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Biomedical subjects

K Hamilton

Publications and source records attributed to K Hamilton.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical validation of a new subtraction radiography technique for periodontal bone loss detection.

BACKGROUND: Diagnostic subtraction radiography (DSR) is a new digital radiographic image subtraction method designed to enhance detection of crestal or periapical bone density changes and to help evaluate caries progression in teeth. In this clinical study, the performance of the DSR method was evaluated for its ability to detect periodontal bone loss and was compared with that of conventional evaluation of radiographs and the standardized cephalostat-guided image acquisition and subtraction technique (LRA) which served as the "gold standard." METHODS: In each of 25 subjects with alveolar crestal bone loss created by periodontal surgery, one set of DSR radiographs and one set of LRA radiographs were obtained before and after the surgery. Subtraction images were then generated by both the proprietary DSR and the LRA techniques. Four viewers evaluated the paired film sets and both subtraction image sets using a 5 point confidence scale to determine the presence or absence of crestal bone loss. Receiver operating characteristics (ROC) statistical procedures were applied to analyze the diagnostic accuracy and statistical differences between the three imaging modalities. RESULTS: The DSR subtraction viewing generated an ROC area of 0.882. For 2 of the viewers this represented a statistically significant gain (P <0.05) over the conventional viewing of the radiographs which had an average ROC area of 0.730. In comparison, the LRA method achieved an area of 0.954. The differences between the LRA and the DSR subtraction methods were not statistically significant, but the statistical power for claiming equality was low ranging from 0.2 to 0.6. CONCLUSIONS: The use of the DSR technique in clinical radiographic image acquisition and subsequent subtraction analysis clearly enhanced the accuracy of alveolar crestal bone loss detection when compared to conventional film viewing. Because this methodology is less resource demanding than LRA and the film exposure techniques and computer-based image analysis skills may be acquired with only a few hours of training, the DSR has potential in clinical practice.

Alveolar Bone Loss↗
PubMed1999

Antioxidants and exercise.

Muscular exercise results in an increased production of radicals and other forms of reactive oxygen species. Further more, growing evidence implicates cytotoxic ROS as an underlying cause in exercise-induced disturbances in muscle redox status that could result in muscle fatigue or injury. Muscle cells contain complex cellular defense mechanisms to minimize the risk for oxidative injury. Two major classes of endogenous protective mechanisms work together to reduce the harmful effects of oxidants in the cell: (1) enzymatic and (2) nonenzymatic antioxidants. Key antioxidant enzymes include superoxide dismutase, glutathione peroxidase, and catalase. These enzymes are responsible for removing superoxide radicals, hydrogen peroxide or organic hydroperoxides, and hydrogen peroxide, respectively. Important nonenzymatic antioxidants include vitamins E and C, beta-carotene, GSH, uric acid, ubiquinone, and bilirubin. Vitamin E, beta-carotene, and ubiquinone are located in lipid regions of the cell, whereas uric acid, GSH, and bilirubin are in aqueous compartments of the cell. Although numerous animal experiments have demonstrated that the addition of antioxidants can improve muscular performance, to date, limited evidence shows that dietary supplementation with antioxidants improves human performance. This is an important area for future research.

Animals↗
PubMed1999

Renal function in chronically catheterized conscious diabetic rats using constant and servo-controlled infusion.

1. Infusion experiments were performed on chronically catheterized conscious rats to assess kidney function before and after the induction of diabetes mellitus with streptozotocin. 2. Two infusion regimens were used, a conventional constant-infusion protocol and a novel computer-driven, servo-controlled fluid replacement technique. The latter enables body fluid status to be maintained throughout a study occasion by servo-controlled replacement of spontaneous urinary fluid losses. 3. The chronically catheterized conscious rat infused using a servo-controlled system appears to be the optimum model for a study of diabetic renal function. The conscious preparation circumvents problems associated with anaesthesia and acute surgery. The servo-controlled infusion protocol maintains the altered fluid status of the diabetic condition. Both hyperfiltration and polyuria, characteristics of human diabetes often absent in anaesthetized and/or constantly infused diabetic rats, were seen in all conscious servo-controlled diabetic animals. 4. The new regimen enables a more accurate assessment of renal function in experimental diabetes than with previous protocols. It should prove useful in future studies, particularly those assessing the role of anti-diabetic drugs on the kidney.

