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Biomedical subjects

R G Miller

Publications and source records attributed to R G Miller.

At least 73 records · Page 4Linked to original sources
PubMed1998

Muscle fiber type-specific myofibrillar actomyosin Ca2+ ATPase activity in multiple sclerosis.

Biopsies of tibialis anterior muscle were analyzed to determine if increased energy demand of contraction, as indirectly reflected by myofibrillar actomyosin Ca2+ ATPase (qATPase) activity, contributes to symptomatic fatigue in multiple sclerosis (MS). qATPase activity showed a fiber-type effect, IIax > IIa > I. Fiber-type qATPase activity, however, was not different between MS patients and healthy controls. We suggest that fatigue in MS does not reflect increased energy demand of contraction.

Calcium↗
PubMed1998

Functional significance of upper and lower motor neuron impairment in amyotrophic lateral sclerosis.

The objective of this study was to examine the contribution of lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction to weakness and impaired motor control in 27 patients with amyotrophic lateral sclerosis (ALS). Isometric strength was measured by dorsiflexor maximum voluntary contraction force (MVC). LMN function was measured by tetanic force, twitch force, and the amplitude of the compound muscle action potential. UMN function was measured by the speed of rapid foot taps, the maximum rate of rise of voluntary force, and the central activation ratio [CAR = MVC/(MVC + superimposed tetanic force)]. The results suggest that (1) LMN loss appears to be the primary cause of progressive weakness in ALS; while (2) UMN impairment in ALS leads to slowing of contraction speed and rapid movements, and modest decreases in central activation; and (3) during 6 months of progression, LMN changes were greater than UMN changes.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Application of solubility parameter theory to dentin-bonding systems and adhesive strength correlations.

The principal aim of this study was to investigate the relationships between the solubility parameters of ectched dentin, and adhesive primer solutions and adhesive bond strength. Solubility parameters characterize the molecular interactions which determine physical properties such as wetting, and thus can serve as tools to aid development of polymeric adhesives and interpenetrating polymer networks. If an adhesive monomer has a solubility parameter close to that of a polymer substrate, then the monomer may act as a solvent for the polymer and penetrate below the surface. Subsequent polymerization of the monomer may then produce an interpenetrating network, thus adhering without necessarily forming primary chemical bonds to the substrate. The dentin substrate considered in this study was abraded dentin treated with ethylenediaminetetraaceitc acid. Solubility parameters delta pr, delta h, and delta d calculated for the etched dentin substrate were 20.3, 23.6, and 16.0 (J/cm3)1/2, respectively. Solubility parameters of the primers were expressed using Hansen's three-dimensional scheme. The data indicate a correlation between the calculated solubility parameters of the etched dentin, and dentin primers and the resulting bond strengths. The results corroborate the significance of solubility parameter considerations for adhesive bonding to dentin.

Acid Etching, Dental↗
PubMed1998

Quality of life for ventilator-dependent ALS patients and their caregivers.

Seven ventilator-dependent ALS patients and eleven caregivers were interviewed in order to assess the impact of ventilator-dependence on patients and their families. The ALS Care Database questionnaires were administered with special attention to components derived from the Health Status Survey (SF-12) and ALS Quality-of-Life Index (ALSQLI) as well as the ALS Patient Caregiver Form. Six patients had difficulty communicating and one patient was totally unable to communicate. Patients had maximal limitation of daily activities as measured by The ALS QLI, yet a self-reported satisfactory quality-of-life. Caregivers were heavily burdened and their outside activities were severely limited.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Toward earlier diagnosis of amyotrophic lateral sclerosis: revised criteria. rhCNTF ALS Study Group.

