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Biomedical subjects

K Hamilton

Publications and source records attributed to K Hamilton.

At least 55 records · Page 3Linked to original sources
PubMed1995

Plasma sialic acid in animal models of diabetes mellitus: evidence for modulation of sialic acid concentrations by insulin deficiency.

An elevated circulating sialic acid concentration is a risk factor for cardiovascular disease. Serum sialic acid levels are elevated in NIDDM but not in uncomplicated IDDM. To study why sialic acid is increased in some types of diabetes, we assayed plasma sialic acid in various animal models of diabetes: obese (ob/ob) mice, before and after streptozotocin treatment, neonatal streptozotocin-treated (nSTZ) rats, and diabetic BB rats during and after insulin treatment. In obese mice, which exhibit moderate hyperglycemia and marked hyperinsulinemia, plasma sialic acid was decreased by 45% (fed) and 42% (fasted), compared to lean controls. Fasting reduced plasma glucose and insulin but increased sialic acid in the obese and lean mice. There was a negative correlation (r = -0.84, P < 0.001) between log plasma insulin and sialic acid in the lean and obese mice. The plasma sialic acid:globulin ratio was reduced by 35% in obese mice vs. lean controls, indicating that there may be altered sialylation of glycoproteins in obese mice. Streptozotocin treatment of obese and lean mice reduced plasma insulin but increased sialic acid. In nSTZ rats, hyperglycemia was associated with mild hypoinsulinemia, but not significantly different from control animals, and sialic acid was not altered. In diabetic BB rats, plasma glucose rose from a mean of 4.9 to 23.5 mM 48 hr after insulin withdrawal but sialic acid did not change. We conclude that an elevated plasma sialic acid level is associated with marked insulin deficiency, rather than hyperglycemia per se. The magnitude and speed of this change in sialic acid varies between species.

Animals↗
PubMed1995

Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice.

For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.

Alkyl and Aryl Transferases↗
PubMed1995

Dissociation of the behavioral and subjective components of nitrogen narcosis and diver adaptation.

We investigated adaptation to nitrogen narcosis by compressing 11 highly experienced divers in a hyperbaric chamber to the equivalent of 54.6 meters of seawater once a day for 5 consecutive days. The behavioral component of narcosis was assessed with a serial choice-reaction time (RT) task, and the subjective component with a global magnitude estimate. Supplementary magnitude estimates were obtained with adjectives describing work effectiveness and body sensations. The results showed that there was no adaptation on the RT task, although learning was evident. In contrast, the global estimate dissociated from RT and showed clear adaptation by Day 3. The work effectiveness adjectives followed RT and did not show adaptation. Some body sensation adjectives showed clear adaptation, but others did not. These results lead to the conclusion that the anecdotal reports of adaptation by divers can probably be attributed to the subjective rather than the behavioral component of narcosis. Dissociation of these components suggests mediation by different brain mechanisms, and it is speculated that the gamma-aminobutyric acidA/benzodiazepine receptor complex, which has been implicated in both the anesthetic and anxiolytic properties of agents such as nitrous oxide, may be involved.

Adaptation, Physiological↗
PubMed1995

Phosphorus-32-chromic phosphate for ovarian cancer: I. Fractionated low-dose intraperitoneal treatments in conjunction with platinum analog chemotherapy.

UNLABELLED: For many years, 32P-chromic phosphate (32P-CP) intraperitoneal instillations and platinum analogue chemotherapy have been used to treat disseminated ovarian cancer. To investigate possible enhancement of 32P-CP irradiation due to the concomitant administration of chemotherapy, in vitro studies were undertaken. Based on those laboratory investigations, a clinical regimen of combined 32P-CP and platinum analogue chemotherapy was developed. METHODS: In vitro enhancement of 32P-CP cytotoxicity by cisplatin was studied in cultured human ovarian adenocarcinoma (CHOA) cell lines and in a fibroblast cell strain. In addition, ovarian cancer cells obtained from the malignant abdominal ascites and pleural effusions of 10 individual patients were also studied ex vivo. As part of routine clinical care, 30 patients with disseminated ovarian adenocarcinoma underwent up to eight monthly cycles of platinum analogue chemotherapy with concomitant intraperitoneal instillation of 5 mCi of 32P-CP at each monthly chemotherapy cycle. RESULTS: There was an enhanced and possibly supra-additive effect of cisplatin on the cytotoxicity from 32P-CP irradiation. For the 30 patients, the survival rate at 3 yr was 63%. CONCLUSION: Phosphorus-32 CP low-dose intraperitoneal treatments in conjunction with platinum analogue chemotherapy is a promising approach for the treatment of disseminated intraperitoneal ovarian cancer.

