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Biomedical subjects

S Knight

Publications and source records attributed to S Knight.

At least 37 records · Page 2Linked to original sources
PubMed1999

Early expression of cyclo-oxygenase-2 during sporadic colorectal carcinogenesis.

Regular administration of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of colorectal cancer by targeting cyclo-oxygenase-2 (Cox-2), a key enzyme in arachidonic acid metabolism. To evaluate the role of Cox-2 in sporadic colorectal cancer development, Cox-2 expression was investigated by immunohistochemistry in 85 adenomas, 53 carcinomas, 34 hyperplastic lesions and 104 samples of histologically normal mucosa adjacent to adenoma or carcinoma. In addition, Cox-2 mRNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) in six adenomas and 14 carcinomas with paired grossly normal mucosa. Immunohistochemistry for the proliferation-associated antigen Ki-67 and in situ end labelling for demonstrating apoptotic bodies were also used to analyse the associations between Cox-2 expression and proliferation and apoptosis. Cox-2 protein expression was increased in 76/85 (89.4 per cent) adenomas and 44/53 (83.0 per cent) carcinomas compared with normal mucosa. Cox-2 protein expression was unrelated either to the degree of dysplasia or to the size of the adenomas (p > 0.50, p > 0.10, respectively) or to differentiation, Dukes stage or lymph node metastasis of carcinomas (all p > 0.50). Interestingly, 20/34 (58.8 per cent) hyperplastic lesions adjacent to adenomas or carcinomas displayed expression higher than in normal mucosa (18.3 per cent) (p < 0.0001) but lower than in adenomas or carcinomas (p < 10(-5), p < 0.001, respectively). There were no correlations between Cox-2 protein expression and proliferative or apoptotic index in either adenomas or carcinomas (all p > 0.25). Cox-2 mRNA expression was significantly increased in adenomas and carcinomas compared with normal mucosa (p < 0.005, p < 0.001, respectively). There were no differences between adenomas and carcinomas in either protein or mRNA levels (p > 0.25, p > 0.90, respectively). These data indicate that enhanced expression of Cox-2 occurs early during colorectal carcinogenesis and may contribute to tumour formation.

Adenoma↗
PubMed1999

Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats.

BACKGROUND: There has not been a noninvasive in vivo longitudinal evaluation of cardiac function in diabetic rats. The objective of this study is to examine the time course of development of cardiac dysfunction in streptozotocin (STZ)-induced diabetic rats. METHODS AND RESULTS: Cardiac function was evaluated by M-mode and Doppler echocardiography in anesthetized Wistar rats at 2, 4, 5, 6, and 8 weeks after injection with 65 mg of STZ/kg and in age-matched control rats before and after the administration of isoproterenol. Body weight (BW) was significantly less and blood glucose level significantly greater in diabetic rats compared with controls at 2 weeks and remained at these levels at all time points. The calculated left ventricular (LV) mass appeared slightly decreased in diabetic rats. However, LV mass-BW ratios were similar in controls and diabetic rats at 2, 4, and 5 weeks, but were significantly greater in diabetic rats at 6 and 8 weeks. Basal heart rate (HR) was significantly lower in diabetic rats at all time points studied. Basal LV systolic and diastolic dimensions, fractional shortening (FS), velocity of circumferential shortening (Vcf), peak emptying rate (PER), peak filling rate (PFR), and aortic peak velocity (APV) were not significantly different between controls and diabetic rats at 2 and 4 weeks. PER and PFR were significantly less in 5-week diabetic rats. However, Vcf, PER, and PFR were significantly less and FS and APV were similar at 6 and 8 weeks. Administration of isoproterenol increased HR, Vcf, FS, PFR, and PER in controls at all time points, but the increases in diabetic rats at 5, 6, and 8 weeks were less compared with those in controls. The increase in APV was significantly less in diabetic rats at all time points studied. CONCLUSION: STZ-induced diabetic rats showed bradycardia before contractile dysfunction. Overt and covert contractile dysfunction unmasked by isoproterenol begins at 5 weeks of diabetes. The overt LV systolic and diastolic dysfunction are fully manifested after 6 weeks of diabetes.

