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Biomedical subjects

K Gill

Publications and source records attributed to K Gill.

At least 19 recordsLinked to original sources
PubMed2001

Overexpression of aromatase leads to hyperplasia and changes in the expression of genes involved in apoptosis, cell cycle, growth, and tumor suppressor functions in the mammary glands of transgenic mice.

Our previous studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in aromatase transgenic mammary glands. In this study, we have examined the effects of aromatase overexpression on biochemical changes in the aromatase transgenic mice. Our results show an increase in the expression of both estrogen and progesterone receptors, and their expression is maintained in the transgenic mammary tissue even without circulating ovarian estrogens. Our results also show an increase in the expression of several growth factors and cell cycle genes in the aromatase transgenic mammary glands, which is consistent with the observed increase in proliferating cell nuclear antigen levels and cellular proliferation. Interestingly, we have also observed a decrease in the expression of epidermal growth factor receptor and its ligands, epidermal growth factor and transforming growth factor alpha, as well as several tumor suppressor genes such as p53 and retinoblastoma. This study presents novel and interesting findings that are consistent with the current models of aromatase influence and the complex interactions of biochemical pathways leading to mammary tumorigenesis.

Animals↗
PubMed2001

Regulation of colony stimulating factor-1 (CSF-1) in endometrial cells: glucocorticoids and oxidative stress regulate the expression of CSF-1 and its receptor c-fms in endometrial cells.

OBJECTIVE: To evaluate the regulation and expression of CSF-1 and its receptor c-fms in endometrial cells. DESIGN: In vitro study. SETTING: Research and teaching institution. PATIENT(S): None. INTERVENTION(S): In vitro experimental study. MAIN OUTCOME MEASURE(S): The effect of glucocorticoid and oxidative stress on the expression of CSF-1 and c-fms in endometrial cells. RESULT(S): Cultured nonmalignant EM42 cells not only express CSF-1 and c-fms but are also capable of responding to exogenous CSF-1. We have also seen that glucocorticoids can regulate the expression of CSF-1/c-fms in endometrial cells. Furthermore, this study shows that oxidative stress plays a significant role in the induction of CSF-1 and its receptor c-fms. CONCLUSION(S): The results suggest that CSF-1 may promote the growth of nonmalignant endometrial cells in both an autocrine and paracrine manner and that endometrial cells under oxidative stress induce CSF-1 and c-fms.

Cell Line↗
PubMed2001

Overexpression of aromatase in transgenic male mice results in the induction of gynecomastia and other biochemical changes in mammary glands.

Our previous studies have shown that overexpression of aromatase in mammary glands results in the induction of hyperplastic and dysplastic changes in female transgenic mice. In this study we show that overexpression of aromatase in male transgenic mice results in increased mammary growth and histopathological changes similar to gynecomastia. Increased estrogenic activity also results in an increase in estrogen and progesterone receptor expression in the mammary glands of transgenic males as compared to the nontransgenic males, as well as an increase in the expression of various genes involved in cell cycle and cell proliferation. We have also observed an increase in certain growth factors, such as bFGF and TGFbeta, as a result of aromatase overexpression in the male transgenic mammary glands. In order to obtain a better understanding of the biological significance of gynecomastia, a reliable model is necessary to explain the mechanisms and correlations associated with human cancers. This model, can potentially serve as a predictable and useful tool for studying gynecomastia, hormonal carcinogenesis and action of other carcinogens on hormone induced cancers.

Animals↗
PubMed2001

An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma.

