Biomedical subjects

P S Albert

Publications and source records attributed to P S Albert.

At least 19 recordsLinked to original sources

PubMed1998

A two-state Markov chain for heterogeneous transitional data: a quasi-likelihood approach.

Many chronic diseases are measured by repeated binary data where the scientific interest is on the transition process between two states of disease activity. Examples include: depression; schizophrenia; multiple sclerosis, and respiratory illness. The course for many of these diseases is inherently heterogeneous, making it difficult to make inference on the transition process. This paper presents a model that incorporates heterogeneity by allowing the transition probabilities to vary randomly across subjects. In the proposed quasi-likelihood formulation for a two-state Markov chain, only the first two moments of the bivariate distribution on the transition probabilities are specified, and we develop a generalized estimating equations (GEE) approach for estimating the mean and variance of this distribution. In addition to estimating the model parameters, we discuss the estimation of derived quantities of the transition matrix such as estimating the expected first passage times and we discuss how we can introduce covariate dependence into the model. We use this methodology to summarize the transitioning pattern of respiratory illness in a group of children with intra-uteral growth retardation, and we conduct a simulation to investigate the finite sample properties of our procedure and to demonstrate marked bias if heterogeneity is ignored.

Chronic Disease↗

PubMed1998

Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans.

The nematode Caenorhabditis elegans responds to overcrowding and scarcity of food by arresting development as a dauer larva, a nonfeeding, long-lived, stress-resistant, alternative third-larval stage. Previous work has shown that mutations in the genes daf-2 (encoding a member of the insulin receptor family) and age-1 (encoding a PI 3-kinase) result in constitutive formation of dauer larvae (Daf-c), increased adult longevity (Age), and increased intrinsic thermotolerance (Itt). Some daf-2 mutants have additional developmental, behavioral, and reproductive defects. We have characterized in detail 15 temperature-sensitive and 1 nonconditional daf-2 allele to investigate the extent of daf-2 mutant defects and to examine whether specific mutant traits correlate with each other. The greatest longevity seen in daf-2 mutant adults was approximately three times that of wild type. The temperature-sensitive daf-2 mutants fell into two overlapping classes, including eight class 1 mutants, which are Daf-c, Age, and Itt, and exhibit low levels of L1 arrest at 25.5 degrees. Seven class 2 mutants also exhibit the class 1 defects as well as some or all of the following: reduced adult motility, abnormal adult body and gonad morphology, high levels of embryonic and L1 arrest, production of progeny late in life, and reduced brood size. The strengths of the Daf-c, Age, and Itt phenotypes largely correlated with each other but not with the strength of class 2-specific defects. This suggests that the DAF-2 receptor is bifunctional. Examination of the null phenotype revealed a maternally rescued egg, L1 lethal component, and a nonconditional Daf-c component. With respect to the Daf-c phenotype, the dauer-defective (Daf-d) mutation daf-12(m20) was epistatic to daf-2 class 1 alleles but not the severe class 2 alleles tested. All daf-2 mutant defects were suppressed by the daf-d mutation daf-16(m26). Our findings suggest a new model for daf-2, age-1, daf-12, and daf-16 interactions.

Adaptation, Physiological↗

PubMed1997

Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure.

MRI is a valuable tool to examine the pathophysiology and natural history of multiple sclerosis (MS), and several large multicenter trials have utilized MRI as a secondary outcome measures. We previously examined the effect of interferon beta-1b on contrast-enhancing lesions on MRI using a baseline versus treatment design, and found that on treatment there is a reduction in mean frequency of enhancing lesions over the group. Using an expanded number of patients and the same trial design, we examined the individual response to treatment more extensively. We find that the effect seen previously is still present, and that there is heterogeneity in the amount of decrease in contrast-enhancing lesions. This expanded number of patients and trial design allows for the discussion of new criteria for individual response to treatment, which are applied in the current trial. These approaches may be useful in the examination, early testing, and comparison of experimental therapeutic agents in MS as well as in the characterization of patients who do or do not have a response seen on MRI.

Adjuvants, Immunologic↗

PubMed1997

A latent process regression model for spatially correlated count data.

This paper proposes a regression model for spatially correlated count data that generalizes the work of Zeger (1988, Biometrika 75, 621-629) developed in a time-series setting. In this approach, spatial correlation is introduced through a latent process, and the marginal mean function may contain spatial trends and covariates. Generalized estimating equations are used to estimate and perform marginal inference on the spatial trend and covariate effects. The feasibility of this approach is demonstrated using an example of the distribution of neuronal cell counts in a laboratory culture dish.

Animals↗

PubMed1997

A generalized estimating equation approach for modeling random length binary vector data.