Adenocarcinoma↗
PubMed1994

Developmental ages of the thymic epithelium and of the T cell precursors together determine the proportions of peripheral CD4+ cells.

In earlier studies on chimeric animals, we found that fetal thymocytes produced peripheral T lymphocyte populations depleted of CD4+ cells. This occurred whether the fetal thymocytes matured in the presence of adult or fetal thymic stromal cells. In contrast, fetal liver cells that differentiated in the adult thymus generated normal proportions of peripheral CD4+ cells. Because fetal liver cells are thought to be the immediate precursors to fetal thymocytes, we proposed that fetal thymic stroma would modulate the differentiation of fetal liver cells; specifically, that fetal liver cells maturing in the fetal thymus would resemble fetal thymocytes and produce low levels of peripheral CD4+ cells. To test this hypothesis, fetal thymic lobes were colonized in vitro with fetal liver cells and subsequently transplanted in vivo to Thy-1 congenic hosts. Under these conditions, fetal liver cells produced reduced proportions of CD4+ peripheral progeny. The under-representation of CD4+ peripheral T cells was apparently governed by the thymic epithelium because similar results were obtained with 2-deoxyguanosine-treated fetal thymuses colonized by fetal liver cells. In contrast, adult bone marrow cells made normal levels of CD4+ peripheral T cells whether maturation occurred in the fetal or the adult thymus. Thus, pre-T cells (fetal liver or adult bone marrow) lose the capacity to respond to fetal thymic stromal cells during development. These results indicate that the proportions of CD4+ cells in peripheral tissues are regulated by a combination of the developmental ages of the T cell precursors and the thymic stromal environment.

Animals↗
PubMed1994

Up-regulation of murine neonatal T helper cell responses by accessory cell factors.

We previously found that lymph node T cells from 4-day-old, naive neonatal mice show diminished Th1-like responses. Neonatal T cells produced low levels of IL-2 and proliferated poorly in response to soluble anti-CD3 stimulation. However, neonatal T cells resembled Th2 cells (or primed adult T cells) in that they produced large amounts of IL-4. Here, we have investigated the importance of accessory cell signals in the diminished Th1-like responses of neonatal T cells. Anti-CD28 mAb greatly augmented IL-2 production by neonatal T cells in response to plate-bound anti-CD3 Ab. In response to soluble anti-CD3 mAb plus accessory cells, exogenous accessory cell-derived cytokines were sufficient to restore neonatal responses to adult-like levels. In the presence of exogenous IL-6, IL-4 production by neonatal T cells was largely unchanged whereas IL-2 production was dramatically increased, reaching the high levels produced by adult T cells. In addition, the presence of exogenous IL-6 enhanced the proliferation of neonatal T cells to adult levels. IL-6 also had marked effects on the capacity of neonatal T cells to respond to secondary stimuli. In the absence of exogenous IL-6, neonatal T cells responded poorly to secondary stimulation. This lack of responsiveness was not overcome by the addition of IL-2 or by stimulation with phorbol ester and calcium ionophore. When IL-6 was present during the primary stimulation, neonatal T cells, like adult T cells, produced high levels of IL-4 and proliferated extensively in response to secondary stimuli. Thus, IL-6 was sufficient to restore both the primary and secondary responses of neonatal T cells to mature, adult-like levels. These results imply that neonatal T cells have a greater requirement for accessory cell signals than do adult T cells and may have important bearing in overcoming neonatal T cell immunodeficiencies in vivo.

Animals↗
PubMed1994

Rochalimaea species stimulate human endothelial cell proliferation and migration in vitro.

Rochalimaea henselae and R. quintana are associated clinically with proliferative neovascular lesions. The effect of Rochalimaea species on human umbilical vein endothelial cell (HUVEC) proliferation and migration was evaluated in vitro. Cocultivation of Rochalimaea organisms with HUVECs resulted in enhanced HUVEC proliferation. Fibroblast proliferation was unaffected by R. henselae. HUVECs were also stimulated to migrate by Rochalimaea. When R. henselae organisms were disrupted and subjected to centrifugation, the ability to enhance HUVEC proliferation and migration was localized to the particulate, noncytosolic fraction. Trypsin treatment of this fraction diminished its stimulatory activity. These data suggest that the neovascular manifestations of infection with Rochalimaea are likely caused by the production of an angiogenic factor by these bacteria.

Bartonella↗
PubMed1993

Developmental regulation of IL-4, IL-2, and IFN-gamma production by murine peripheral T lymphocytes.