We modified the World Federation of Neurology (WFN) diagnostic criteria for ALS to facilitate early diagnosis and used these criteria for enrollment of ALS patients in a clinical trial. The criteria developed required lower motor neuron (LMN) involvement in at least two limbs and upper motor neuron involvement in at least one region (bulbar, cervical, or lumbosacral). The EMG finding of fibrillation potentials was required for evidence of LMN involvement. Electrodiagnostic studies, neuroimaging, and laboratory studies were also used to exclude disorders that might mimic ALS. Using these criteria, the diagnosis of ALS was made at a mean time of 9.7 months from onset of symptoms, which compares favorably with the 12-month period cited in the literature. Using clinical assessment at completion of the trial, the diagnosis of ALS was believed to be accurate in those patients entered in the trial. However, pathologic confirmation of the diagnosis of ALS was not obtained. Based on our preliminary experience, we propose that these ALS diagnostic criteria will facilitate early diagnosis of ALS. Future studies should prospectively compare these criteria with the WFN criteria currently in use.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS.

The primary objectives of this study were to test whether 1) N-acetylaspartate (NAA), a neuronal marker, is reduced in motor cortex and corticospinal-tract (CST) brain regions of ALS patients; and 2) motor cortex NAA correlates to a clinical measurement of upper motor neuron function in ALS patients. Ten probable or definite ALS patients and nine neurologically normal control subjects were studied. Three axial planes of two-dimensional 1H MRSI data were collected, using a single spin-echo multislice sequence (TE140/TR2000). Two of the 1H MRSI planes were positioned superior to the lateral ventricles, and one plane was positioned at the level of the internal capsule. Spectroscopy voxels were selected from motor cortex, frontal cortex, parietal cortex, medial gray matter, centrum semiovale white matter, anterior internal capsule, and posterior internal capsule. Peak integrals were obtained for the three major 1H MRSI singlet resonances, NAA, creatine and phosphocreatine (Cr), and cholines (Cho). Maximum finger-tap rate was used as a clinical measurement of upper motor neuron function. In ALS, brain NAA/(Cho+Cr) was reduced 19% (p=0.024) in the motor cortex and 16% (p=0.021) in the CST (centrum semiovale and posterior internal capsule) regions. NAA/ (Cho+Cr) was not reduced in frontal cortex, parietal cortex, medial gray matter, or anterior internal capsule. There was a significant relation between ALS motor cortex NAA/(Cho+Cr) and maximum finger-tap rate (r=0.80; p=0.014). NAA/(Cho+Cr) was reduced in motor cortex and CST regions and unchanged in other brain regions of ALS patients when compared with controls. These findings are consistent with the known distribution of neuronal loss in ALS. The positive correlation between motor cortex NAA/(Cho+Cr) and maximum finger-tap rate suggests that reduced NAA/(Cho+Cr) is a surrogate marker of motor cortex neuron loss in ALS. These findings support the study of 1H MRSI NAA measurement as an objective and quantitative measurement of upper motor neuron dysfunction in ALS.

Adult↗
PubMed1998

Comprehensive management of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease that poses a myriad of clinical problems. Patients with ALS are best treated in a multidisciplinary setting involving physicians, clinical nursing specialists, and physical, occupational, speech, and respiratory therapists, as well as psychologists and social workers. Palliative and rehabilitative strategies may ease suffering, while new treatments provide hope for effective treatment of this disease.

Algorithms↗
PubMed1997

Mouse natural killer subsets defined by their target specificity and their ability to be separately rendered unresponsive in vivo.

NK cells from F1(AxB) hybrid mice are known to reject bone marrow grafts from either parent A or parent B (hybrid resistance). Using cold target competition in an in vitro hybrid resistance assay, we demonstrate in this work that parent A and parent B are killed by different NK subsets. As confirmation of the existence of these subsets, and to determine whether they undergo a selection/education process during NK cell ontogeny, we constructed bone marrow chimeras in which NK1.1-depleted bone marrow cells from F1 mice were allowed to mature in the microenvironment of either parent A or parent B. These F1-reconstituted chimeras were shown to have normal NK cell numbers and lytic ability in terms of YAC-1 killing and Ab-mediated redirected lysis. Using a three-color flow cytometry analysis in an in vivo hybrid resistance assay, we found that A targets, but not B targets, were less effectively removed by the F1 NK cells that develop in an A recipient (F1-->A chimeras) than in normal F1 or F1-->F1 chimeric mice. IL-2-activated killer cultures of cells from these chimeras, however, did not show a significant difference in the anti-parent killing response in an in vitro assay. These results suggest that NK cells exist in subsets and that self-reactive NK subsets can be rendered unresponsive by radioresistant host element(s). However, this unresponsiveness can be broken when the NK cells are removed from the in vivo environment.