A common measure in clinical trials and epidemiologic studies is the number of events such as seizures, hospitalizations, or bouts of disease. Frequently, a binary measure of severity for each event is available but is not incorporated in the analysis. This paper proposes methodology for jointly modeling the number of events and the vector of correlated binary severity measures. Our formulation exploits the notion that a given covariate may affect both outcomes in a similar way. We functionally link the regression parameters for the counts and binary means and discuss a generalized estimating equation (GEE) approach for parameter estimation. We discuss conditions under which the proposed joint modeling approach provides marked gains in efficiency relative to the common procedure of simply modeling the counts, and we illustrate the methodology with epilepsy clinical trial data.

Anticonvulsants↗

PubMed1996

Control of C. elegans larval development by neuronal expression of a TGF-beta homolog.

The Caenorhabditis elegans dauer larva is specialized for dispersal without growth and is formed under conditions of overcrowding and limited food. The daf-7 gene, required for transducing environmental cues that support continuous development with plentiful food, encodes a transforming growth factor-beta (TGF-beta) superfamily member. A daf-7 reporter construct is expressed in the ASI chemosensory neurons. Dauer-inducing pheromone inhibits daf-7 expression and promotes dauer formation, whereas food reactivates daf-7 expression and promotes recovery from the dauer state. When the food/pheromone ratio is high, the level of daf-7 mRNA peaks during the L1 larval stage, when commitment to non-dauer development is made.

Amino Acid Sequence↗

PubMed1996

Environmental induction and genetic control of surface antigen switching in the nematode Caenorhabditis elegans.

Nematodes can alter their surface coat protein compositions at the molts between developmental stages or in response to environmental changes; such surface alterations may enable parasitic nematodes to evade host immune defenses during the course of infection. Surface antigen switching mechanisms are presently unknown. In a genetic study of surface antigen switching, we have used a monoclonal antibody, M37, that recognizes a surface antigen on the first larval stage of the free-living nematode Caenorhabditis elegans. We demonstrate that wild-type C. elegans can be induced to display the M37 antigen on a later larval stage by altering the growth conditions. Mutations that result in nonconditional display of this antigen on all four larval stages fall into two classes. One class defines the new gene srf-6 II. The other mutations are in previously identified dauer-constitutive genes involved in transducing environmental signals that modulate formation of the dauer larva, a developmentally arrested dispersal stage. Although surface antigen switching is affected by some of the genes that control dauer formation, these two process can be blocked separately by specific mutations or induced separately by environmental factors. Based on these results, the mechanisms of nematode surface antigen switching can now be investigated directly.

Animals↗

PubMed1996

Relationship between sleep and mood in patients with rapid-cycling bipolar disorder.

The relationship between sleep and mood was examined in a longitudinal, naturalistic data set derived from out-patients with rapid-cycling bipolar disorder. Eleven patients completed daily self-ratings of mood and sleep logs for 18 months. Using logistic regression with autoregressive terms, we examined the effect of prior sleep (sleep duration, time of sleep onset, and time of wake onset) on the probability of being in a depressed, manic, or hypomanic episode on one or more subsequent days. Of the three sleep parameters, decreased sleep duration was the best predictor of mania or hypomania the next day, followed by wake onset time. The association between sleep duration and subsequent mood was less consistent for depression than for mania or hypomania. Four of the patients showed no relationship between mood and any of the sleep variables measured. These results reinforce the importance of monitoring, and perhaps controlling, sleep duration and wake onset time in at least some patients with rapid-cycling bipolar disorder.

Adult↗

PubMed1996

Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force.

Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.

Clinical Trials as Topic↗

PubMed1995

Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis.

T cell activation requires both Ag/MHC recognition and costimulatory signals. The present studies were designed to test whether the loss of tolerance to myelin basic protein (MBP) requires costimulation by members of the B7 receptor family. CTLA-4Ig, a fusion protein ligand for B7-1 and B7-2, was used to assess the role of B7-mediated costimulation in chronic relapsing experimental allergic encephalomyelitis (EAE) induced by the transfer of MBP specific T cell lines. In adoptively transferred EAE, administering CTLA-4Ig to donor mice or during in vitro activation of MBP specific-T cells resulted in diminution of clinical disease. The presence of CTLA-4Ig during both the immunization and in vitro activation stages was most effective in preventing clinical signs of disease. This diminution in clinical disease was paralleled by a decreased proliferative response and reduced production of IL-2 and IL-4, but not IFN-gamma, after antigenic stimulation of encephalitogenic T cells in vitro. In contrast, CTLA-4Ig treatment of recipient animals after the transfer of MBP-activated T cells affected neither disease course nor severity. These results indicate that additional costimulatory pathways may be involved in established EAE, or that some cells are independent of costimulation or, alternatively, that CTLA-4Ig does not enter brain parenchyma in therapeutic concentrations. Thus, we conclude that costimulation provided by B7 molecules plays a major role in the development of encephalitogenic T cells and in the establishment of chronic relapsing EAE, a prototypic CD4+ T cell-mediated autoimmune disease.

