Search PubMed⌕ Search

Biomedical subjects

A McDermott

Publications and source records attributed to A McDermott.

At least 19 recordsLinked to original sources
PubMed2001

Autoantigen glycoprotein 70 expression is regulated by a single locus, which acts as a checkpoint for pathogenic anti-glycoprotein 70 autoantibody production and hence for the corresponding development of severe nephritis, in lupus-prone PXSB mice.

Retroviral envelope glycoprotein gp70 is present in the sera of immunologically normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and these have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB x (C57BL/10 x BXSB)F(1))- and (C57BL/10 x (C57BL/10 x BXSB)F(1))-backcrossed male mice. Production of gp70 mapped to a single major locus located on chromosome 13 (Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 x 10(-38)). The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 levels were greater than a threshold value of approximately 4.0 microg/ml. The subdivision of the (BXSB x (C57BL/10 x BXSB)F(1))-backcrossed mice into those homozygous or heterozygous for Bxs6 enabled a remarkable association to be observed between high levels of gp70IC and severe nephritis in the Bxs6 homozygote population. A further mapping study in these two subgroups identified a previously unrecognized interval associated with the production of autoantibodies.

Animals↗
PubMed2001

Spontaneous chronic corneal epithelial defects (SCCED) in dogs: clinical features, innervation, and effect of topical SP, with or without IGF-1.

PURPOSE: To delineate the clinical features and alterations in innervation and substance P (SP) content in spontaneous chronic corneal epithelial defects (SCCED) in dogs and to conduct a preliminary investigation evaluating the efficacy of topical SP, with or without insulin-like growth factor (IGF)-1, in the treatment of this disorder. METHODS: Complete ophthalmic examinations, including Cochet-Bonnet aesthesiometry, were performed in 45 canine patients that had spontaneous corneal epithelial defects of at least 3 weeks' duration and with no identifiable cause. Eighteen patients had superficial keratectomies performed, and the corneal nerves were labeled immunohistochemically with antibodies against protein gene product (PGP)-9.5, SP, vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). Relative fiber densities were assessed qualitatively and quantitatively. Corneal epithelial cell and tear SP contents were determined in affected and normal dogs by an enzyme immunoassay. A preliminary open-label treatment trial of topical SP, with and without IGF-1, was conducted in 21 dogs. RESULTS: The duration of the erosion before admittance into the study was a mean of 9.22 weeks (range, 3-52). The average patient was middle aged (mean, 9.25 +/- 1.85 years [SD]); no sex predisposition of the disease was identified. Boxers, golden retrievers, and keeshonds were overrepresented when compared with the normal hospital population. Corneal sensation was normal. Marked alterations in corneal innervation were identified in affected dogs with abnormal increased SP and calcitonin gene-related peptide (CGRP)-immunoreactive nerve plexuses identified surrounding the periphery of the epithelial defect. The SP content of epithelial cells surrounding the defect increased, whereas the tear SP content remained unchanged. Of the canine patients treated with SP, with or without IGF-1, 70% to 75% had complete healing of the defect. CONCLUSIONS: This idiopathic spontaneous corneal disease in dogs shares clinical features with chronic epithelial defects in humans. The presence of marked alterations in peptidergic innervation and positive response to topical therapy with SP suggest that SP plays a critical role in corneal wound-healing processes.

Administration, Topical↗
PubMed2000

Protein kinase C-beta contributes to NADPH oxidase activation in neutrophils.

We have analysed the involvement of the beta isotype of the protein kinase C (PKC) family in the activation of NADPH oxidase in primary neutrophils. Using immunofluorescence and cell fractionation, PKC-beta is shown to be recruited to the plasma membrane upon stimulation with phorbol ester and to the phagosomal membrane upon phagocytosis of IgG-coated particles (Fcgamma-receptor stimulus). The time course of recruitment is similar to that of NADPH oxidase activation by these stimuli. The PKC-beta specific inhibitor 379196 inhibits the response to PMA as well as to IgG-coated bacteria. Partial inhibition occurs between 10 and 100 nM of inhibitor, the concentration at which PKC-beta, but not other PKC isotypes, is targeted. Neutrophils isolated from a mouse that lacks PKC-beta also showed an inhibition of NADPH oxidase activation by PMA and IgG-coated particles. The level of inhibition is comparable to that achieved with 379196 in human neutrophils. Thus the PKC-beta isotype mediates activation of NADPH oxidase by PMA and by stimulation of Fcgamma receptors in neutrophils.