Lymph node T cells from naive, 4-day-old neonatal mice resemble activated adult T cells in that they produce low levels of IL-2 but high levels of IL-4 in response to anti-CD3 stimulation in vitro. Herein, we show that the capacity for high level IL-4 production is rapidly lost in the early postnatal period. A decline is first evident at 5 days postbirth. By 6 days postbirth, T cells secrete IL-4 at low levels, similar to those produced by T cells from naive, adult animals. In contrast, the acquisition of high, adultlike IL-2 or IFN-gamma production does not occur until approximately 6 wk of life. Thus, the loss of high level IL-4 production and the acquisition of high level IL-2 and IFN-gamma production are distinct developmental events, occurring at widely separated intervals. There are two phases in the transition to adultlike IL-2 production. In the early neonatal period, the underproduction of IL-2 appears to be due to a combination of intrinsic nonresponsiveness to CD3-mediated stimulation and the production of a soluble inhibitor of IL-2 production. The inhibitory activity required the presence of IL-4 because neutralizing anti-IL-4 antibody completely eliminated inhibition. Moreover, experiments using rIL-4 showed that IL-4 alone was sufficient to dramatically inhibit IL-2 production by T cells from naive, adult animals in a primary stimulation. Between 4 to 5 days and 6 wk of life, the underproduction of IL-2 and IFN-gamma appears to result solely from a lowered responsiveness of the T cells. Thus, the progression to adultlike lymphokine production involves a combination of changes in the types of lymphokines produced and in the magnitude of the response to activation signals.

Animals↗
PubMed1993

The oral examination in anaesthetic resident evaluation.

Oral examinations have a traditional place in training and evaluation of professionals. Despite a lack of evidence identifying their value in assessment of candidates seeking anaesthetic specialty certification, oral examinations continue to be widely used. Although there is a considerable body of literature concerning oral examinations, there is no description of how this technique is employed in anaesthesia in Canada. The objective of this review is to provide faculty and residents with information concerning the strengths and weaknesses of this format, and the structure of the oral examination as practised in anaesthesia. Reliability of oral examinations can be affected by a number of factors dependent on the examiner, candidate, and the format. Properly constructed and prepared questions have well-defined characteristics. Components tested during the oral examination include: evaluation of a clinical situation, choice of therapy, medical knowledge, ability to deal with emergency situations, decision-making ability, and communication skills. When appropriately planned, the oral examination can be a useful component of the certification process.

Anesthesiology↗
PubMed1993

Visual/vestibular effects of inert gas narcosis.

Divers breathing compressed air at depths beyond 30 m experience a type of behavioural impairment known as inert gas narcosis. This condition degrades performance on a wide range of tasks and has the potential to compromise safety. Symptoms associated with narcosis include slowed response time, amnesia, and euphoria. Studies have also found disturbances to mechanisms regulating ocular control in response to vestibular stimulation; however, these experiments have been limited to very low frequency head movement (0.2 Hz). Thus, to further examine the effects of narcosis on visual/vestibular mechanisms, the vestibular ocular reflex (VOR) was assessed across a range of higher frequencies more representative of natural head movement (2.0-4.7 Hz). Seven subjects were tested prior to, during and after exposure to narcosis which was induced using 30% nitrous oxide. Standard room air was breathed as a control. The results indicated that narcosis decreased the velocity of compensatory eye movements in response to head rotation (decrease in VOR-gain), with more pronounced decreases occurring at the higher frequencies. The lag between eye and head position (phase lag) was also decreased by nitrous oxide; an effect that was again more pronounced at higher frequencies. These results indicate that narcosis disrupts ocular regulatory mechanisms which help to stabilize images on the retina during head movement.

Adult↗
PubMed1993

Sexual abuse and body-image distortion in the eating disorders.

It has been suggested that there is a link between sexual abuse and bodily self-deprecation in women with eating disorders. In order to test that model, this study considers whether reported sexual abuse is associated with body-image distortion in anorexia and bulimia nervosa. There was no association with the reported presence of a history of abuse. However, the nature of any abuse was important. In particular, women who reported more recent abuse had a substantially greater level of bodysize overestimation. The clinical implications of this finding are discussed.

Adolescent↗
PubMed1993

Media influences on body size estimation in anorexia and bulimia. An experimental study.

Anorexic and bulimic women overestimate their body sizes substantially more than comparison women, but little is known about the factors that influence this overestimation. This study examined the influence of media portrayal of idealized female bodies in women's fashion magazines. Comparison women were not affected by the nature of the photographs that they saw, but eating-disordered women were--they overestimated more when they had seen the pictures of women than when they saw photographs of neutral objects.