Animals↗
PubMed1997

Myoblast implantation in Duchenne muscular dystrophy: the San Francisco study.

We evaluated myoblast implantation in 10 boys with Duchenne muscular dystrophy (DMD) and absent dystrophin (age 5-10 years) who were implanted with 100 million myoblasts in the anterior tibial muscle of one leg and placebo in the other. Cyclosporine (5 mg/kg/day) was administered for 7 months. Pre- and postimplantation (after 1 and 6 months) muscle biopsies were analyzed. Force generation (tetanic tension and maximum voluntary contraction) was measured monthly in a double-blind design. There was increased force generation in both legs of all boys, probably due to cyclosporine. Using the polymerase chain reaction, evidence of myoblast survival and dystrophin mRNA expression was obtained in 3 patients after 1 month and in 1 patient after 6 months. These studies suggest a salutary effect of cyclosporine upon muscular force generation in Duchenne muscular dystrophy; however, myoblast implantation was not effective in replacing clinically significant amounts of dystrophin in DMD muscle.

Adult↗
PubMed1997

Reliability of maximal voluntary isometric contraction testing in a multicenter study of patients with amyotrophic lateral sclerosis. Syntex/Synergen Neuroscience Joint Venture rhCNTF ALS Study Group.

Maximal voluntary isometric contraction (MVIC) is becoming widely used for monitoring disease progression in amyotrophic lateral sclerosis (ALS). We evaluated the variability of MVIC in a large multicenter (29 sites) drug trial in ALS. Intra- and interrater variability were assessed twice during the 19-month study. Intrarater reliability increased from the first to the second test, approaching the reliability reported for a single experienced clinical evaluator, but interrater reliability did not. Multiple clinical evaluators in a single site increased the variability of MVIC measurements. Rigorous quality assurance standards and monitoring of clinical evaluators should be incorporated into the design of multicenter studies using MVIC, since low variability is necessary to detect a modest treatment effect.

Adult↗
PubMed1997

Central motor drive is increased during voluntary muscle contractions in multiple sclerosis.

To test the hypothesis that central motor drive is increased during voluntary contractions in multiple sclerosis (MS) patients, we recorded the surface electromyogram (EMG) and force from the tibialis anterior muscle during isometric dorsiflexion in 14 MS and 18 control subjects. Measurements were obtained during contractions at 10-100% of maximal voluntary contraction (MVC), incremented by 10% MVC. Integrated EMG (% maximum) was elevated in MS compared to controls from 10 to 70% MVC (pairwise, P < 0.05; main effect, P=0.001). MS severity (Expanded Disability Status Scale) was highly correlated to the individual slopes of the EMG/force relationship (r=-0.87, P < 0.001). We conclude that central motor drive in MS is increased throughout a large range of submaximal contractions and that this increase is associated with overall disease severity.

Adult↗
PubMed1997

Stable isotopic quantitation of protein metabolism and energy expenditure in neonates on- and post-extracorporeal life support.

It is generally assumed that extracorporeal life support (ECLS) provides a metabolic "rest state" by replacing approximately 80% of cardiopulmonary work. The aim of this study was to precisely quantify neonatal energy expenditure (EE) and whole-body protein metabolism on (during) and post (after) venoarterial ECLS using stable isotope tracer techniques. Nine parenterally fed neonates on-ECLS were studied at 7.8 +/- 1.0 days of life (mean +/- SE), five of which were studied post-ECLS on 27.0 +/- 5.4 days of life. EE and whole-body protein metabolism were quantified using a primed, continuous infusion of L-[1-(13)C]leucine and NaH13CO3. The neonates studied on- and post-ECLS had similar rates of endogenous leucine flux (370 +/- 46 micromol/kg/h v 339 +/- 76 micromol/kg/h), leucine oxidation (161 +/- 22 micromol/kg/h v 121 +/- 25 micromol/kg/h), nonoxidative disposal rates of leucine (313 +/- 37 micromol/kg/h v 331 +/- 75 micromol/kg/h), net protein balance (-2.31 +/- 0.8 g/kg/d v -0.33 +/- 1.1 g/kg/d), and EE (88.6 +/- 7.7 kcal/kg/d v 84.3 +/- 9.2 kcal/kg/d). These results demonstrate that neonates on-ECLS are in hypermetabolic and protein catabolic states that continue in the post-ECLS phase. The authors conclude that ECLS does not provide a metabolic "rest state."