Animals↗
PubMed1999

Quantitative effects of valacyclovir on the replication of cytomegalovirus (CMV) in persons with advanced human immunodeficiency virus disease: baseline CMV load dictates time to disease and survival. The AIDS Clinical Trials Group 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group.

Virus load is a major risk factor for disease in many human viral infections, especially human immunodeficiency virus (HIV) disease. The effect of cytomegalovirus (CMV) load on disease progression and the influence of antiviral chemotherapy on surrogate markers of replication was investigated in 310 patients with advanced HIV disease in a randomized controlled trial that compared the effects of valacyclovir with those of acyclovir. Sequential blood and urine samples were analyzed by polymerase chain reaction (PCR), for human CMV (HCMV) DNA. In multivariate analyses, elevated virus load in both blood and urine at baseline was associated with increased risk of HCMV disease (relative hazard, 1.49 and 1.44 per log increase, respectively). Elevated virus load in blood at baseline was also associated with a significantly shorter survival time (log rank, P=. 0001). In time-updated analyses, valacyclovir significantly suppressed the virus load in subjects who were PCR positive at baseline (in blood or urine), when compared with the combined acyclovir arms.

AIDS-Related Opportunistic Infections↗
PubMed1999

Application and results of the Manchester Short Assessment of Quality of Life (MANSA).

BACKGROUND: Based on experiences and empirical evidence gained in studies using the Lancashire Quality of Life Profile (LQLP), the Manchester Short Assessment of Quality of Life (MANSA) has been developed as a condensed and slightly modified instrument for assessing quality of life. Its properties have been tested in a sample of community care patients. METHOD: Fifty-five randomly selected patients on the Care Programme Approach were interviewed using the LQLP, the MANSA and the Brief Psychiatric Rating Scale. RESULTS: Correlations between subjective quality of life scores on MANSA and LQLP were all 0.83 or higher (0.94 for the satisfaction mean score). Cronbach's alpha for satisfaction ratings was 0.74, and association with psychopathology was in line with results for LQLP as reported in the literature. CONCLUSIONS: The MANSA is a brief instrument for assessing quality of life focusing on satisfaction with life as a whole and with life domains. Its psychometric properties appear satisfactory.

Adult↗
PubMed1999

Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors.

PURPOSE: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity. PATIENTS AND METHODS: Patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. Plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients. RESULTS: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery. Plasma uracil changed from a median less than 0.2 micromol/L before therapy to 27.76 micromol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples. CONCLUSION: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme. The mechanism of inactivation is at the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer.

Adenocarcinoma↗
PubMed1999

Prehospital emergency care for children at school and nonschool locations.

