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L McMahon

Publications and source records attributed to L McMahon.

At least 19 recordsLinked to original sources
PubMed2002

Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients.

Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti-proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single-dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half-life was similar. Single-dose everolimus co-administration did not affect the steady-state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice-daily dosing schedule used in adults.

Administration, Oral↗
PubMed2001

Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress.

Nitric oxide metabolism is altered during the acute chest syndrome of sickle cell disease. In the presence of oxygen and oxygen-related molecules, nitric oxide can preferentially form the powerful oxidants nitrite, nitrate, and peroxynitrite. We hypothesized that increased oxidative stress may contribute to the pathogenesis of acute chest syndrome and measured F2 isoprostanes, a nonenzymatically generated molecule resulting from free radical catalyzed lipid peroxidation in patients with sickle cell disease in various stages of disease. Plasma samples were obtained from nineteen patients with sickle cell disease during acute chest syndrome (pre- and postexchange transfusion), vasoocclusive crisis, and/or at baseline; 12 normal volunteers served as controls. F2 isoprostanes were measured by gas chromatography/mass spectrophotometry. There was a 9-fold increase in F2 isoprostanes in patients with acute chest syndrome as compared with normal volunteers. There was approximately a 50-60% decline in isoprostanes postexchange transfusion to a level similar to that of patients with sickle cell disease at baseline. There was no difference in isoprostanes between vasoocclusive crisis and patients with sickle cell disease at baseline. Increased oxidative stress, measured by generation of F2 isoprostanes, occurs during acute chest syndrome and may have an important role in the pathogenesis of this disease process.

Acute Disease↗
PubMed2001

The Caenorhabditis elegans gene lin-26 can trigger epithelial differentiation without conferring tissue specificity.

How epithelial cell fates become specified is poorly understood. We have previously shown that the putative C2H2 zinc-finger transcription factor LIN-26 is required for the differentiation of ectodermal and mesodermal epithelial cells in Caenorhabditis elegans. Here, we report that ectopic LIN-26 expression during early gastrulation transforms most blastomeres into epithelial-like cells. Specifically, LIN-26 induced the expression of three epithelial markers: the adherens junction protein JAM-1; DLG-1, which is essential for the assembly of JAM-1 at junctions; and CHE-14, which is involved in apical trafficking. Furthermore, ultrastructural studies revealed that ectopic LIN-26 expression induced the formation of adherens-like junctions. However, ectopic lin-26 expression did not confer any tissue-specific cell fate, such as the epidermal cell fate, as evidenced from the observation that several epidermal-specific genes were not induced. Conversely, we show that epidermal cells displayed some polarity defects in lin-26 mutants. We conclude that lin-26 can induce epithelial differentiation and that epitheliogenesis is not a default pathway in C. elegans.

Animals↗
PubMed2001

Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications.

BACKGROUND: Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation. METHODS: A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation. The data were evaluated in a nonlinear mixed-effects model. The influence of demographic characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored. RESULTS: For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone immunosuppressive regimen, the absorption rate constant was 6.07 h(-1) (standard error [SE], 0.70 h(-1)), the apparent clearance was 8.8 L/h (SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L). There were no clinically relevant influences of age, weight, or sex on clearance. No significant difference in clearance was detected for Asian patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients. Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance. One patient receiving itraconazole had a 74% reduction in clearance. After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36%. The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31%. CONCLUSIONS: Dose adjustment of everolimus on the basis of weight does not appear necessary. Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients. Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations.

Adolescent↗
PubMed2001

Assembly of C. elegans apical junctions involves positioning and compaction by LET-413 and protein aggregation by the MAGUK protein DLG-1.

