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Biomedical subjects

R E Morton

Publications and source records attributed to R E Morton.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phorbol 12-myristate 13-acetate stimulates lysophosphatidic acid secretion from ovarian and cervical cancer cells but not from breast or leukemia cells.

Lysophosphatidic acid (LPA) is present in ascites from patients with ovarian cancer. It stimulates calcium release and growth of ovarian cancer cells both in vitro and in vivo. Recently, we found that LPA levels were significantly elevated in plasma from patients with ovarian cancer and other gynecological cancers. In contrast, LPA levels were not elevated in patients with breast cancer and leukemias. In view of this, we investigated whether gynecological cancer cells could produce LPA. LPA was extracted from the supernatant of cells cultured in vitro and purified by thin layer chromatography. After hydrolysis and transmethylation, the fatty acid derivatives were analyzed by gas chromatography. We found that the phorbol ester, phorbol 12-myristate 13-acetate (PMA), significantly stimulated the production of LPA in ovarian and cervical cancer cells. In contrast, a small or negligible amount of LPA was produced in breast cancer and leukemia cells upon PMA stimulation. This cell type specificity correlates with our values of plasma LPA, suggesting that gynecological tumor cells may be an important source of the elevated LPA noted in the plasma of patients with these cancers. The cytosolic PLA2 (cPLA2)/Ca2+-independent PLA2 (iPLA2) inhibitor, AACOCF3, inhibited 75.6% PMA-stimulated LPA secretion in ovarian cancer cells, suggesting a cPLA2/iPLA2 activity was involved in LPA production from ovarian cancer cells.

Breast Neoplasms↗
PubMed1997

Plasma lipoproteins from patients with poorly controlled diabetes mellitus and "in vitro" glycation of lipoproteins enhance the transfer rate of cholesteryl ester from HDL to apo-B-containing lipoproteins.

Alterations in the reverse cholesterol transport system have been described in diabetic mellitus patients in several but not all studies. Furthermore, recently published investigations suggest that a faster "in vitro" transfer rate of cholesteryl ester from high density lipoproteins to apoB-containing lipoproteins could be solely ascribed to variation of the plasma lipoprotein composition and concentration in the diabetic state. The present study analysed the influence of lipoprotein glycation on the cholesteryl ester transfer protein-mediated transfer of esterified cholesterol from high density lipoprotein and its subfractions to lighter density lipoproteins. For this purpose two sets of "in vitro" experiments were carried out utilizing:1) plasma lipoproteins drawn from diabetic and from normal subjects and; 2) normal lipoproteins or partially purified cholesteryl ester transfer protein submitted to "in vitro" glycation. The transfer rate of 14C-cholesteryl ester labelled HDL subfractions to low or very low density lipoproteins was measured in all experiments. After incubations with plasma d > 1.21 g/ml or with purified cholesteryl ester transfer protein, apoB-containing lipoproteins were precipitated with a dextran sulfate/MgCl2 solution. The "in vitro" glycation of the partially purified cholesteryl ester transfer protein, markedly impaired its activity. However, greater transfer rates were observed when lipoproteins from diabetic individuals or the "in vitro" glycated lipoproteins were utilized. This effect was attributed to glycation of the protein component of HDL. In conclusion, lipoprotein glycation elicits an enrichment of the apoB-containing lipoproteins with cholesteryl ester that is likely related to the premature atherosclerosis in patients with poorly controlled diabetes.

Apolipoproteins B↗
PubMed1997

Resistance of lipoproteins from continuous ambulatory peritoneal dialysis patients to in vitro oxidation.

Patients with end-stage renal failure on continuous ambulatory peritoneal dialysis (CAPD) develop abnormalities in plasma lipoproteins that may contribute to their increased risk for atherosclerosis. The oxidative modification of lipoproteins is considered to play a central role in atherogenesis. This study examines the susceptibility to oxidation in vitro of low- and high-density lipoprotein (LDL and HDL, respectively) obtained from long-term CAPD patients. CAPD LDL was less susceptible to copper-mediated protein derivatization (fluorescence) compared with control LDL CAPD LDL and HDL displayed less copper-promoted conjugated-diene production and lipid peroxide generation, suggesting a greater resistance of CAPD lipoprotein lipids to oxidation. Autooxidation during long-term storage was also much lower in CAPD LDL and HDL. However, when 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP) was used to initiate oxidation, there was no difference in conjugated-diene generation between CAPD and the control. CAPD LDL contained slightly less oxidizable, polyunsaturated fatty acid, but the vitamin E content of CAPD and control LDL was equivalent. Our findings indicate that lipoproteins from uremic patients undergoing long-term CAPD are more resistant to in vitro oxidation than control lipoproteins.