OBJECTIVE: The purpose of this study was to ascertain whether school-based emergency medical services (EMS) incidents are different from nonschool-based EMS incidents for school-aged children. METHODS: We examined South Dakota EMS incident reports involving children ages 5 to 18 years old from 1994 through 1996 (n = 12603). Patient characteristics, dispatch reason, primary medical complaint, injury type, contributing factor of injury, and performed interventions were analyzed. RESULTS: During the study period, there were 140455 total EMS incident reports, of which 12603 (9.0%) were for school-aged children. EMS dispatches to a school represented 755 (6.0%) of all EMS incidents for school-aged children. The number of school-based EMS incidents was highest at the beginning of the school year, whereas the number of nonschool-based EMS incidents was highest during the summer months. School-based EMS incidents peaked at noon, whereas nonschool-based EMS incidents peaked after school. For both locations, the average age of the patient was 14 years old. The dispatch reason for school-based EMS incidents differed from those for nonschool-based EMS incidents. The top three school-based EMS dispatch reasons were falls (36.2%), other trauma (27.0%), and medical illness (24.5%). Motor vehicle crashes (30.8%), medical illness (26.2%), and other trauma (11.4%) were the leading nonschool-based EMS dispatch reasons. Injuries accounted for a significantly greater proportion of school-based than nonschool-based EMS incidents (70.7% vs 62.6%). Excluding pain, the most frequent type of injury was a fracture or dislocation in school-based EMS incidents and open soft-tissue injury in nonschool-based EMS incidents. A total of 11 students sustained an injury resulting in paralysis. The body region that was most commonly injured was a lower extremity (23%) in school-based incidents, whereas the head was the most commonly injured body region in nonschool-based incidents (20%). Sports were the largest contributing factor in school-based incidents, whereas alcohol/drug use was the largest contributing factor in nonschool-based EMS incidents among school-aged children. A medical illness was the primary complaint for 206 (27.3%) of the school-based incidents and 3599 (30.4%) of the nonschool-based incidents. The chief medical complaints were breathing difficulty (18.4%), seizure (16%), and other illness (12.3%) for school-based EMS incidents. Other illness (20.0%), breathing difficulty (13.7%), and abdominal pain (12.0%) were the chief complaints for nonschool-based EMS incidents. Treatment was rendered by the EMS provider in 11 753 (93.3%) of the incidents. Frequency of EMS intervention was the same for school-based incidents and nonschool-based incidents. Transportation to a medical facility was more frequent in school-based incidents than nonschool-based incidents. CONCLUSION: Compared with nonschool-based EMS incidents, school-based EMS incidents are more often attributable to injury, more often related to a sports activity, and more often result in transport to a medical facility. Understanding the characteristics of school emergencies resulting in an EMS dispatch may help emergency medical providers be better prepared for school-based incidents. School personnel may benefit from increased knowledge about the EMS system and EMS programs. In addition, EMS incident data may provide useful information about school-based injuries and may provide a means for injury surveillance.

Adolescent↗
PubMed1999

Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres.

Recently much attention has been given to the detection of submicroscopic chromosome rearrangements in patients with idiopathic mental retardation. We have screened 27 subjects with mental retardation and dysmorphic features for such rearrangements using a genetic marker panel screening. The screening was a pilot project using markers from the subtelomeric regions of all 41 chromosome arms. The markers were informative for monosomy in both parents at 3661902 loci (40.6%, 95% confidence interval 37.0-44.2%) in the 22 families where DNA was available from both parents. In two of the 27 subjects, submicroscopic chromosomal aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome 18q and the second patient had a 4 Mb deletion of chromosome 1p. The identification of two deletions in 27 cases gave an aberration frequency of 7.5% without adjustment for marker informativeness (95% confidence interval 1-24%) and an estimated frequency of 18% if marker informativeness for monosomy was taken into account. This frequency is higher than previous estimates of the number of subtelomeric chromosome abnormalities in children with idiopathic mental retardation (5-10%) although the confidence interval is overlapping. Our study suggests that in spite of the low informativeness of this pilot screening, submicroscopic chromosome aberrations may be a common cause of dysmorphic features and mental retardation.

Adolescent↗
PubMed1998

Periplasmic chaperone recognition motif of subunits mediates quaternary interactions in the pilus.

The class of proteins collectively known as periplasmic immunoglobulin-like chaperones play an essential role in the assembly of a diverse set of adhesive organelles used by pathogenic strains of Gram-negative bacteria. Herein, we present a combination of genetic and structural data that sheds new light on chaperone-subunit and subunit-subunit interactions in the prototypical P pilus system, and provides new insights into how PapD controls pilus biogenesis. New crystallographic data of PapD with the C-terminal fragment of a subunit suggest a mechanism for how periplasmic chaperones mediate the extraction of pilus subunits from the inner membrane, a prerequisite step for subunit folding. In addition, the conserved N- and C-terminal regions of pilus subunits are shown to participate in the quaternary interactions of the mature pilus following their uncapping by the chaperone. By coupling the folding of subunit proteins to the capping of their nascent assembly surfaces, periplasmic chaperones are thereby able to protect pilus subunits from premature oligomerization until their delivery to the outer membrane assembly site.