Carbon Dioxide↗
PubMed1997

Does extracorporeal membrane oxygenation benefit neonates with congenital diaphragmatic hernia? Application of a predictive equation.

The overall survival of neonates with congenital diaphragmatic hernia (CDH) remains poor despite the advent of extracorporeal membrane oxygenation (ECMO). Attempts at accurately predicting survival have been largely unsuccessful. The purpose of this study was twofold: (1) to identify independent predictors of survival from a cohort of CDH neonates treated at the authors' institution when ECMO was not available and combine them to form a predictive equation, and (2) to apply the equation prospectively in a cohort of CDH neonates, treated at the same institution when ECMO was available, to determine whether ECMO improves outcome. From the clinical data of 62 CDH neonates treated at the authors' center by the same team of university neonatologists and pediatric surgeons between 1983 and 1993 (before ECMO availability), 15 preoperative and seven operative variables were selected as potential independent predictors. When subjected to multivariate, stepwise logistic regression analysis, four variables were identified as statistically significant (P < .05), independent predictors of survival: (1) ventilatory index (VI), (2) best preoperative PaCO2, (3) birth weight (BW), and (4) Apgar score at 5 minutes. When combined via logistic regression analysis, the following predictive equation was formulated: P (probability of survival to discharge) = [1 + e(x)]-1 where x = 4.9 - 0.68 (Apgar) - 0.0032 (BW) + 0.0063 (VI) + 0.063 (PaCO2). Applying a standard cut-off rate of survival at less than 20%, the equation yielded a sensitivity of 94% and a specificity of 82% in identifying the correct outcome of patients treated with conventional ventilatory management. The overall survival rate was 66%. Since the availability of ECMO at the center, 32 CDH neonates were treated using the same conventional ventilatory treatment and surgical repair by the same university staff. The overall survival rate was 69%. The predictive equation was applied prospectively to all neonates to determine predicted outcome, but was not used to decide the treatment method. Eighteen neonates received conventional therapy alone; 16 of 18 survived (89%). Fifteen of the 16 patients who survived had their outcomes predicted correctly (94%). Fourteen neonates did not respond to conventional therapy and required ECMO; 6 of 14 survived (43%). Six of the eight patients predicted to survive, lived (75%). All six patients predicted to die, died despite the addition of ECMO therapy (100%). The mean hospital cost, per ECMO patient who died, was $277,264.75 +/- $59,500.71 (SE). An odds ratio analysis, using the four independent predictors to standardize for degree of illness, was performed to assess the risk associated with adding ECMO therapy. The result was 1.25 (P = 0.75). Although the cohort was not large enough to eliminate significant beta error, the data strongly suggested no advantage of ECMO. At this center, absolute survival rates for neonates with CDH have not been significantly altered since ECMO has become available (66% v 69%). The authors conclude that the predictive equation remains an accurate measurement of survival at their center even when ECMO is used as a salvage therapy. The method of creating a predictive equation may be applied at any institution to determine the potential outcome of CDH neonates and assess the effect of ECMO, or other salvage therapies, on survival rates.

Decision Support Techniques↗
PubMed1997

Are CD8+ dendritic cells (DC) veto cells? The role of CD8 on DC in DC development and in the regulation of CD4 and CD8 T cell responses.