Amidines↗
PubMed1997

Feeding ability in Rett syndrome.

Feeding abilities in 20 individuals with Rett syndrome aged 1 1/2 to 33 years were investigated by history and clinical assessment during a meal, followed by videofluoroscopy of feeding. All were shown to have reduced movements of the mid and posterior tongue, with premature spillover of food and liquid from the mouth into the pharynx. They also showed delayed pharyngeal swallow, but otherwise pharyngeal problems were minimal. These findings were noted to be similar to those in Parkinson's disease. Those individuals with the most general neurological impairment tended to have the worst feeding problems and were smaller and malnourished.

Activities of Daily Living↗
PubMed1997

Respiration patterns during feeding in Rett syndrome.

Feeding problems are common in Rett syndrome in which there are characteristic oropharyngeal abnormalities. This study investigated the ways in which individuals regulated their respiration accordingly, and how this affected their overall feeding ability. Respiration during feeding was studied in 28 individuals, recording nasal airflow, chest and abdominal movements, and swallow sounds. Time to first swallow was defined as that between introduction of liquid/solid on a spoon and the first swallow. Six individuals also had videofluoroscopy with simultaneous respiration monitoring. Results indicated different respiratory patterns according to the time to first swallow and neurological status; the amount of time spent in apnoea was particularly important. Videofluoroscopy showed that apnoeas occurred most often when liquid was delayed in the pharynx, but this could be overcome in subjects with a lower level of disability. The carer's estimate of the time for feeding was significantly related to the time spent in apnoea with liquids.

Adolescent↗
PubMed1997

Dentato-olivary dysplasia in sibs: an autosomal recessive disorder?

The cases of a brother and sister with dentato-olivary dysplasia are described. Both had severe developmental delay, severe epilepsy of early onset, evolving hypertonic quadriplegia, and death in early childhood. Postmortem examination of the brain in one child showed a particular form of dentato-olivary dysplasia. These children show many features in common with previously described cases of this condition, but this is the first report of occurrence in sibs.

Dentate Gyrus↗
PubMed1997

Suppression of lipid transfer inhibitor protein activity by oleate. A novel mechanism of cholesteryl ester transfer protein regulation by plasma free fatty acids.

Cholesteryl ester transfer protein (CETP) mediates the interlipoprotein exchange of cholesteryl ester (CE) and triglyceride. A second plasma protein, lipid transfer inhibitor protein (LTIP), binds to lipoproteins and inhibits CETP activity by displacing CETP from the lipoprotein surface. Since free fatty acids (FFAs) enhance the binding of CETP to lipoproteins, we have examined the possible role of FFAs in modulating LTIP activity. Partially purified CETP, LTIP, and lipoproteins were incubated with 0 to 30 mumol/L sodium oleate, and the transfer of CE between a labeled donor lipoprotein and a given acceptor lipoprotein was measured. Without LTIP, oleate stimulated CETP-mediated CE transfer between VLDL, LDL, and HDL up to threefold. This stimulation was unique in both magnitude and oleate concentration dependence for each donor-acceptor lipoprotein pair. In contrast to CETP activity, in transfer reactions involving LDL or VLDL as donor, LTIP activity was suppressed (> 80%) by 10 to 15 mumol/L oleate. LTIP activity in transfer reactions with HDL as donor was less sensitive. Similar results to these were observed when lipid transfer reactions were measured in the total lipoprotein fraction isolated from FFA-enriched plasma. The FFA content of lipoproteins was strongly influenced by the concentration of FFA in plasma; lipoprotein FFA levels sufficient to suppress LTIP activity by 50% to 100% were achieved in plasma containing 0.8 to 1.0 mmol/L FFA. We conclude that LTIP may be functionally inactive during periods of transient elevations of plasma FFA levels, such as during postprandial lipemia or overnight fasting, or chronically suppressed in disease states in which plasma FFA levels are increased. The suppression of LTIP activity by FFA allows for maximum CETP-mediated lipid transfer between all lipoproteins, including lipid transfer reactions involving LDL that are normally preferentially suppressed by LTIP.