Animals↗
PubMed2000

Partial NMR assignments for uniformly (13C, 15N)-enriched BPTI in the solid state.

We demonstrate that high-resolution multidimensional solid state NMR methods can be used to correlate many backbone and side chain chemical shifts for hydrated micro-crystalline U-13C,15N Basic Pancreatic Trypsin Inhibitor (BPTI), using a field strength of 800 MHz for protons, magic angle sample spinning rates of 20 kHz and proton decoupling field strengths of 140 kHz. Results from two homonuclear transfer methods, radio frequency driven dipolar recoupling and spin diffusion, were compared. Typical 13C peak line widths are 0.5 ppm, resulting in Calpha-Cbeta and Calpha-CO regions that exhibit many resolved peaks. Two-dimensional carbon-carbon correlation spectra of BPTI have sufficient resolution to identify and correlate many of the spin systems associated with the amino acids. As a result, we have been able to assign a large number of the spin systems in this protein. The agreement between shifts measured in the solid state and those in solution is typically very good, although some shifts near the ion binding sites differ by at least 1.5 ppm. These studies were conducted with approximately 0.2 to 0.4 micromol of enriched material; the sensitivity of this method is apparently adequate for other biological systems as well.

Aprotinin↗
PubMed2000

De novo laryngeal carcinoma in childhood.

Numerous factors contribute towards a late diagnosis of laryngeal malignancy in childhood. These include its rarity, the similarity of its early symptoms to those of other benign, common childhood conditions as well as the relative difficulty encountered during paediatric laryngeal examination. We believe that these cases are of sufficient interest when they occur to warrant reporting since the consequences of late diagnosis in these young patients can be serious. We present a case of an 11-year-old boy with advanced squamous cell carcinoma of the larynx (T3N0M0), who was successfully treated with primary total laryngectomy and bilateral selective neck dissections to avoid the potential additional morbidity of radical radiotherapy.

Carcinoma, Squamous Cell↗
PubMed1999

A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution.

OBJECTIVE: Body fat redistribution ('lipodystrophy'), with gain in abdominal and trunk fat, and decline in facial and limb fat, is a newly recognized problem in patients with HIV infection that has been linked to use of HIV-1 protease inhibitors. Increased abdominal fat may predispose these patients to hypertension, diabetes, and coronary artery disease. At this time no effective treatment is available. We examined whether exercise training could reduce trunk fat in men with fat redistribution. DESIGN: Open-label pilot study. METHODS: Ten men with increasing abdominal girth participated in a 16 week pilot study of progressive resistance training with an aerobic component. They trained in a community health club three times per week. Total body lean and fat mass, and trunk fat mass, were assessed by dual-energy x-ray absorptiometry (DXA). RESULTS: After 16 weeks of exercise, strength increased for three of the four exercises tested (leg press + 13% [p < 0.02], leg extension + 19% [p < 0.03], seated row + 7% [p < 0.13], chest press + 18% [p < 0.0051). There was a significant decline in total body fat by 1.5 kg (= 2.1 percentage points, p < 0.01); most of the decline in body fat occurred in trunk fat, which decreased by 1.1 kg (p < 0.03). Weight, lean mass (+ 1.1 + 2.6 kg, p = 0.23), and bone mineral density measured by DXA did not change. No adverse effects were seen from the training. CONCLUSIONS: Exercise training may reduce trunk fat mass in HIV-positive men with fat redistribution. Controls trials of this approach are warranted.

Abdomen↗
PubMed1999

Solid state NMR studies of hydrogen bonding in a citrate synthase inhibitor complex.