Animals↗
PubMed1999

The spouse as a kidney donor: ethically sound?

A shortage of cadaver donor organs requires transplant units to examine all possible alternatives. Transplantation from living donors accounts for only approximately 10% of kidney transplants in the UK. Recent studies have shown that the results of kidney transplantation between spouses are at least as good as those of well-matched cadaver organs, but very few transplants of this type have been performed in this country so far. As part of the assessment process, the proposed donor and recipient are required to provide written statements about the issues. We reproduce here the personal statements made by one of our patients and his wife: we believe that the statements support our contention that spousal transplantation is ethically justifiable and should be more widely available. We report our early experience in Bristol with seven kidney transplants from spousal donors and we encourage other renal units in this country and elsewhere to consider this method of improving the prospects of kidney transplantation for their patients.

Adult↗
PubMed1999

Cancer incidence in a cohort of licensed pesticide applicators in Florida.

This study is a standardized incidence ratio (SIR) analysis of cancer incidence of licensed pesticide applicators in Florida, compared with that of Florida's general population. Through extensive data linkages, 33,658 applicators were assembled who had 1266 incident cancers and 279,397 person-years from January 1, 1975, to December 31, 1993. Disease risk from ethanol and tobacco use were significantly decreased. Among males, prostate cancer (SIR = 1.91; 95% confidence interval [CI], 1.72-2.13) and testicular cancer (SIR = 2.48; 95% CI, 1.57-3.72) were significantly elevated. No confirmed cases of soft tissue sarcoma (STS) were found, and the incidence of non-Hodgkin's lymphoma was not increased. There were few female applicators; nevertheless, cervical cancer incidence (SIR = 3.69; 95% CI, 1.84-6.61) was significantly increased, while the incidence of breast cancer was significantly decreased. Cancers that have been associated with estrogen disrupters were found in male, but not female, pesticide applicators. The lack of soft tissue sarcoma is at odds with prior literature associated with the use of phenoxy herbicides.

Adult↗
PubMed1999

Mortality in a cohort of licensed pesticide applicators in Florida.

OBJECTIVES: Although the primary hazard to humans associated with pesticide exposure is acute poisoning, there has been considerable concern surrounding the possibility of cancer and other chronic health effects in humans. Given the huge volume of pesticides now used throughout the world, as well as environmental and food residue contamination leading to chronic low level exposure, the study of possible chronic human health effects is important. METHODS: This was a retrospective cohort study, analysed by general standardised mortality ratio (SMR) of licensed pesticide applicators in Florida compared with the general population of Florida. A cohort of 33,658 (10% female) licensed pesticide applicators assembled through extensive data linkages yielded 1874 deaths with 320,250 person-years from 1 January 1975 to 31 December 1993. RESULTS: The pesticide applicators were consistently and significantly healthier than the general population of Florida. As with many occupational cohorts, the risks of cardiovascular disease and of diseases associated with alcohol and tobacco use were significantly lower, even in the subpopulations--for example, men, women, and licence subcategories. Among male applicators, prostate cancer mortality (SMR 2.38 (95% confidence interval (95% CI) 1.83 to 3.04) was significantly increased. No cases of soft tissue sarcoma were confirmed in this cohort, and non-Hodgkin's lymphoma was not increased. The number of female applicators was small, as were the numbers of deaths. Mortality from cervical cancer and breast cancer was not increased. Additional subcohort and exposure analyses were performed. CONCLUSIONS: Consistent with previous publications on farmers but at odds with current theories about the protective effects of vitamin D, prostate cancer was increased in these pesticide applicators. Female breast cancer was not increased despite theories linking risk of breast cancer with exposure to oestrogen disruptors--such as the organochlorines. The lack of cases of soft tissue sarcoma is at odds with previous publications associating the use of the phenoxy herbicides with an increased risk of these cancers.

Adult↗
PubMed1998

Localization of leptin receptor immunoreactivity in the lean and obese Zucker rat brain.