Biological Transport↗
PubMed1997

Lipid transfer inhibitor protein activity deficiency in normolipidemic uremic patients on continuous ambulatory peritoneal dialysis.

We previously demonstrated that lipid transfer inhibitor protein (LTIP) is a potent modifier of lipid transfer protein (LTP) function in vitro. Based on these studies, we proposed that LTIP activity is an important determinant of lipoprotein size and composition, which leads to a stimulation of reverse cholesterol transport. To further evaluate this hypothesis, we have studied a normolipidemic, uremic patient population undergoing continuous ambulatory peritoneal dialysis (CAPD) that is deficient in LTIP activity (< 18% of control). LDL from CAPD plasma was triglyceride enriched; the diameters of both CAPD LDL and HDL were increased and CAPD HDL was dominated by the largest subfraction, HDL2b. In CAPD patients, the plasma cholesterol esterification rate was only 61% of control; this decrease was due mainly to the poor reactivity of CAPD lipoproteins. CAPD lipoprotein-deficient plasma promoted twofold greater transfer of radiolabeled cholesteryl ester (CE) between standard lipoproteins than control, although LTP itself was increased only 39%. This twofold increase was not equally expressed among individual lipoprotein classes; CE transfers involving LDL were increased 2.4-fold, whereas those not involving LDL were increased only 50%. In whole plasma, CE net mass transfer to VLDL was slightly increased in CAPD plasma; relative to their CE content, control HDL contributed twofold more CE mass to VLDL than control LDL, but in CAPD plasma this preferential transfer of CE from HDL was absent. Collectively, the aberrations in CAPD lipoprotein composition and metabolism are consistent with the hypothesized role of LTIP. The data further support the role of LTIP in modulating the participation of HDL in CE mass transfers to VLDL. This is the first report of LTIP activity deficiency in humans.

Carrier Proteins↗
PubMed1997

Spondyloepimetaphyseal dysplasia and abnormal dentition in siblings: a new autosomal recessive syndrome.

The clinical and radiological features are described in male and female siblings with a unique form of spondyloepimetaphyseal dysplasia. In addition to generalized platyspondyly with epiphyseal and metaphyseal involvement, these children also have thin tapering fingers with accentuated palmar creases and abnormal dentition with oligodontia and pointed incisors. Parental consanguinity suggests that this is an autosomal recessive disorder.

Adolescent↗
PubMed1996

Differences in lipoprotein concentration and composition modify the plasma distribution of free and liposomal annamycin.

PURPOSE: The purpose of these studies were to determine the distribution of a lipophilic antineoplastic agent, annamycin (Ann), and its liposomal counterpart (LAnn) in plasma which had been altered in its lipoprotein concentration and lipid composition. METHODS: Ann, LAnn, and doxorubicin (a hydrophilic control) were incubated in human plasma for 1 hour at 37 degrees C. Following incubation plasma samples were assayed by fluorimetry for drug in each of the lipoprotein and lipoprotein-deficient plasma (LPDP) fractions. To assess the influence of modified lipoprotein concentrations and lipid composition on plasma distribution of Ann and LAnn, either Ann or LAnn were incubated in human plasma which had been supplemented with very low density lipoproteins (VLDL) or low density lipoproteins (LDL). RESULTS: When unbound Ann or doxorubicin was incubated in plasma for 1 hour at 37 degrees C, the majority of drug was found in the LPDP fraction. However, when Ann was incorporated into liposomes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol (LAnn) the majority of Ann was recovered in the high-density lipoprotein (HDL) fraction. Elevation of plasma LDL-cholesterol or VLDL-triglyceride concentrations increased the amounts of Ann and LAnn associated with these lipoprotein classes. Alterations in HDL composition decreased the amount of Ann, but increased the amount of L-Ann within the HDL fraction. Lipid transfer protein (LTP) activity did not significantly modify the plasma distribution of Ann and LAnn in short-term experiments, but the modified lipoprotein composition that LTP facilitates in long-term incubations reduced the capacity of VLDL and LDL to accept drug. CONCLUSIONS: These findings suggest that lipoprotein concentration and composition alter the plasma distribution of Ann and LAnn and may help to explain the discrepancies observed in the pharmacokinetics of Ann and LAnn when they are administered to healthy versus cancer patients.

Antibiotics, Antineoplastic↗
PubMed1996

Chickenpox in mid-trimester pregnancy: always innocent?