This study was designed to assess the efficacy and safety of substituting cisplatin with oxaliplatin in the DHAP (dexamethasone, cytarabine and cisplatin) regimen for patients with relapsed or refractory non-Hodgkin's lymphoma. Twenty-four evaluable patients with intermediate or high-grade non-Hodgkin's lymphoma were treated at 3-weekly intervals with oxaliplatin (130 mg/m2, d 1), cytarabine (2 g/m2 for two doses, d 2) and dexamethasone (40 mg, d 1-4). The median age of the patients was 58 (range 18-70). Histological subtypes were diffuse large B cell, 20; mantle cell, two; anaplastic large cell, one; and peripheral T cell, one. The overall objective response rate (RR) was 50% [95% confidence interval (CI) = 29-71%] including four complete responses and eight partial responses. RR for those patients treated at first relapse was higher than those treated at second and subsequent relapse (77% versus 29%). Grade 3 and 4 toxicity was mainly haematological: anaemia 17%, neutropenia 75% and thrombocytopenia 75%. No grade 4 non-haematological toxicity was reported. No significant renal and neurotoxicity was demonstrated. Median survival was 10.6 months. Probabilities of 1-year progression-free survival and overall survival were 47% (95% CI = 26-66%) and 50% (95% CI = 23-72%) respectively. In conclusion, dexamethasone, cytarabine and oxaliplatin (DHAX) is a novel combination in salvage therapy for relapsed or refractory non-Hodgkin's lymphoma. It has clinically significant activity with an acceptable toxicity profile. Lack of renal toxicity makes DHAX an attractive cytoreductive regimen before high-dose chemotherapy.

Adolescent↗
PubMed2001

Neuropsychological functioning in substance-dependent patients.

The present study examined neurocognitive functioning in groups of individuals addicted to various psychoactive substances. One hundred ten patients admitted to treatment for substance misuse were assessed using a semistructured clinical interview, the Beck Depression Inventory, the Symptom CheckList-90, the Trail Making A and B tests, and the Shipley Institute of Living Scale. Results revealed that at intake, alcohol- and benzodiazepine-addicted clients exhibited higher levels of cognitive impairment and psychological distress than patients dependent on other drugs. Regression analysis showed that the Shipley vocabulary raw score was a significant predictor of length of stay in treatment.

Adult↗
PubMed2001

Sensitivity of AXB/BXA recombinant inbred lines of mice to the locomotor activating effects of cocaine: a quantitative trait loci analysis.

The present study was conducted in order to characterize putative quantitative trait loci (QTL) for cocaine-induced activation in the AXB/BXA recombinant inbred (RI) lines of mice. Locomotor activity was measured in the AXB/BXA and progenitor A/J and C57BL/6J strains using a computerized open-field apparatus following saline or cocaine (0, 5, 10, 20 mg/kg) administration (i.p.). Analyses were conducted on phenotypes including both novelty (responses under initial saline conditions) and cocaine-induced locomotor activity. Significant differences were observed across RI lines on all measures. Gender differences in sensitivity to the activating effects of cocaine were not observed. The wide and continuous distributions of phenotypic responses in the AXB/BXA RI lines suggested polygenic regulation. Initial basal locomotor activity was significantly correlated with cocaine-induced activation (raw scores) (r = 0.60, P = 0.0021) but not with cocaine difference scores (r = 0.370, P = 0.082). Simple regression and interval mapping were used to initially identify significant gene markers associated with novelty and cocaine-induced activation. Subsequently, composite interval mapping was used to increase the accuracy in mapping individual loci. QTL analysis of cocaine-induced activation (difference scores--20 mg/kg dose) identified significant loci on chromosomes 12 (23 cM), and 15 (46.8 cM). The significant QTLs were identified on chromosomes 12 and 15 map to regions in proximity to genes for the somatostatin 1 (Smstr1 -23 cM) and 3 (Smstr3 -46.3 cM) receptors, respectively. Further research employing AcB/BcA recombinant congenic lines of mice will be employed to confirm the QTL on chromosomes 12 and 15 identified in the present study.

Animals↗
PubMed2001

An audit of oral care practice and staff knowledge in hospital palliative care.

Mouth care is considered one of the most basic of nursing activities, and palliative care patients are especially vulnerable to oral problems (Macmillan Practice Development Unit, 1995). This article describes a project on developing oral care practice and staff knowledge, by nursing staff and Macmillan nurses at a hospital in central England. A baseline audit (audit I) was carried out to examine all aspects of current oral care practice and nursing knowledge, including assessment, implementation, prescribing and evaluation of care. Oral care guidelines and a programme of ward-based teaching were then introduced. Several months later a follow-up audit (audit II) was conducted. Results showed an improvement in all aspects of oral care and staff knowledge. Additional benefits of this process included improved professional relationships and the promotion of further audits in hospital palliative care. Recommendations include the need for further nursing research into oral care to build the evidence base further. Additionally, it is suggested that nurses must recognize their important and central role in improving this aspect of palliative care. Education and training is pivotal to this process.