The ionization state and hydrogen bonding environment of the transition state analogue (TSA) inhibitor, carboxymethyldethia coenzyme A (CMX), bound to citrate synthase have been investigated using solid state NMR. This enzyme-inhibitor complex has been studied in connection with the postulated contribution of short hydrogen bonds to binding energies and enzyme catalysis: the X-ray crystal structure of this complex revealed an unusually short hydrogen bond between the carboxylate group of the inhibitor and an aspartic acid side chain [Usher et al. (1994) Biochemistry 33, 7753-7759]. To further investigate the nature of this short hydrogen bond, low spinning speed 13C NMR spectra of the CMX-citrate synthase complex were obtained under a variety of sample conditions. Tensor values describing the chemical shift anisotropy of the carboxyl groups of the inhibitor were obtained by simulating MAS spectra (233 +/- 4, 206 +/- 5, and 105 +/- 2 ppm vs TMS). Comparison of these values with our previously reported database and ab initio calculations of carbon shift tensor values clearly indicates that the carboxyl is deprotonated. New data from model compounds suggest that hydrogen bonds in a syn arrangement with respect to the carboxylate group have a pronounced effect upon the shift tensors for the carboxylate, while anti hydrogen bonds, regardless of their length, apparently do not perturb the shift tensors of the carboxyl group. Thus the tensor values for the enzyme-inhibitor complex could be consistent with either a very long syn hydrogen bond or an anti hydrogen bond; the latter would agree very well with previous crystallographic results. Two-dimensional 1H-13C heteronuclear correlation spectra of the enzyme-inhibitor complex were obtained. Strong cross-peaks were observed from the carboxyl carbon to proton(s) with chemical shift(s) of 22 +/- 5 ppm. Both the proton chemical shift and the intensity of the cross-peak indicate a very short hydrogen bond to the carboxyl group of the inhibitor, the C.H distance based upon the cross-peak intensity being 2.0 +/- 0.4 A. This proton resonance is assigned to Hdelta2 of Asp 375, on the basis of comparison with crystal structures and the fact that this cross-peak was absent in the heteronuclear correlation spectrum of the inhibitor-D375G mutant enzyme complex. In summary, our NMR studies support the suggestion that a very short hydrogen bond is formed between the TSA and the Asp carboxylate.

Acyl Coenzyme A↗
PubMed1999

Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus.

BACKGROUND: To assess the efficacy of progressive resistance training (PRT) in increasing strength and lean body mass (LBM) in HIV-infected adults. METHODS: Twenty-five adults with HIV infection were trained using a highly intensive PRT regimen for 8 weeks, followed by an additional 8 weeks of observation under ad libitum physical activity conditions. RESULTS: Twenty-four of the 25 patients completed the first phase of the study. They had significant increases in strength on all four exercises tested (P < 0.0001), and an increase in LBM of 1.75 +/- 1.94 kg (mean +/- SD, P < 0.0002), with a concomitant decline in fat of 0.92 +/- 2.22 kg (P < 0.05), and no significant change in weight or bone mineral content. Twenty-one of the patients returned for follow-up 8 weeks after completing the PRT. Compared with their baseline values, their mean lean mass remained 1.40 +/- 1.8 kg higher (P < 0.003). Among those who continued to train to some extent, lean mass increased by a mean of 1.1 +/- 1.6 kg (n = 9, P < 0.05 versus end of PRT), whereas those who did no further training showed an increase in lean mass of 0.28 +/- 1.4 kg (n = 12, P = NS versus end of PRT). The difference between the two groups was not, however, significant (P = 0.25). Among six patients with AIDS wasting, the increase in LBM was larger than among non-wasted patients (2.8 versus 1.4 kg, P < 0.06), and there was an increase in both weight (+3.9 versus -0.2 kg, P < 0.002) and fat mass (+ 0.95 versus -1.5 kg, P < 0.002) at 8 weeks, which persisted at 16 weeks (weight: +4.0 versus -1.6 kg, P < 0.0002; fat: +1.6 versus -1.9 kg, P < 0.01). CONCLUSION: This preliminary study suggests that short-term, high intensity PRT can significantly increase LBM and strength in HIV infection, and may be used as an alternative or adjunct to pharmacological anabolic treatments in this disease.