A case of congenital varicella infection is presented, in which despite profound cerebral damage, the cardinal features of cicatricial skin lesions and limb shortening were absent. The case is compared with previously described cases, and with published series, in which this combination is uncommon. The risks of maternal varicella infection to the developing fetus are discussed in the light of recent prospective studies which demonstrate a rather lower risk than had previously been thought to be the case.

Brain↗
PubMed1996

Plasma cholesteryl ester transfer activity is modulated by the phase transition of the lipoprotein core.

Previous studies have shown that lipid transfer protein (LTP) activity is strongly temperature dependent, demonstrating a dramatic rise in activity near 37 degrees C. We have investigated the origin of this rapid rise in LTP activity. LTP-mediated transfers of radiolabeled cholesteryl ester (CE) from LDL to HDL, HDL to LDL, LDL to biotin-LDL, HDL to biotin-HDL, and between liposomes were determined as a function of assay temperature. Only assays containing LDL demonstrated this rapid rise in CE transfer activity. In contrast, TG transfer was almost linear with assay temperature. As human LDL CE undergoes a thermal phase transition near 37 degrees C, we investigated whether the rapid rise in CE transfer was dependent on this transition. Monkey LDL were isolated from animals consuming diets containing cholesterol and enriched in saturated, monounsaturated, or polyunsaturated fatty acids. With these LDL as substrate, the CE transfer between 21 degrees and 49 degrees C could be described by two straight lines, the intersection of which defined the inflection temperature. Among eight LDL samples, the inflection temperature was highly correlated with the CE phase transition determined by differential scanning calorimetry (r2 = 0.86). Both calorimetry and CE transfer activity inflection values were correlated with the saturated + monoene/polyene ratio of the LDL cholesteryl esters (r2 = 0.733 and 0.612, respectively). For LDL with inflection temperatures below 37 degrees C, CE transfer activity at 37 degrees C increased 10-14% for each 1 degree C decrease in the inflection temperature. We conclude that LTP activity is markedly affected by the physical state of the core CE. Diets rich in saturated fatty acids may result in LDL that are poor LTP substrates, which may hinder LTP's ability to promote normal lipoprotein remodeling.

Animals↗
PubMed1995

Atlantoaxial instability in Down's syndrome: a five year follow up study.

In 1986 all 90 children aged 4-19 years with Down's syndrome attending school in the area served by the Southern Derbyshire Health Authority underwent radiography to identify atlantoaxial instability (AAI). This study details repeat observations five years later. Full results were available on 67 (74%), information on health status was available on the remaining 19 (21%); four (4%) were untraced. There was an overall significant reduction in the atlanto-axial gap over five years. No one developed AAI on repeat testing who had not had it earlier. One child who had previously had normal neck radiography developed acute symptomatic AAI after ear, nose, and throat surgery. Radiographs were done on three occasions on the same day in 49 individuals, ensuring full flexion of the upper neck. There were no significant differences between the radiographs, even in five subjects with AAI. Management of AAI in Down's syndrome is discussed in the light of these findings. Radiography can reliably detect children with chronic AAI who may be at risk of gradually developing symptoms; this may justify a screening programme. This must be distinguished from those who develop symptoms after acute trauma or anaesthesia, for which specific precautions are needed, and previous screening radiographs are unhelpful.

Adolescent↗
PubMed1994

Decreased toxicity of liposomal amphotericin B due to association of amphotericin B with high-density lipoproteins: role of lipid transfer protein.

Previously, we have shown that liposomal amphotericin B (L-AmpB) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) was less nephrotoxic but equally as effective as Fungizone, which consists of amphotericin (AmpB) and deoxycholate. We have also observed that AmpB predominantly associates with high-density lipoproteins (HDL) in human serum and that the amount of AmpB associated with HDL increases when AmpB is incorporated into negatively charged liposomes. Furthermore, we observe that AmpB was less toxic in vitro to pig kidney cells when associated with HDL, but still toxic when associated with LDL. To further understand why HDL-associated AmpB causes reduced renal toxicity, we first examined LLC PK1 cells for the presence of LDL and HDL receptors and then the cytotoxic effects of HDL- and LDL-associated AmpB following trypsin treatment of LLC PK1 renal cells, which removed only the high-affinity LDL receptors. We found that LLC PK1 renal cells expressed high- and low-affinity LDL receptors but only low-affinity HDL receptors. Furthermore, when LLC PK1 cells were treated with trypsin, HDL- and LDL-associated AmpB were less toxic to the cells than was AmpB. The reduced renal cell toxicity of HDL-associated AmpB may be due to its lack of interaction with renal cells because of the absence of HDL receptors. Since AmpB interacts with cholesteryl esters (CE) whose transfer among lipoproteins is regulated by lipid transfer protein (LTP), the role of LTP on the distribution of AmpB to HDL and LDL was next investigated. We observed that LTP facilitated the transfer of AmpB, but not L-AmpB, from HDL to LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed1994

Enhanced detection of lipid transfer inhibitor protein activity by an assay involving only low density lipoprotein.