Humans↗
PubMed2000

Alcohol-induced locomotor activation in C57BL/6J, A/J, and AXB/BXA recombinant inbred mice: strain distribution patterns and quantitative trait loci analysis.

RATIONALE: Quantitative trait loci (QTLs) for initial sensitivity to alcohol have been identified in a number of mouse strains (e.g. BXD); however, confirmation is required. OBJECTIVES: The present paper aimed to characterize the C57BL/6J, A/J, and AXB/BXA recombinant inbred (RI) strains of mice for basal and ethanol-induced locomotor activation as measured in an open field and to provide provisional location of QTLs for these phenotypes. METHODS: A/J and C57BL/6J mice were habituated to handling and then randomly assigned to receive one of four alcohol doses (0, 0.5, 1.0, 2.0 g/kg). Subsequently, all available strains of the AXB/BXA RI were tested with the 2 g/kg dose of ethanol or vehicle control. RESULTS: Simple regression and interval mapping were used initially to identify significant gene markers associated with ethanol-induced activation (calculated as total activity on alcohol day-total activity on saline day). Subsequently, composite interval mapping (CIM) was used to increase the accuracy in mapping individual loci. Genetic markers on chromosomes 2, 3, 8, 13, 16, 18 and 19 were associated with ethanol-induced activation. CONCLUSIONS: Three significant markers identified through CIM accounted for 86% of the genetic variance in the ethanol-induced activation. QTLs on chromosome 16 (45.6 cM) and 19 (24 cM) previously associated with alcohol consumption in the AXB/BXA RI mice were found to overlap with QTLs for ethanol-induced activation identified in the present study.

Animals↗
PubMed2000

Overexpression of aromatase leads to development of testicular leydig cell tumors : an in vivo model for hormone-mediated TesticularCancer.

Despite recent advances in diagnosis and treatment of testicular cancer, its causes remain unknown. The most common conditions known to be associated with testicular cancer are cryptorchidism, infertility, and overexposure to pesticides or radiation. Recent studies also indicate hormones may play a crucial role in testicular tumorigenesis. Our studies show that about half of the male transgenic mice overexpressing aromatase in testis were infertile and/or had larger than normal testicles. Gross pathology and histological analysis showed the mice to have Leydig cell tumors, unilaterally or bilaterally. Serum estradiol levels for transgenic mice were at least twice as high as those for nontransgenic mice. Expression of aromatase and estrogen receptor were also very high in testicular tissue of transgenic mice compared to nontransgenic mice. Consistent with increased estrogenic activity in the testicular tissue, we also saw an increase in the levels of genes involved in cell cycle that are regulated by the estrogen. To obtain a better understanding of the biological significance of testicular tumorigenesis, a reliable animal model is necessary to clarify the mechanisms and correlations associated with human cancers. Here we describe such a model, which shows that overexpression of aromatase results in increased estrogen production and a changed hormone milieu, leading to the induction of testicular cancer (Leydig cell tumors). This predictable and useful model is a potential tool for the study of testicular tumorigenesis, hormonal carcinogenesis, synergistic action of other carcinogens on hormone-induced tumors, and tumor dependency on endocrine factors.

Animals↗
PubMed2000

An unusual cause of femoral embolus.

Acute lower limb ischaemia is associated with high morbidity and mortality. The authors describe an unusual cause of arterial occlusion two weeks following aorto-coronary bypass surgery. This case should make vascular surgeons aware of the possibility of prosthetic materials acting as emboli. Furthermore, they should also be mindful that the presenting symptom may be at a site and time remote from the original intervention.

Aged↗
PubMed2000

An abstinence-oriented program for substance use disorders: poorer outcome associated with opiate dependence.

OBJECTIVES: To evaluate the characteristics of patients with various substance-related disorders, and to examine rates of retention in treatment. METHODS: We assessed the demographic characteristics, substance abuse, and psychological distress of 239 men and women at admission. Six-month performance was evaluated, using as criteria length of stay in treatment, abstinence, attendance in therapy sessions, and completion status at discharge. RESULTS: Moderate to severe psychological distress was observed among these individuals. Higher levels of depression were found among women and in individuals with alcohol and sedative use disorders. The primary drug of abuse, frequency of use, and reason for entering treatment were the most significant predictors of retention. CONCLUSIONS: Opiate-addicted clients had the worst prognosis and treatment profiles. Further research is needed to identify factors that would optimize treatment for opiate dependence.