The CD8-expressing dendritic cells (DC) present in mouse spleen have been shown to have a regulatory effect on the CD4 and CD8 T cells they activate, restricting subsequent T cell proliferation by either inducing apoptotic T cell death (CD4 T cells) or by limiting endogenous cytokine production (CD8 T cells). To determine the role of the CD8 molecule itself in these regulatory phenomena, the DC from CD8 null mice were studied. The DC marker DEC-205 (NLDC 145) was used as a surrogate marker for CD8, since the expression of these two molecules on splenic DC was closely correlated. DC levels were normal, and the incidence of DEC-205+ and DEC-205- DC was normal in CD8 null mice, indicating that the absence of CD8 did not affect DC development. The proliferative response of T cells to allogeneic DEC-205+ DC from either CD8-/- or CD8+/+ mice was similar and was much less than the response to DEC-205- DC from these mice. This applied to both the CD4 and the CD8 T cell responses. Thus the lack of the CD8 molecule did not affect the stimulatory or regulatory properties of the DC. The regulatory CD8+ DEC-205+ DC therefore differ in that respect from antigen-presenting 'veto' cells, where CD8 itself is involved in transmitting negative signals to the T cells. DEC-205 may prove to be a more pertinent marker of the regulatory DC population.

Animals↗
PubMed1997

Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis.

This study examined functional, biochemical, and morphological characteristics of skeletal muscle in nine multiple sclerosis (MS) patients and eight healthy controls in an effort to ascertain whether intramuscular adaptations could account for excessive fatigue in this disease. Analyses of biopsies of the tibialis anterior muscle showed that there were fewer type I fibers (66 +/- 6 vs. 76 +/- 6%), and that fibers of all types were smaller (average downward arrow26%) and had lower succinic dehydrogenase (SDH; average downward arrow40%) and SDH/alpha-glycerol-phosphate dehydrogenase (GPDH) but not GPDH activities in MS vs. control subjects, suggesting that muscle in this disease is smaller and relies more on anaerobic than aerobic-oxidative energy supply than does muscle of healthy individuals. Maximal voluntary isometric force for dorsiflexion was associated with both average fiber cross-sectional area (r = 0.71, P = 0.005) and muscle fat-free cross-sectional area by magnetic resonance imaging (r = 0.80, P < 0. 001). Physical activity, assessed by accelerometer, was associated with average fiber SDH/GPDH (r = 0.78, P = 0.008). There was a tendency for symptomatic fatigue to be inversely associated with average fiber SDH activity (r = -0.57, P = 0.068). The results of this study suggest that the inherent characteristics of skeletal muscle fibers per se and of skeletal muscle as a whole are altered in the direction of disuse in MS. They also suggest that changes in skeletal muscle in MS may significantly affect function.

Adult↗
PubMed1997

Serum IgM monoclonal autoantibody binding to the 301 to 314 amino acid epitope of beta-tubulin: clinical association with slowly progressive demyelinating polyneuropathy.

We identified five patients with IgM monoclonal autoantibodies that bound to human brain tubulin. In a companion study, we found that IgM in these sera selectively recognized one of three epitopes on tubulin. IgM from three patients bound selectively to a small epitope on human beta-tubulin comprising amino acids 301 to 314. The other two sera recognized tubulin amino acids 215 to 235 and 315 to 336. In this study, we compared the clinical syndromes in these patients with the tubulin epitope recognized by their serum IgM. The three patients with IgM binding to tubulin amino acids 301 to 314 all had chronic inflammatory demyelinating polyneuropathy (CIDP) syndromes with slowly progressive weakness, hyporeflexia, and electrophysiologic studies consistent with demyelination. Two of these patients had significant asymmetry to their weakness. The two other patients had diagnoses of polyradiculopathy and amyotrophic lateral sclerosis with no evidence of peripheral nerve demyelination. We conclude that IgM monoclonal anti-tubulin antibodies have some association with demyelinating polyneuropathy syndromes, but may occur in patients with other clinical syndromes as well. A stronger association with demyelinating polyneuropathies may occur if the anti-tubulin antibodies recognize the 301 to 314 amino acid epitope on tubulin. This tubulin epitope, or a similar one on another molecule, could play an important antigenic role in the development of demyelinating polyneuropathies with features of CIDP.

Aged↗