Adult↗
PubMed1998

Solid state NMR studies of photoinduced polarization in photosynthetic reaction centers: mechanism and simulations.

We simulate Photo-Chemically Induced Dynamic Nuclear Polarization in the 15N-solid-state NMR of 15N-labeled photosynthetic reaction centers using a Radical Pair Mechanism (RPM). According to the experimental data, the directly polarized nuclei include all eight nitrogens in the ground state of the bacteriochlorophyll special pair (P), and N-II in the bacteriopheophytin acceptor (H) [M.G. Zysmilich, A.E. McDermott, J. Am. Chem. Soc., 116 (1994) 8362-8363.] [M.G. Zysmilich, A. McDermott, J. Am. Chem. Soc., 118 (1996) 5867-5873.] [M.G. Zysmilich, A. McDermott, Proc. Natl. Acad. Sci. U.S.A., 93 (1996) 6857-6860.]; other signals are polarized in nonspecifically labeled samples, but the polarization apparently results from magnetization exchange with neighboring polarized nitrogens, and these are not treated in this work. Two quantitative models for the polarization associated with the RPM are presented and are used to test the validity of the proposal that this mechanism is cooperative in the reaction centers. The kinetic models can treat the steady state polarizations as well as the approach to steady state, and in principle could be expanded to include anisotropic effects, or pulse-probe experiments. Several features of the detailed simulations of the steady-state amplitudes and the kinetics of the approach to steady-state are compared with our data, including the signs and approximate absolute magnitudes of the polarization on the nitrogen nuclei in P and H(L), and the changes in the relative amplitudes with the change in the lifetime of the molecular triplet, photoaccumulation time, nuclear relaxation rate and illumination intensity. The simulations demonstrate that the polarization intensities are in qualitative agreement with those predicted for the RPM, including the curious observation of strong polariza-tion on the pheophytin acceptor for certain experimental conditions. However, this agreement requires efficient relaxation of the nitrogens on H(L) by 3P, due to a fortuitous low nanosecond value for the spin-lattice relaxation for the electrons in the molecular triplet of the donor, T1e of 3P. Whether this fortuitous match is valid is unproven.

Anisotropy↗
PubMed1998

The epidemic of prostate cancer and the medical literature: a causal association?

The diagnosis of prostate cancer has undergone an unprecedented recent increase, while mortality has increased much more slowly. We examined new prostate cancer diagnoses from 1987-1992 in a nationwide prospective cohort study of 51 529 men enrolled in the Health Professionals Follow-up Study, a population likely to be medically sophisticated and thus early to adopt medical innovations. The age-adjusted incidence of prostate cancer rose approximately 2(1/2) fold during the study period. Nearly all of the increase occurred among organ-confined tumors, with a smaller increase for regionally-advanced tumors and none for metastatic tumors. Using a Poisson regression model of newly-diagnosed cancers, we found organ-confined cancers rose abruptly by 86% (95% CI: 36-256%; P=0.0001) and regionally-advanced tumors by 73% (95% CI:12-267%; P=0.01) after March, 1991, when a study advocating screening using the prostate specific antigen (PSA) was published in the New England Journal of Medicine. The recent increase in the incidence of prostate cancer is probably due to the increased PSA screening of asymptomatic men, resulting in the diagnosis of large numbers of men with early-stage disease from 1990 onward. Despite ongoing debate over the value of PSA screening, the rate of diagnosis accelerated sharply after the publication of a well-publicized but inconclusive study advocating screening. In a context of growing disease awareness, well-publicized research reports may result in unexpectedly amplified acceptance into medical practice.

Journal Article↗
PubMed1997

Complementary strand analysis: a new approach for allelic separation in complex polyallelic genetic systems.

We describe a method, complementary strand analysis (CSA), for separating alleles potentially from any heterozygous genetic locus. Locus specific PCR is performed generating two allelic products. The antisense strands are isolated and hybridised with a sense reference strand to form a chimeric DNA duplex for each allele which is then separated by non-denaturing PAGE. We demonstrate the application of CSA for separation of highly polymorphic HLA-A, -B and -Cw alleles and characterisation of HLA identity in related bone marrow donors and patients. CSA is capable of resolving one nucleotide differences in a DNA fragment nearly as large as a kilobase in length.