Adhesins, Bacterial↗
PubMed1998

Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes.

Ruthenium red is a well known inhibitor of Ca2+ uptake into mitochondria in vitro. However, its utility as an inhibitor of Ca2+ uptake into mitochondria in vivo or in situ in intact cells is limited because of its inhibitory effects on sarcoplasmic reticulum Ca2+ release channel and other cellular processes. We have synthesized a ruthenium derivative and found it to be an oxygen-bridged dinuclear ruthenium amine complex. It has the same chemical structure as Ru360 reported previously (Emerson, J., Clarke, M. J., Ying, W-L., and Sanadi, D. R. (1993) J. Am. Chem. Soc. 115, 11799-11805). Ru360 has been shown to be a potent inhibitor of Ca2+-stimulated respiration of liver mitochondria in vitro. However, the specificity of Ru360 on Ca2+ uptake into mitochondria in vitro or in intact cells has not been determined. The present study reports in detail the potency, the effectiveness, and the mechanism of inhibition of mitochondrial Ca2+ uptake by Ru360 and its specificity in vitro in isolated mitochondria and in situ in isolated cardiac myocytes. Ru360 was more potent (IC50 = 0.184 nM) than ruthenium red (IC50 = 6.85 nM) in inhibiting Ca2+ uptake into mitochondria. 103Ru360 was found to bind to isolated mitochondria with high affinity (Kd = 0.34 nM, Bmax = 80 fmol/mg of mitochondrial protein). The IC50 of 103Ru360 for the inhibition of Ca2+ uptake into mitochondria was also 0.2 nM, indicating that saturation of a specific binding site is responsible for the inhibition of Ca2+ uptake. Ru360, as high as 10 microM, produced no effect on sarcoplasmic reticulum Ca2+ uptake or release, sarcolemmal Na+/Ca2+ exchange, actomyosin ATPase activity, L-type Ca2+ channel current, cytosolic Ca2+ transients, or cell shortening. 103Ru360 was taken up by isolated myocytes in a time-dependent biphasic manner. Ru360 (10 microM) applied outside intact voltage-clamped ventricular myocytes prevented Ca2+ uptake into mitochondria in situ where the cells were progressively loaded with Ca2+ via sarcolemmal Na+/Ca2+ exchange by depolarization to +110 mV. We conclude that Ru360 specifically blocks Ca2+ uptake into mitochondria and can be used in intact cells.

Animals↗
PubMed1998

Dyskeratosis Congenita (DC) Registry: identification of new features of DC.

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X-linked. As well as a variety of noncutaneous abnormalities, the majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality. In addition to BM hypoplasia, some patients also developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X-linked DC had clinical features. Carriers of X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele have a growth/survival advantage over cells that express the mutant allele. Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X-linked form of DC, is located within Xq28 and facilitated its positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expression of DKC1 suggest that, as well as having a critical role in normal haemopoiesis, this gene has a key role in normal cell biology.

Adolescent↗
PubMed1998

A study of the 'lived' experience of change during a period of curriculum and organizational reform in a department of nurse education.

In this paper an attempt is made to illustrate the experience of lecturers in a department of nursing preparing to implement the adult branch component of the pre-registration Higher Education Diploma in Nursing Studies. The study was conducted in a college of health in England at a time when the college was only beginning to discuss the possibility of closer links with universities. It highlights the grief responses associated with change exhibited by nursing lecturers during a period of organizational upheaval and curriculum change and maps the transition through stages of adaptation over a 2-year period. The analysis of the effects of change and the coping strategies adopted by nursing lecturers presented here is most relevant to educational managers who are charged with integrating nurse education into higher education.

Adaptation, Psychological↗