Abatacept↗

PubMed1995

Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelination. Retinoids regulate cell differentiation and growth by binding to and activating retinoic acid receptors, which seem to be nuclear transcription factors. The effect of retinoids on chronic relapsing EAE produced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MBP-specific LNC activation resulted in a considerable increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-gamma was decreased. Increased IL-4 also was detected in culture supernatants. However, the presence of a neutralizing Ab to IL-4 (11B11) during MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given after disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 phenotype, which, in turn, might be responsible for the decrease in the encephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which the protective cytokines of Th2-like cells predominate may have potential relevance for human demyelinating diseases such as multiple sclerosis.

Animals↗

PubMed1995

The effect of interferon-beta on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis.

Magnetic resonance imaging (MRI) has been a valuable tool to understand the pathophysiology and natural history of multiple sclerosis (MS), and increasing attention is focusing on the use of MRI findings as outcome measures in treatment trials in MS. The recently completed trial of interferon-beta-1b (IFN-beta 1b) demonstrated a decrease in accumulation of diseased tissue on T2-weighted images and a reduction in new lesions on T2-weighted images. To examine the effect of IFN-beta 1b on blood-brain barrier (BBB) breakdown, and to provide additional insights into the usefulness of MRI in the evolution of effectiveness of experimental treatments in MS, we used the contrast-enhanced lesion frequency of 7-month baseline MRIs compared with the enhanced lesion frequency for 6-month treatment period MRIs in 14 relapsing-remitting (RR) MS patients. Longer baselines were also available for analysis in a subset of 8 patients, as these patients had been followed by monthly MRI in a natural history study for up to 4 years prior to the current study. A significant reduction in the total or new enhancing lesion frequency was detected in the patients analyzed as a whole, and 13 of 14 of the patients demonstrated a reduction in enhancing lesion frequency on treatment over the 6 months studied. These findings suggest that IFN-beta has a mechanism of action that at least temporarily inhibits the opening of the BBB in RRMS patients. This trial also illustrates the usefulness of a baseline versus treatment trial design to evaluate the effect of drug therapy in MS.

Adult↗

PubMed1995

Genes that regulate both development and longevity in Caenorhabditis elegans.

The nematode Caenorhabditis elegans responds to conditions of overcrowding and limited food by arresting development as a dauer larva. Genetic analysis of mutations that alter dauer larva formation (daf mutations) is presented along with an updated genetic pathway for dauer vs. nondauer development. Mutations in the daf-2 and daf-23 genes double adult life span, whereas mutations in four other dauer-constitutive genes positioned in a separate branch of this pathway (daf-1, daf-4, daf-7 and daf-8) do not. The increased life spans are suppressed completely by a daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.

Animals↗

PubMed1995

Changes in the amount of diseased white matter over time in patients with relapsing-remitting multiple sclerosis.

MRI is a sensitive technique for assessing disease activity in MS. Diseased white matter (WM) can be identified on T2-weighted images, and active disease is reflected by abnormalities in the blood-brain barrier (BBB) shown on T1-weighted images after administration of paramagnetic contrast agents. Active disease may be demonstrated by contrast-enhanced MRI in patients with early, mild relapsing-remitting (RR) MS even during periods of clinical stability, which indicates that MS is an active process even during the early phase of the illness. To examine the amount of abnormal WM at frequent intervals over time, we studied seven mildly affected RRMS patients, all of whom had frequent contrast-enhancing lesions. These RRMS patients were imaged monthly for 26 to 36 months at 1.5 tesla; the area of abnormal increased WM signal was calculated by image-processing software that utilizes both the T2- and T1-weighted images. All patients showed fluctuations over time in amount of abnormal WM signal, which reflected factors such as the amount of BBB breakdown (measured by number or area of enhancing lesions) and measurement error. All seven RRMS patients, however, showed an overall increase in abnormal WM. Because of the fluctuations between individual measurements, the increase was most accurately reflected when the mean of the first 6 months' measurements was compared with the mean of the final 6 months' measurements, or when a linear regression model was applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: relationship to course, gender, and age.