Alleles↗
PubMed1997

Measurement error correction for logistic regression models with an "alloyed gold standard".

Recently, some authors have questioned the validity of methods which correct relative risk estimates for measurement error and misclassification when the "gold standard" used to obtain information about the measurement error process is itself imperfect. When such an "alloyed" gold standard is used to validate the usual exposure measurement, the bias in the "regression calibration" (Rosner et al., Stat Med 1989; 8:1051-69) measurement-error correction factor for relative risks estimated from logistic regression models is derived. This quantity is a function of the correlations of the "alloyed" gold standard (X) and the usual exposure assessment method (Z) with the truth, of the ratio of the variances of X and Z, and of the correlation between the errors in the "alloyed" gold standard and the errors in the usual exposure assessment method. In this paper, it is proven that if the errors between Z and X are uncorrelated, the regression calibration method has no bias even when the gold standard is "alloyed." When a third method of exposure assessment is available and it is reasonable to assume that the errors in this method are uncorrelated with the errors in the other two exposure assessment methods, point and interval estimates of the correlation between the errors in X and Z are derived. These methods are illustrated here with data on the measurement of physical activity, vitamins A and E, and poly- and monounsaturated fat. In addition, when a third exposure assessment method is available, a modification of standard regression calibration is derived which can be used to calculate point and interval estimates of relative risk that are corrected for measurement error in both X and Z. This new method is illustrated here with data from the Health Professionals Follow-up Study, a study investigating the associations between physical activity and colon cancer incidence and between vitamin E intake and coronary heart disease. It is shown that in these examples, correlations of the errors in X and Z tended to be small. Even when moderate, estimates of relative risk corrected for error in both X and Z were not very different from the estimates which assumed that X was a true gold standard.

Bias↗
PubMed1997

Regression calibration method for correcting measurement-error bias in nutritional epidemiology.

Regression calibration is a statistical method for adjusting point and interval estimates of effect obtained from regression models commonly used in epidemiology for bias due to measurement error in assessing nutrients or other variables. Previous work developed regression calibration for use in estimating odds ratios from logistic regression. We extend this here to estimating incidence rate ratios from Cox proportional hazards models and regression slopes from linear-regression models. Regression calibration is appropriate when a gold standard is available in a validation study and a linear measurement error with constant variance applies or when replicate measurements are available in a reliability study and linear random within-person error can be assumed. In this paper, the method is illustrated by correction of rate ratios describing the relations between the incidence of breast cancer and dietary intakes of vitamin A, alcohol, and total energy in the Nurses' Health Study. An example using linear regression is based on estimation of the relation between ultradistal radius bone density and dietary intakes of caffeine, calcium, and total energy in the Massachusetts Women's Health Study. Software implementing these methods uses SAS macros.

Adult↗
PubMed1996

Natural abundance solid-state carbon NMR studies of photosynthetic reaction centers with photoinduced polarization.

Solid-state NMR spectra of natural abundance 13C in reaction centers from photosynthetic bacteria Rhodobacter sphaeroides R-26 was measured. When the quinone acceptors were removed and continuous visible illumination of the sample was provided, exceptionally strong nuclear spin polarization was observed in NMR lines with chemical shifts resembling those of the aromatic carbons in bacteriochlorophyll and bacteriopheophytin. The observation of spin polarized 15N nuclei in bacteriochlorophyll and bacteriopheophytin was previously demonstrated with nonspecifically 15N-labeled reaction centers. Both the carbon and the nitrogen NMR studies indicate that the polarization is developed on species that carry unpaired electrons in the early electron transfer steps, including the bacteriochlorophyll dimer donor P860 and probably the bacteriopheophytin acceptor. I. Both enhanced-absorptive and emissive polarization were seen in the carbon spectrum; most lines were absorptive but the methine carbons of the porphyrin ring (alpha, beta, gamma, ) exhibited emissive polarization. The change in the sign of the hyperfine coupling at these sites indicates the existence of nodes in the spin density distribution on the tetrapyrrole cofactors flanking each methine carbon bridge.