Lipid transfer inhibitor protein (LTIP) activity has been typically quantitated by its ability to suppress lipid transfer protein-mediated lipid movement between low density lipoprotein (LDL) and high density lipoprotein (HDL). In an attempt to establish an LTIP activity assay that is more sensitive, we have exploited the reported preference of the inhibitor protein to interact with LDL. A lipid transfer assay was established that involves LDL as both the donor and the acceptor; LDL in one of these two pools was biotinylated to facilitate its removal with immobilized avidin. Compared to the standard LDL to HDL assay, LTIP inhibited lipid transfer from radiolabeled LDL to biotin-LDL 7-fold more. In the absence of LTIP, lipid transfer activity was the same in both assays. An added benefit of this assay was the near linearity (up to 85%) of the inhibitory response, in contrast to the highly curvilinear response of LTIP in LDL to HDL transfer assays. The high sensitivity of the LDL to biotin-LDL transfer assay in measuring LTIP activity could not be duplicated by other transfer assays including assays containing only HDL (HDL to biotin-HDL), assays between liposomes and LDL, or assays between LDL and HDL where the concentration of lipoproteins was reduced 10-fold. Thus, LTIP activity is most effectively measured in homologous lipid transfer assays involving only LDL (and its biotin derivative). This increased sensitivity to LTIP suggests that the inhibitor binds more avidly to the LDL surface than does lipid transfer protein.

Biological Transport↗
PubMed1994

Regulation of lipid transfer between lipoproteins by an endogenous plasma protein: selective inhibition among lipoprotein classes.

Lipid transfer protein (LTP) remodels plasma lipoproteins by promoting mass transfers of cholesteryl ester (CE) and triglyceride between lipoproteins. We have investigated the capacity of an additional plasma protein, lipid transfer inhibitor protein (LTIP) to modify the functional activity of LTP in a complex mixture of lipoproteins. Transfer assays containing isolated LTP, LTIP, and the three major lipoprotein classes, and assays with intact human plasma supplemented with exogenous LTIP were used. In both assays, the inhibition of CE transfer by LTIP varied markedly depending on the lipoproteins involved and was dependent on LTIP concentration. Inhibition of lipid transfer between a given pair of lipoproteins was similar. However, between lipoprotein pairs the extent of inhibition was very different, varying up to 7-fold. Inhibition followed the order of very low density lipoprotein (VLDL)-low density lipoprotein (LDL) transfers > LDL-high density lipoprotein (HDL) transfers > VLDL-HDL transfers. Consistent with the preferential inhibition of transfer events involving LDL, LTIP was shown by gel filtration studies to associate primarily with LDL in plasma. The addition of LTIP to native plasma stimulated the LTP-mediated efflux of CE from HDL to VLDL; this occurred at the expense of LDL CE depletion. Thus, LTIP alters the pattern of lipid transfer reactions in plasma by uniquely affecting the individual transfer events mediated by LTP. By preferentially diminishing transfer events involving LDL, especially those between VLDL and LDL, LTIP enhances the ability of LTP to remove CE from HDL, and thus alters HDL metabolism.

Blood Proteins↗
PubMed1993

Videofluoroscopy in the assessment of feeding disorders of children with neurological problems.

A multidisciplinary assessment, including videofluoroscopy, was carried out on 14 children with feeding difficulties associated with neurological problems. Recommendations were made on all aspects of feeding and the trunk position was changed for half of the patients. A later interview with the parents confirmed that the recommendations had been helpful. The optimum trunk position for feeding was determined during videofluoroscopy by positioning the patient in the erect or reclined position, and also by analysis of relative difficulties during the oral and pharyngeal phases of swallowing. Those with difficulties mainly in the oral phase fed best in the reclined position; those with difficulties mainly in the pharyngeal phase fed best in the erect position, particularly if they had upper-oesophageal sphincter spasm in association with a tonic labyrinthine reflex.

Adolescent↗