding was demonstrated for serum UA. Levels of both biochemical markers were associated with the degree of organ function and with higher antioxidant and UA levels present in patients with more severe organ dysfunction. In addition, serum UA was significantly correlated to serum TAS and probably accounted for much of the antioxidant activity observed. CONCLUSIONS: The increased TAS and UA levels observed may simply be a response to the degree of renal dysfunction observed as those patients with worse renal function had higher TAS and UA levels. In conclusion, measurement of serum TAS appears to be a reflection of UA concentration and results should be interpreted with caution particularly in patients who have renal dysfunction.

Adult↗

PubMed1999

SCH 57790: a novel M2 receptor selective antagonist.

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Acetylcholine↗

PubMed1999

Quality of life 5-10 years after primary surgery for oral and oro-pharyngeal cancer.

This study reports the quality of life in long-term survivors of oral cancer treated by primary surgery. Two hundred and twenty patients were treated at the Regional Maxillofacial Unit between the years 1987 and 1992, of which 48 were alive and disease free in July 1997. Thirty-eight patients self-completed the following questionnaires: University of Washington Quality of Life Scale (UW-QOL), the European Organisation for Research and Treatment of Cancer (EORTC) core QOQ-C30 (v2) and the EORTC Head and Neck (H&N35). Results for this group were compared with the one year findings of a similar prospective cohort treated in 1995. Long-term survivors tended to report a good or excellent quality of life. Quality of life deficits in the long-term survivors were similar to those at one year. However, a larger longitudinal study is required to test this relationship more rigorously. The similarity of domain scores suggests that quality of life evaluation at one year is a useful marker of long-term outcome.

Adult↗

PubMed1999

Effect of material deprivation on Epstein-Barr virus infection in Hodgkin's disease in the West Midlands.

We have used Townsend scores from postcode data to compare levels of material deprivation and Epstein-Barr virus (EBV)-positivity for 223 patients diagnosed with Hodgkin's disease (HD) in the period 1981-1997. The presence of EBV in HD tumours was determined using in situ hybridization to target the abundantly expressed EBV early RNAs. EBV was detected in the malignant Hodgkin and Reed-Sternberg cells in 47/223 HD cases (21%). There was found to be a tendency for higher Townsend scores (indicative of higher levels of material deprivation) in EBV-positive HD patients, but this association was not statistically significant. When various subgroups of patients from the study were examined separately the indication of higher Townsend scores in EBV-positive patients was found to be more marked for patients with mixed cellularity disease (P = 0.09) and for females (P = 0.03). The results of this study suggest that differences in the level of material deprivation are important in determining the likelihood of EBV-positive HD in the UK, particularly for certain subgroups of patients. It is not known what specific socioeconomic factors are responsible for these differences, although alterations in the timing or rate of primary EBV infection, or decline in the level of EBV-specific immunity, may be important.

Adolescent↗

PubMed1999

An RNA polymerase III transcription unit located in the upstream control regions of the human proliferating-cell nucleolar protein p120 gene is transcribed in vitro and in vivo.

An RNA polymerase III (Pol III) transcription unit containing homology to highly repeated Alu sequences was identified in the upstream flanking sequences of the gene for the human proliferating-cell nucleolar antigen p120. When transcribed in vitro, this Pol III unit produced three RNA transcripts, designated by nucleotide length as T150, T385 and T635; RNA transcript T635 was the most abundant accounting for over 90%. The transcription initiates at nucleotide -729 of the human p120 promoter and proceeds in the opposite orientation to the p120 gene transcription. Northern blot analysis and cDNA cloning followed by sequencing showed the presence of the T635 RNA in HeLa cells, indicating that this Pol III transcription unit is functional and transcribed in vivo. Disruption of this Pol III transcription unit by deletion of the Box A residues (-733 to -744) resulted in a sixfold reduction of the p120 gene transcription. A possible role for this Pol III transcription unit in p120 gene transcription is discussed.

Base Sequence↗

PubMed1999

N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study.

OBJECTIVES: To investigate whether prolonged infusion of N-acetylcysteine (NAC) that is commenced immediately after admission to the intensive care unit could ameliorate the development or progression of multisystem organ failure and improve mortality. DESIGN: Prospective, randomized, double-blinded clinical trial. SETTING: Six-bed intensive care unit in a teaching hospital. PATIENTS: Of the 100 patients recruited (14 withdrew), 86 patients were studied. INTERVENTIONS: After randomization, the treatment group (n = 41) received NAC (150 mg/kg bolus followed by a continuous infusion of 12 mg/kg/hr) and the placebo group (n = 45) received 5% dextrose, from a minimum of 3 days up to a maximum of 5 days. MEASUREMENTS AND MAIN RESULTS: There was no statistically significant difference between the two groups regarding outcome as indicated by mortality and the required days of inotropic support, mechanical ventilation, and intensive care. The time interval between hospital and intensive care unit admission showed great variability, with a median of 24 hrs for the whole sample. By splitting the groups with this median value, the effect of NAC was examined on patients admitted within 24 hrs and after 24 hrs of arrival to the hospital. There was a nonsignificant difference in mortality in favor of NAC. Patients admitted after 24 hrs of hospital admission had a significantly worse mortality in the NAC-treated group (61% vs. 32% for controls; p = .05). CONCLUSIONS: We found a nonsignificant difference in outcome between NAC and placebo-treated patients. Our results suggest that the initiation of NAC treatment >24 hrs after hospital admission may potentially be harmful, and further studies should be undertaken to investigate the clinical use of the early application of NAC in critically ill patients.

APACHE↗

PubMed1999

Role of MR imaging in the selection of patients with early cervical carcinoma for fertility-preserving surgery: initial experience.

PURPOSE: To assess whether magnetic resonance (MR) imaging can be used for reliable prediction of proximal extension of cervical carcinoma into the myometrium. MATERIALS AND METHODS: Thirty patients with early cervical carcinoma underwent MR imaging with use of a 1.5-T magnet prior to surgery. The MR images were analyzed by two radiologists, unaware of the histopathologic findings, for the relationship of the tumor to the internal os and extension of the tumor into the myometrium. Findings at MR imaging were compared with those at histopathologic examination. RESULTS: At MR imaging, 24 patients were considered not to have tumor extension proximal to the internal os and into the myometrium. All tumors were confirmed histopathologically. In six patients thought to have myometrial tumor invasion at MR imaging, five tumors were confirmed histopathologically; in one, tumor extended up to the internal os but did not involve the myometrium. CONCLUSION: This is a small study, but MR imaging appears accurate in the prediction of myometrial tumor involvement and in showing the relationship of cervical carcinoma to the internal os and, hence, the patient's suitability for trachelectomy.

Adult↗

PubMed1999

Asian American health care attitudes.

This paper describes the results of a survey of health care attitudes of a sample of respondents primarily of Asian American background. The importance of bilingualism, Asian background, age, and other attributes of a physician are discussed with relation to subgroups in the sample. The relative importance of the influence of doctors, family, and friends on the choice of physician and health care facility are also presented. The findings may help with the development of effective market segmentation and improved health care service to the Asian American community.

Age Factors↗