Journal Article↗
PubMed1996

The age-related decline in female fecundity: a quantitative controlled study of implanting capacity and survival of individual embryos after in vitro fertilization.

OBJECTIVE: To determine strictly comparable rates per embryo of implantation and birth of a baby related to the woman's age, which would be representative of natural fertility at least in relative terms. DESIGN: Comparative study of IVF-ET results controlling for confounding variables including cause and duration of infertility, history of previous pregnancy, hormonal treatment, rank cycle of treatment, and numbers of embryos transferred and available. SETTING: University comprehensive fertility service. PATIENTS: All couples (n = 561) in their first cycle of treatment reaching oocyte collection, women with normal uterus and ovulatory cycles, and men with normal sperm. INTERVENTIONS: Standardized methods of pituitary desensitization, ovarian stimulation, and IVF-ET, and maximum of three embryos transferred. MAIN OUTCOME MEASURES: Oocytes, pregnancies, and live births per cycle; fertilization and cleavage rates; embryo implantation and live baby rates. RESULTS: The numbers of oocytes and consequent embryos declined with age but fertilization and cleavage rates rose slightly. Embryo implantation rates were reduced when no more than three embryos were available (9.3 percent), especially in women aged 35 to 39 years (6.2 percent) or older compared with four or more embryos (17.1 percent) but were equally low in all women over 40 years even with more embryos (6.1 percent). In the age bands 25 to 29, 30 to 34, 35 to 39, and 40 to 44 years, the rates per embryo of implantation were 18.2 percent, 16.1 percent, 15.3 percent, and 6.1 percent, respectively, and of a live baby were 15.7 percent, 12.1 percent, 12.0 percent, and 3.5 percent. CONCLUSIONS: Embryo implanting ability and survival decline gradually after 30 years of age, but by more than two thirds after 40 years and in younger women with reduced ovarian capacity.

Adult↗
PubMed1996

Hydrogen bonding effects on amine rotation rates in crystalline amino acids.

Rates of rotation for amines in a variety of crystalline environments are reported, and the trends are explained in terms of the strengths of local hydrogen bonding interactions. Proton spin-lattice relaxation times (T1) and deuterium broad-line NMR spectra have been measured for D-, DL- and L- aspartic acid, two polymorphs of glycine, alanine, and leucine in the temperature range from -40 to 110 degrees C. The energy barriers for amine rotation are 27 +/- 2 kJ mol-1 for D- or L-aspartic acid and 22 +/- 2 kJ mol-1 for DL-aspartic acid; these energies are slightly lower than the previously reported value for the L from based on direct proton T1 measurements at 60 MHz. The values for the alpha and gamma forms of glycine were 24 +/- 2 and 30 +/- 2 kJ mol-1 respectively, that for L-alanine was 40 +/- 2 and that for L-leucine was 49 +/- 3 kJ mol-1. These are all in rough agreement with previously reported values (although the differences for the polymorphs of glycine and for L- vs. DL-aspartic acid were not reported). Crystal structures of these amino acids indicate differences in hydrogen bonding environments around the R-NH3+ groups that are probably responsible for the different activation barriers. A molecular mechanics calculation of the rotation energy barriers for L- and DL-aspartic acid based on the crystal structures gave satisfactory agreement with experimental results if a uniform (and arbitrarily chosen) dielectric constant of 2.5 was assumed. Differences between L- and DL-aspartic acids and between two polymorphs of glycine were well represented qualitatively. Including additional neighboring molecules not involved in the hydrogen bonding or including periodic boundary conditions to describe the crystal packing did not significantly affect these results. If vacuum dielectric constants are used, the barriers are uniformly overestimated, and if the experimental macroscopic dielectric constant values are used, the barriers are generally underestimated. Dielectric constants differ substantially from one amino acid to another and significantly affect the estimated barriers; in fact, the bulk dielectric constants appear to be the major difference between the highest and the lowest values. The difficulty of accurately including dielectric relaxation into molecular mechanics calculations resulted in the disagreement between experimental measurements and theoretical calculations.

Amines↗