Adult↗
PubMed1992

Freshly isolated, murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation.

In previous studies of chimeric animals, we found that fetal intrathymic T cell precursors give rise to phenotypically abnormal peripheral T cell populations. Because most peripheral T lymphocytes in newborn mice are the progeny of fetal T cell precursors, this result led to the hypothesis that neonatal and adult T cells differ in their functional capacities. To investigate this issue, the responses of neonatal and adult T cells to anti-CD3 antibody and TCR-independent stimulation were compared. When stimulated with soluble anti-CD3 antibody in the presence of adult accessory cells, neonatal T cell proliferation was markedly decreased compared with that of adult T cells. This reduction in proliferation was associated with both quantitative and qualitative differences in lymphokine production. At 48 h of stimulation with anti-CD3 antibody, neonatal T cells produced at least 10-fold less IL-2 than adult T cells. This apparently accounted for their reduced proliferation because the addition of exogenous IL-2 restored their proliferation to the levels achieved by adult T cells. In striking contrast to adult T cells, neonatal T cells secreted large amounts of IL-4 upon primary stimulation in vitro. The differences between neonatal and adult T cells in proliferation and lymphokine production were shown to be specific for CD3-mediated stimulation. In the presence of phorbol ester and calcium ionophore, neonatal and adult T cells showed equivalent proliferation and IL-2 production. Under these conditions, IL-4 production by neonatal or adult T cells was essentially undetectable. Thus, in response to TCR-independent stimulation, freshly isolated neonatal and adult T cells show similar functional responses. However, when stimulation occurs via the CD3 components of the TCR, the responses of neonatal T cells resemble those of primed T cells from adult animals.

Animals↗
PubMed1992

Subjective and behavioral effects associated with repeated exposure to narcosis.

Below 30 m, nitrogen narcosis can severely degrade the performance of air breathing divers. Within the diving community it is generally thought that this effect can be reduced by repeating deep air dives on successive days but laboratory studies have found no strong evidence to support the notion of adaptation to narcosis. One possible explanation for this discrepancy is that one's subjective impression or perception of narcosis may decrease during repeated exposure to hyperbaric air without parallel improvement on task performance. To examine this possibility, symptoms and performance were examined over the course of 5 days of repeated exposure to 30% nitrous oxide at 1 ATA. While the results revealed no clear cut changes in global perceptions of narcosis across days, several symptoms from an adjective checklist showed unequivocal signs of adaptation. With respect to performance effects, reaction time yielded no indications of improvement over days relative to the control. These findings suggest that subjective adaptation can occur without parallel performance improvement, an effect which could compromise safety and which may be of concern in other operational settings that involve repeated exposure to stimulus conditions which impact on performance and symptoms.

Adaptation, Physiological↗
PubMed1991

Glycosphingolipids: 2H NMR study of the influence of carbohydrate headgroup structure on ceramide acyl chain behavior in glycolipid-phospholipid bilayers.

Galactosyl- and glucosylceramide, globoside, and dihydrolactosylceramide, bearing [2,2-2H2]stearic acid, have been studied at a concentration of 10 mol% in bilayers of dimyristoylphosphatidylcholine by 2H NMR. The quadrupolar splitting delta vQ of the C2 deuterons were measured at several temperatures in the range of 30-60 degrees C. Spin-lattice relaxation times T1 of C2 deuterons were determined in the same temperature range for all lipids but globoside. T1 values at 30 and 50 degrees C were unexpectedly short (6-8 ms), indicating reduced mobility of the ceramide acyl chains compared to that of the host phospholipid. At all temperatures, both delta vQ and T1 were essentially identical for the monoglycosylated species, GalCer and GlcCer, indicating that the order and dynamics of the upper portion of the fatty acyl chain are insensitive to this small change in the headgroup structure. In the case of globoside, where the glycolipid headgroup is equivalent to that of GlcCer extended by three sugar residues, values for the quadrupolar splittings associated with the acyl chain C2-position were very close to those obtained for Gal- and GlcCer. In contrast, the delta vQ values obtained for the diglycosyl species, LacCer, were significantly different at all temperatures. This different behavior of LacCer relative to that of the other glycolipids most likely originates from an orientational change of the acyl chain at the C2-position due to the absence of a 4,5 double bond in dihydrosphingosine. T1 values for the GlcCer and GalCer systems increased with temperature, indicating that the motions responsible for relaxation were in the short correlation time regime.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceramides↗