Leptin, a product of the obese (ob) gene, is secreted by adipocytes and appears to act as a hormone to regulate food intake, metabolism and body weight. Subcutaneous administration of leptin causes reductions in food intake and body and fat-depot weights in both lean and genetically obese (ob/ob) mice, and leptin infusion into the lateral cerebral ventricles decreases feeding with short latency, suggesting a central site of action. A gene defect in the Zucker obese rat causes an amino acid substitution in the leptin receptor and reduced leptin binding at the cell surface. An antiserum to a portion of the mouse leptin receptor (AA 877-894) located within the intracellular domain was used to label Zucker lean (Fa/?) and obese (fa/fa) rat brain sections. At optimal dilution (1:8000), only cells in the basal forebrain, preoptic area, hypothalamus and brainstem were moderately or intensely labeled. The most intensely-labeled nuclei, the anterior commissural, magnocellular paraventricular, supraoptic, circularis in the anterior hypothalamus and fornical in the lateral hypothalamus contain large neurons that synthesize and secrete vasopressin or oxytocin and their respective neurophysins. Diminished leptin transport into the central nervous system or defective signal transduction in Zucker obese rats may sufficiently compromise leptin regulation of the HPA axis, NPY-immunoreactive neurons or other hypothalamic elements to cause obesity.

Animals↗
PubMed1998

A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis.

The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resultant tumor regression, MMTV-v-Ha-ras mice were interbred with p53(-/-) mice. Tumors in ras/p53(-/-) mice treated with L-744,832 regressed as efficiently as MMTV-v-Ha-ras tumors, although this response was found to be mediated by both the induction of apoptosis and an increase in G1 with a corresponding decrease in the S-phase fraction. MMTV-v-Ha-ras mice were also interbred with MMTV-c-myc mice to determine whether ras/myc tumors, which possess high levels of spontaneous apoptosis, have the potential to regress through a further increase in apoptosis levels. The ras/myc tumors were found to respond nearly as efficiently to L-744,832 treatment as the MMTV-v-Ha-ras tumors, although no induction of apoptosis was observed. Rather, the tumor regression in the ras/myc mice was found to be mediated by a large reduction in the S-phase fraction. In contrast, treatment of transgenic mice harboring an activated MMTV-c-neu gene did not result in tumor regression. These results demonstrate that a farnesyltransferase inhibitor can induce regression of v-Ha-ras-bearing tumors by multiple mechanisms, including the activation of a suppressed apoptotic pathway, which is largely p53 independent, or by cell cycle alterations, depending upon the presence of various other oncogenic genetic alterations.

Alkyl and Aryl Transferases↗
PubMed1998

Is central nervous system prophylaxis necessary in ocular adnexal lymphoma?

PURPOSE: To examine the frequency of metastasis to the eye and central nervous system (CNS) from ocular adnexal lymphomas and to evaluate whether CNS prophylaxis is appropriate for these tumors. PATIENTS AND METHODS: Seventy-one patients with biopsy-confirmed ocular adnexal lymphomas were evaluated between 1989 and 1995. The lymphomas were subclassified histopathologically according to the new Revised European-American Lymphoma (REAL) criteria. Molecular genetic analysis of tumor cell DNA was done by Southern blot. Patients had a complete ophthalmologic evaluation and metastatic work-up and were then routinely followed up by an ophthalmologist and a medical oncologist. RESULTS: The 34 men and 37 women studied had a median age of 67 years (23 to 92). Ocular adnexal lymphomas were situated in the orbit in 54 patients, in the conjunctiva in 14 patients, and in the eyelid in 3 patients. Bilateral involvement occurred in 11 patients. The most common histologic diagnoses were (54 patients, 76%) extra-nodal marginal zone lymphomas and small lymphocytic lymphomas in 10 patients (14%). Molecular genetic analysis performed in all patients confirmed a monoclonal B-cell population in 55 patients (77%), including a single rearrangement of the immunoglobulin heavy chain gene in 14 patients, and more than two rearrangements in 41 patients. No patients had isolated T-cell gene rearrangements. Localized ocular adnexal lymphoma was diagnosed in 43 patients (61%), 17 patients (24%) were found to have concurrent extraocular lymphoma on metastatic work-up and 11 patients (15%) had a previous diagnosis of systemic lymphoma before the onset of their ocular tumor. The median duration of follow-up was 20 months. Overall, 32 patients (45%) had tumors, which remained localized to the orbit adnexa. Eleven patients (15%) relapsed, but none had eye or central nervous system involvement nor required CNS-directed therapy. Although eight patients died, only two died as a direct result of systemic lymphoma. No patient received CNS prophylaxis with either intrathecal chemotherapy and/or radiation therapy. CONCLUSION: Ocular adnexal lymphomas are rare non-Hodgkin's B-cell lymphomas. Metastatic involvement of the eye or central nervous system is rare and CNS prophylaxis with radiotherapy or chemotherapy is unnecessary.