Specialised subapical junctions play a critical role in maintaining epithelial cell polarity and tissue integrity, and provide a platform for intracellular signalling. Here we analyse the roles of C. elegans genes let-413 and dlg-1, a homologue of Drosophila lethal discs large, in the assembly of the C. elegans apical junction (CeAJ), and provide the first characterisation of this structure. We have identified dlg-1 as an essential gene in an RNA interference screen against C. elegans homologues of genes encoding proteins involved in tight or septate junction formation. We show that DLG-1 colocalises with the junctional protein JAM-1 at CeAJs in a unit distinct from HMP-1/alpha-catenin, and apical to the laterally localised LET-413. Loss of dlg-1 activity leads to JAM-1 mislocalisation and the disappearance of the electron-dense component of the CeAJs, but only mild adhesion and polarity defects. In contrast, loss of let-413 activity leads to the formation of basally extended discontinuous CeAJs and strong adhesion and polarity defects. Interestingly, in LET-413-deficient embryos, CeAJ markers are localised along the lateral membrane in a manner resembling that observed in wild-type embryos at the onset of epithelial differentiation. We conclude that the primary function of LET-413 is to correctly position CeAJ components at a discrete subapical position. Furthermore, we propose that DLG-1 is required to aggregate JAM-1 and other proteins forming the electron-dense CeAJ structure. Our data suggest that epithelial adhesion is maintained by several redundant systems in C. elegans.

Animals↗
PubMed1999

Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease.

High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.

Adolescent↗
PubMed1999

Otologic findings in a pediatric cohort with sickle cell disease.

OBJECTIVE: Sensorineural hearing loss (SNHL) has been associated with sickle cell disease (SCD) in older children and adults. Few studies have investigated this association in younger children. DESIGN: In a cohort of pediatric patients followed at our sickle cell clinic, with a mean age of 7.8 years, 154 audiograms were completed on 84 patients. RESULTS: This produced 22 subjects with abnormal audiograms. Middle ear effusion was the etiology of 19 subjects' audiometric findings. Three children were found to have mild SNHL. None of the subjects had hearing loss of severity which would warrant amplification. The prevalence rate for SNHL in our cohort of pediatric patients was 3.5%. CONCLUSION: This differs from past reports, and may reflect an age dependent prevalence of SNHL in this disease.

Anemia, Sickle Cell↗
PubMed1999

Comparison of allelic ratios from paired blood and paraffin-embedded normal tissue for use in a polymerase chain reaction to assess loss of heterozygosity.

BACKGROUND: One method to assess loss of heterozygosity (LOH) of various genes is the amplification of DNA from neoplastic tissue by using microsatellite markers. LOH can best be considered on a quantitative basis as a comparison of allelic ratios of neoplastic tissue to that of the normal control. We will illustrate through quantitative methods the importance of using the appropriate controls when determining allelic loss. METHODS AND RESULTS: DNA extracted from 28 paired blood and formalin-fixed, paraffin-embedded normal mucosal tissue was amplified using the DP1 microsatellite marker, consisting of a variable number of CA repeats. This marker is located within the D5S346 (DP1) region on chromosome 5 and is linked to the adenomatous polyposis coli gene. Allelic ratios were calculated after scanning autoradiographs on a densitometer. Ratio values approaching 1 were observed when the two alleles were close in molecular weight, whereas ratios less than 1 were detected when the two alleles had very different molecular weights. This discrepancy was more pronounced in paraffin-embedded tissue than with blood samples. CONCLUSION: For LOH amplification assays, it is best to use normal control samples that are of the same tissue source as the neoplastic sample being analyzed. When assessing LOH in neoplastic tissue, a quantitative value rather than visual assessment of the alleles should be considered. The values may be normalized by dividing the ratio of the two tumor alleles by the ratio of the two normal alleles.

Alleles↗
PubMed1999

Leader behavior impact on staff nurse empowerment, job tension, and work effectiveness.

OBJECTIVE: The authors tested a model linking specific leader-empowering behaviors to staff nurse perceptions of workplace empowerment, occupational stress, and work effectiveness in a recently-merged Canadian acute care hospital. SUMMARY BACKGROUND DATA: An integration of Kanter's organizational empowerment theory and Conger and Kunungo's model of the leader empowerment process constituted the theoretical framework for the study. Few published studies were found in which specific leader behaviors were linked empirically to staff nurses' workplace empowerment. METHODS: Staff nurses (n = 537) were surveyed shortly after a merger of two large tertiary hospitals. Structural equation modeling techniques were used to test the proposed model. RESULTS: Leader-empowering behaviors significantly influenced employees perceptions of formal and informal power and access to empowerment structures (information support, resources, and opportunity). Higher perceived access to empowerment structures predicted lower levels of job tension and increased work effectiveness. The amount of explained variance in the final model was 42%. CONCLUSIONS: Support for the model tested in this study highlights the importance of nurse managers' leadership behaviors within current turbulent healthcare organizations.