MRI has provided insight into the pathophysiology and course of MS, particularly through the use of a paramagnetic contrast agent that allows visualization of blood-brain barrier (BBB) breakdown. Neither the overall frequency of BBB breakdown in MS patients nor the characteristics associated with BBB breakdown in MS are known. We studied 68 relapsing-remitting MS (RRMS) patients with three monthly MRIs to examine these questions. Seventy-eight percent of the RRMS patients studied had evidence of BBB breakdown on at least one MRI. While there was a great deal of variability among patients in terms of mean enhancing lesion frequency, BBB breakdown was associated with younger age at onset of disease, measured by age at first symptom or age at diagnosis, and more severe disease as measured by Expanded Disability Status Scale scores equal to or greater than 4.0. We found no relationship between BBB breakdown and duration of disease or gender. We conclude that BBB breakdown is a relatively common phenomenon in RRMS patients and may be most commonly found in patients with more aggressive disease and younger onset. These findings have implications for clinical trials that use MRI as an outcome measure.

Adolescent↗

PubMed1995

A generalized estimating equations approach for spatially correlated binary data: applications to the analysis of neuroimaging data.

This paper proposes a generalized estimating equations approach for the analysis of spatially correlated binary data when there are large numbers of spatially correlated observations on a moderate number of subjects. This approach is useful when the scientific focus is on modeling the marginal mean structure. Proper modeling of the spatial correlation structure is shown to provide large efficiency gains along with precise standard error estimates for inference on mean structure parameters. Generalized estimating equations for estimating the parameters of both the mean and spatial correlation structure are proposed. The use of semivariogram models for parameterizing the correlation structure is discussed, and estimation of the sample semivariogram is proposed as a technique for choosing parametric models and starting values for generalized estimating equations estimation. The methodology is illustrated with neuroimaging data collected as part of the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank. A simulation study demonstrates the importance of accurate modeling of the spatial correlation structure in data with large numbers of spatially correlated observations such as those found in neuroimaging studies.

Brain↗

PubMed1994

HLA restriction and TCR usage of T lymphocytes specific for a novel candidate autoantigen, X2 MBP, in multiple sclerosis.

Previous investigations of the major 18.5-kDa isoform of myelin basic protein (MBP) as a target autoantigen in multiple sclerosis (MS) have failed to identify an epitope uniformly recognized with higher frequency in MS patients compared with controls. Because remyelination has been observed in MS plaques, we were prompted to investigate T cells specific for myelin protein isoforms with up-regulated expression during remyelination. We have recently described such T cells that recognize the exon 2-encoded region of MBP (X2 MBP), a sequence included in the 21.5- and 20.2-kDa isoforms of MBP. These cells were shown to be CD4+, HLA class II restricted, and cytolytic. In members of one multiplex MS family, X2 MBP-specific T lymphocytes were as prevalent as T cells specific for immunodominant regions within the major 18.5-kDa isoform of MBP. The present study characterizes X2 MBP-specific T cell responses in additional multiplex MS family members as well as in heterogeneous (non-familial) MS patients and in healthy controls. The frequencies of X2 MBP-specific T cells in each of the affected family members from two of three MS families were significantly increased as compared with both the heterogeneous MS group and the healthy control group. Also, X2 MBP-specific T cell lines from affected family members were primarily restricted to molecules encoded by the DR2/DQw1 allele. Although TCR usage was generally heterogeneous, there was evidence of intraindividual sequence identity. These data suggest that: 1) Myelin proteins with up-regulated expression during the course of disease should be considered as candidate autoantigens in MS. 2) The functional basis for the association of DR2/DQw1 inheritance with MS susceptibility may be related to presentation of autoantigens by this allele. 3) TCR therapy will need to be individually tailored to target the most prevalent autoantigen-specific response.

Adult↗

PubMed1994

Serial contrast-enhanced magnetic resonance imaging in patients with early relapsing-remitting multiple sclerosis: implications for treatment trials.

Serial monthly contrast-enhanced MRIs were performed in 10 early relapsing-remitting patients with multiple sclerosis and 2 patients with chronic progressive disease for a period of 12 to 55 months. MRI was performed at 1.5 T using contiguous 5-mm slices with pre- and postgadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) T1-weighted and T2-weighted images. New and total number of Gd-DTPA-enhancing lesions were numbered and counted and lesion areas were correlated to an increase of > or = 0.5 in Expanded Disability Status Scale (EDSS) scores. The frequency of enhancing lesions varied from patient to patient; however, there was a correlation between a burst of enhancing lesion number and area above the individual's mean lesion frequency to an increase in EDSS score. A bootstrap analysis of the lesion count was performed to develop a statistical basis for determining population sizes for treatment trials. These results provide a basis for the potential use of contrast-enhanced MRI as a primary outcome measure in phase II treatment trials involving patients with relapsing-remitting MS.

Adult↗