Adult↗
PubMed1998

Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett's esophagus and esophageal adenocarcinomas.

Loss of expression and function of the E-cadherin/catenin membrane complex can result in loss of cell adhesion and contribute to invasive or metastatic potential in carcinomas. The aim of this study was to examine the expression of alpha- and beta-catenin and E-cadherin in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinomas and to identify any relationship with tumor growth pattern and clinical outcome. Immunoperoxidase staining for alpha- and beta-catenin and E-cadherin was performed on specimens of Barrett's esophagus with and without dysplasia and on 54 esophageal adenocarcinoma specimens. Membranous staining for all of the components was seen in normal gastric and esophageal mucosa. Abnormal expression of beta-catenin, alpha-catenin, and E-cadherin was significantly associated with higher degrees of dysplasia in Barrett's esophagus. Fourteen of 16 cases of high grade dysplasia and 7 of 7 cases of intramucosal carcinoma showed abnormal expression of beta-catenin, compared with 3 of 6 cases indefinite for dysplasia and 11 of 17 cases with low grade dysplasia (P = 0.022). Similar results were seen for expression of alpha-catenin (P < .01) and E-cadherin (P = .049). In esophageal adenocarcinomas, preserved expression of these proteins occurred more frequently in well-differentiated tumors; abnormal expression was more common in diffusely infiltrative poorly differentiated tumors that did not form glands. Focal nuclear staining for beta-catenin was present in two high-grade dysplasias, two intramucosal carcinomas, and five adenocarcinomas. No survival advantage was demonstrated for patients whose tumors retained expression of these cell adhesion components. In conclusion, abnormal expression of the E-cadherin/catenin membrane complex is common in esophageal adenocarcinoma and occurs early in the dysplasia/carcinoma sequence in Barrett's esophagus, indicating that disturbances in this cell adhesion complex might be important in tumorigenesis and tumor progression in this disorder.

Adenocarcinoma↗
PubMed1997

Clinical application of the Ottawa ankle rules for the use of radiography in acute ankle injuries: an independent site assessment.

OBJECTIVE: Previous studies show that the clinical criteria known as the Ottawa ankle rules (OAR), used for determining the need for radiographs of the ankle when a fracture is suspected, have a sensitivity of 100%, a specificity of 50%, and an overall reduction in radiographs of the ankle of 28%. The purpose of this study was to further assess the clinical usefulness of the OAR when implemented in an emergency department of a level 1 trauma center. SUBJECTS AND METHODS: Over a 1-year period, all patients who were between 18 and 55 years old and who presented to the emergency department with blunt ankle trauma were examined by emergency department clinicians who used the OAR to determine the need for ordering ankle radiographs. RESULTS: Of 926 patients with blunt ankle trauma, 759 met OAR criteria for ordering radiographs of the ankle. Of these patients, 152 were found to have a fracture. Another 167 of the patients were determined not to need ankle radiographs. Through either telephone contact or medical records review. 152 (91%) of these 167 patients were successfully followed up for the purpose of detecting any missed fractures. Two missed fractures were discovered, but only one required plaster immobilization. Based on these numbers, overall sensitivity using the OAR was 99% (confidence interval, 95-100%), and specificity was 22%. We found an overall 16% reduction in the number of ankle films ordered. CONCLUSION: When implemented at a level 1 trauma center, the OAR can adequately screen for ankle fractures.

Acute Disease↗
PubMed1996

Selection of potent inhibitors of farnesyl-protein transferase from a synthetic tetrapeptide combinatorial library.