Adult↗
PubMed1998

MRA of the intracranial circulation in asymptomatic patients with sickle cell disease.

BACKGROUND: MR angiography (MRA) provides a mechanism for non-invasively studying blood flow, thus providing a new opportunity to study the intracranial circulation in asymptomatic sickle cell disease (SCD) patients. Although conventional angiography is the gold standard for the depiction of vascular anatomy, this is too invasive for an asymptomatic population. OBJECTIVE: To establish the range of appearances in asymptomatic SCD patients and to correlate brain MRI results (either sub-clinical abnormalities or normal brain parenchyma) with the MRA findings. MATERIALS AND METHODS: Brain MRI and MRA of the intracranial circulation was performed on 22 patients (13 male and 9 female, median age 7.5 years, range 1.3-20 years). Fourteen were homozygous SS and eight were SC. The median haematocrit at the time of MRI was 25.9 (range 13.8-33.3). RESULTS: On MR imaging, four patients had infarcts in eight vascular territories (six anterior and two posterior). In 3/4 of anterior vascular territories with infarction, long ( >/= 6 mm) segments of abnormal signal were seen at the internal carotid artery bifurcation with associated reduced distal flow. Short focal areas of abnormal signal were commonly seen where vessels branched, bifurcated or curved and were not associated with infarcts. These areas probably represent turbulence-related dephasing secondary to high velocity flow found in SCD. CONCLUSION: Long segments ( >/= 6 mm) of abnormal signal with reduced distal flow correlated with sub-clinical infarction.

Adolescent↗
PubMed1998

Spontaneous labyrinthine hemorrhage in sickle cell disease.

We report the clinical and MR imaging findings in two African-American patients with manifestations of sickle cell disease affecting the inner ear. Both suffered sudden-onset sensorineural hearing loss and vestibular symptoms, and both had high labyrinthine signal on T1-weighted MR images attributed to labyrinthine hemorrhage. Follow-up studies of the first patient revealed a decrease in abnormal vestibular signal. Careful attention to the labyrinth on T1-weighted MR images can reveal vestibulocochlear clinical findings in sickle cell patients, with important implications for management and prognosis.

Adult↗
PubMed1995

Isolation and photodynamic effects of hematoporphyrin derivative components: a chromatographic analysis of the starting materials.

Twenty different fractions of hematoporphyrin derivatives (HpD) and eight fractions of an HpD dimer mixture were isolated utilizing isocratic reversed-phase ion-pair high-performance liquid chromatography. These fractions were characterized by UV-visible and fluorescence spectrophotometry. Fluorescence quantum yields and photokill efficiency for each fraction in PTK2 epithelial cells were obtained. Results indicate that some part of the photoactivity exhibited by HpD may be due to impurities present in the HpD starting material, hematoporphyrin-IX dihydrochloride, depending on its source. It was also found that hematoporphyrin D, a commercial acetylated product formed during synthesis of HpD, contained a higher percentage of monomers than would be expected.

Animals↗
PubMed1995

Isobolographic assessment of the effects of combinations of phenylpropanolamine and fenfluramine on food intake in rats.

Phenylpropanolamine (PPA) suppresses appetite in rats via activation of alpha 1-adrenergic receptors within the paraventricular hypothalamus (PVN). The serotonergic (5-HT) agonist fenfluramine (FEN) is thought to suppress appetite via stimulation of 5-HT release within the PVN rather than activation of adrenergic receptors. Whether a mixture of these neurochemically distinct anorexic drugs will serve as an effective appetite suppressant is unknown. In the present experiment, drug-drug interactions between PPA and FEN were explored using an isobologram technique. Fixed doses of PPA (0 vs. 5 mg/kg) were combined with various doses of FEN (1.25, 2.5, and 5.0 mg/kg) and fixed doses of FEN (0 vs. 2.5 mg/kg) were combined with various doses of PPA (0, 5, 10, and 15 mg/kg). Drug combinations were injected IP 30 min before a 1-h feeding trial in 16-h food-deprived rats. PPA and FEN were dose-additive in this paradigm, an outcome that supports the feasibility of a new appetite suppressant composed of a mixture of PPA and FEN.

Animals↗