Adult↗
PubMed2000

A comparison of algorithms for initiation of lipid lowering therapy in primary prevention of coronary heart disease.

OBJECTIVE: To compare nine different algorithms for determining the necessity for drug treatment of hyperlipidaemia in patients without cardiovascular disease. DESIGN: Risk-factor data on 400 patients were obtained. Algorithms assessed included the Framingham model, National Cholesterol Education Program, European, British, New Zealand, British Regional Heart Study, Sheffield, Munster Heart Study and Dundee guidelines and a local general rule for treatment of atheroma (General Rule to Enable Atheroma Treatment). SETTING: Three hospital lipid clinics. RESULTS: Patients were 56% male, aged 53.8 +/- 12.3 years, 38% smoked, 55% had a family history of disease (37% familial hypercholesterolaemia, 33% hypertension and 5.2% left ventricular hypertrophy); 31% were moderately obese and 15% were diabetic. The average cholesterol level was 7.9 +/- 2.6 mmol/l. Median Framingham risk was 1.66%/year and this risk was > 2%/year for 37% and > 3%/year for 17.5%. Treatment was required for 86% by National Cholesterol Education Program, 70% by General Rule to Enable Atheroma Treatment and European, 61% by New Zealand, 58% by British, 42% by Dundee, 40% by Munster Heart Study, 25% by British Regional Heart Study and 16% by Sheffield guidelines. Algorithms varied regarding recommendations for treatment of men, women, patients with familial hypercholesterolaemia and diabetes. Confounders included risk levels, definitions and weightings for additional risk factors. CONCLUSIONS: Different algorithms vary widely in their predictions of need for drug treatment of this high-risk population with hyperlipidaemia. Authors of guidelines for cardiovascular disease need to unify risk thresholds and definitions and audit the effects of additional weighting factors so that patients can be treated consistently.

Adult↗
PubMed2000

Recurrent superior vena caval obstruction due to invasion by malignant thymoma: treatment using a stent-graft.

A stent-graft was used to palliate superior vena caval obstruction in a 50-year-old patient with histologically proven ingrowth of malignant thymoma through three previously inserted non-covered stents. The stent-graft is still patent 12 months later. This is the first report of such a procedure where histological evidence of tumour ingrowth is available and long-term patency is verified.

Female↗
PubMed2000

Interbody cages.

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Humans↗
PubMed1999

Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea.

STUDY OBJECTIVE: To determine the acute effects of paroxetine on genioglossus activity during NREM sleep. DESIGN: A single dose of Paroxetine (40 mg) or placebo was administered four hours before bedtime on nights separated by one week in a double blind randomized crossover manner. The moving time average of genioglossus muscle activity (EMGgg) expressed as a percentage of maximum was measured using a mouthpiece electrode customized for each subject. The peak inspiratory and tonic values of EMGgg and the corresponding esophageal pressure deflections (DP) during the last three occluded breaths of obstructive apneas during NREM sleep were analyzed. SETTING: NA. PARTICIPANTS: 8 adult men with severe obstructive sleep apnea (OSA). INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Paroxetine increased the peak inspiratory EMGgg (29.8+/-2.4 (SE) versus 24.4+/-2.7 % max, p<0.05) and peak EMGgg/DP ratio (0.78+/-0.12 versus 0.65+/-0.11 % max/cm H2O, p<0.01) but not the tonic EMGgg (11.6+/-0.9 versus 9.8+/-0.7 % max) nor the DP (39.4+/-2.2 versus 38.2+/-2.8 cm H2O). Linear regression analysis of the peak inspiratory EMGgg versus DP relationship showed that paroxetine increased the slope (0.62+/-0.11 versus 0.49+/-0.09 % max/cm H2O, p<0.01). However, the apnea + hypopnea index (paroxetine: 75.2+/-5.5 versus placebo: 73.7+/-6.9 events/hour) did not differ. CONCLUSIONS: Paroxetine augmented peak inspiratory genioglossus activity during NREM sleep but this effect was not sufficient to decrease the frequency of obstructive apnea in this group with severe OSA.

Adult↗
PubMed1999

An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans.

OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided.

Adult↗
PubMed1999

Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands.

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

Animals↗