Inhibitors of farnesyl-protein transferase (FPTase) show promise as anticancer agents. Based on the sequence of the protein substrates of FPTase (the CAAX sequence), potent and selective peptidomimetic inhibitors have been developed; these compounds share with the peptide substrate a free thiol and a C-terminal carboxylate. We have used a synthetic tetrapeptide combinatorial library to screen for new leads devoid of these features: the peptides were C-terminally amidated, and no free thiol was included in the combinatorial building blocks. To compensate for this negative bias, an expanded set of 68 amino acids was used, including both L and D as well as many non-coded residues. Sixteen individual tetrapeptides derived from the consensus were synthesized and tested; all were active, showing IC50 values ranging from low micromolar to low nanomolar. The most active peptide, D-tryptophan-D-methionine-D-4-chlorophenylalanine-L-gamma- carboxyglutamic acid (Ki = 2 nM), is also very selective showing little inhibitory activity against the related enzyme geranylgeranyl-protein transferase type I (IC50 > 50 microM). In contrast to CAAX-based peptidomimetics, D-tryptophan-D-methionine-D-4-chlorophenylalanine-L-gamma-carboxyglut amic acid appeared to mimic the isoprenoid substrate farnesyl diphosphate as determined by kinetic and physical measurements. D-Tryptophan-Dmethionine-D-4-chlorophenylalanine-L-gamma- carboxyglutamic acid was a competitive inhibitor of FPTase with respect to farnesyl diphosphate substrate and uncompetitive with respect to CAAX substrate. Furthermore, we demonstrated that FPTase undergoes ligand dependent conformational changes in its circular dichroism spectrum and that D-tryptophan-D-methionine-D-4-chlorophenylalanine-L-gamma- carboxyglutamic acid induced a conformational change identical to that observed with farnesyl diphosphate ligand.

Alkyl and Aryl Transferases↗
PubMed1996

Naive murine neonatal T cells undergo apoptosis in response to primary stimulation.

The cellular mechanisms controlling deficient immune responses in newborn animals are not well understood. Our earlier studies showed that developmental regulation of Th cell activity may be one of the major causes of immunodeficiency in neonatal animals. Naive murine neonatal T cells showed poor Th1 activity but robust Th2 activity in response to primary stimulation in vitro. Although they produced high levels of IL-4, neonatal T cells proliferated poorly, suggesting that neonatal T cell survival in primary cultures may be limited. We show here that, unlike adult T cells, naive neonatal T cells undergo apoptosis in response to primary TCR-mediated stimulation. Ligation of the TCR alone, in the absence of accessory cell costimulation, is sufficient to induce apoptosis. Moreover, CD4+ and CD8+ T cells show equivalent levels of apoptosis. Lastly, this apoptosis can be prevented by the addition of excess IL-2 or by conditions promoting a high level of IL-2 production (TCR-independent stimulation, anti-CD28 mAb, or exogenous IL-6) by neonatal T cells. However, IL-2 alone is not sufficient to support functional rescue from apoptosis; only IL-6 supports the ability of these cells both to survive and to mount vigorous secondary responses. The identification of conditions allowing functional rescue from apoptosis in vitro has important implications for enhancing vaccine responsiveness in vivo.

Animals↗
PubMed1996

Cytokine-induced alteration of platelet and hemostatic function.

A number of nonplatelet-specific cytokines that augment platelet recovery following chemo/radiotherapy have been described. The members of the interleukin 6 (IL-6) family have properties that influence the hematopoietic system beyond their modest thrombocytopoietic effects. Studies performed in a canine model with IL-6 have shown that this factor augments plasma fibrinogen and von Willebrand factor (vWf) concentrations and decreases the level of free protein S. IL-6 appears to decrease the bleeding time in thrombocytopenic dogs, although this effect does not seem to be due to a direct influence of the factor on endothelial vWf or tissue factor production. The factor does not directly alter platelet function in vitro, but when administered to dogs, it increases the sensitivity of the platelets to activation by thrombin. Normal platelets injected into IL-6-treated dogs, and platelets from IL-6-treated dogs injected into normal animals, survive normally. Following injection of either IL-6 or the more specific thrombocytopoietic cytokine thrombopoietin (TPO), IL-6 increases platelet responsiveness to thrombin-induced activation to a greater extent than does TPO. The data show that IL-6 has certain properties that might be construed as prohemostatic, and these properties may prove to be useful clinically.

Animals↗