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Biomedical subjects

K P Johnson

Publications and source records attributed to K P Johnson.

At least 19 recordsLinked to original sources
PubMed2006

A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients.

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of 'Withdrawn' patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received > or =1 GA dose since 1991; 'Ongoing' patients (n = 108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to approximately 1 relapse/5 years; median time to > or = 1 EDSS point increase was 8.8 years; mean EDSS change was 0.73 +/- 1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.50 +/- 1.65; 62% were stable/improved; and 24,8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.24 +/- 1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Adult↗
PubMed2005

Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data.

OBJECTIVE: To assess the long-term effectiveness of continuous glatiramer acetate (GA) therapy in relapsing-remitting multiple sclerosis (RRMS). METHODS: This open-label extension followed a randomized, placebo-controlled, double-blind study of GA of approximately 30 months duration. Patients originally randomized to GA continued on it (group A) and those randomized to placebo switched to GA (group B). RESULTS: Of 251 original patients, 142 (56.6%) remained in the study after 8 years. Annual relapse rate for both groups declined to approximately 0.2 (approximately one relapse every 5 years). However, a significantly larger proportion of patients in group A had stable or improved Expanded Disability Status Scale scores compared with group B (65.3% vs 50.4%, respectively; P = 0.0263), possibly attributable to the delay of GA treatment for approximately 30 months in group B. GA was well tolerated and no drug-related laboratory changes were observed. CONCLUSIONS: These data support early initiation of GA therapy as an efficacious and well-tolerated long-term treatment for RRMS patients.

Disability Evaluation↗
PubMed2003

Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial.

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.

Disability Evaluation↗
PubMed2002

Sustained immunological effects of Glatiramer acetate in patients with multiple sclerosis treated for over 6 years.

The availability of a group of multiple sclerosis (MS) patients at the University of Maryland, who had participated in the pivotal Copaxone trial in the early 1990s, provided an opportunity to examine the long-term immunologic effects of Glatiramer acetate (GA) treatment in MS. Forty-eight GA-reactive T-cell lines (TCL) were generated from 10 MS patients who have been receiving GA treatment for 6-9 years. Proliferative responses, cytokine production, and cross-reactivity with myelin basic protein (MBP) and the MBP immunodominant peptide 83-99 were compared to responses obtained from 10 MS patients who were tested pretreatment and after a shorter period of treatment ranging from 1 to 10 months. The results indicate that while long-term treatment with GA results in a 2.9-fold decrease in the estimated precursor frequency of GA-reactive T-cells, the sustained response to GA remains Th2-biased and in part cross-reactive with MBP and MBP (83-99) as measured by proliferation and cytokine release assays. The results indicate that despite a drop in the precursor frequency of GA-reactive T-cells with long-term treatment, the sustained response remains predominantly Th2-biased and cross-reactive with MBP, which is consistent with the anti-inflammatory effects of the drug and bystander suppression.

Biomarkers↗
PubMed2002

Louse (Insecta: Phthiraptera) mitochondrial 12S rRNA secondary structure is highly variable.

Lice are ectoparasitic insects hosted by birds and mammals. Mitochondrial 12S rRNA sequences obtained from lice show considerable length variation and are very difficult to align. We show that the louse 12S rRNA domain III secondary structure displays considerable variation compared to other insects, in both the shape and number of stems and loops. Phylogenetic trees constructed from tree edit distances between louse 12S rRNA structures do not closely resemble trees constructed from sequence data, suggesting that at least some of this structural variation has arisen independently in different louse lineages. Taken together with previous work on mitochondrial gene order and elevated rates of substitution in louse mitochondrial sequences, the structural variation in louse 12S rRNA confirms the highly distinctive nature of molecular evolution in these insects.

Animals↗
PubMed2001

Sexual selection. Are ducks impressed by drakes' display?

Surprisingly few birds have penises, but among those that do, the Argentine lake duck (Oxyura vittata) tops the bill - the penis of this small stifftail duck from South America is shaped like a corkscrew and, at almost half a metre long, is the largest of any bird measured so far. Factors responsible for the evolution of this remarkable organ could include runaway selection, whereby drakes with longer penises gain dominance and copulate with more females, or preference by females for drakes with longer and more decorated penises.

Animals↗
PubMed2001

Current therapy of multiple sclerosis.

The list of medications for both immune modulation and symptomatic relief continues to grow. Ideally, however, drug therapy should be part of a multidisciplinary approach that also includes such elements as patient education and physical therapy.

Adjuvants, Immunologic↗
PubMed2001

Phylogenetic analysis of partial sequences of elongation factor 1alpha identifies major groups of lice (Insecta: Phthiraptera).

As a first attempt to use molecular data to resolve the relationships between the four suborders of lice and within the suborder Ischnocera, we sequenced a 347-bp fragment of the elongation factor 1alpha gene of 127 lice (Insecta: Phthiraptera) as well as outgroup taxa from the order Psocoptera. A number of well-supported monophyletic groups were found but the relationships among many of these groups could not be resolved. While it is probable that multiple substitutions at high divergences and ancient radiation over a short period of time have contributed to the problem, we attribute most of this lack of resolution to the high ratio of taxa to characters. Nevertheless, the sequence data unequivocally support a number of important relationships that are at variance with the conclusions of morphological taxonomy. These include the sister group relationship of Chelopistes and Oxylipeurus, two lice occupying different ecological niches on the same host, which have previously been assigned to different families. These results provide evidence in support of the hypothesis that lice have speciated in situ on the host in response to niche specialization and that this has given rise to convergent morphologies in the lice of different host groups which share similar ecological niches. We discuss our attempts to overcome the limitations of this large data set, including the use of leaf stability analysis, a new method for analyzing the stability of taxa in a phylogenetic tree, and examine a number of hypotheses of relationships based on both traditional taxonomy and host associations.

Animals↗
PubMed2001

Elevated rates of nonsynonymous substitution in island birds.

Slightly deleterious mutations are expected to fix at relatively higher rates in small populations than in large populations. Support for this prediction of the nearly-neutral theory of molecular evolution comes from many cases in which lineages inferred to differ in long-term average population size have different rates of nonsynonymous substitution. However, in most of these cases, the lineages differ in many other ways as well, leaving open the possibility that some factor other than population size might have caused the difference in substitution rates. We compared synonymous and nonsynonymous substitutions in the mitochondrial cyt b and ND2 genes of nine closely related island and mainland lineages of ducks and doves. We assumed that island taxa had smaller average population sizes than those of their mainland sister taxa for most of the time since they were established. In all nine cases, more nonsynonymous substitutions occurred on the island branch, but synonymous substitutions showed no significant bias. As in previous comparisons of this kind, the lineages with smaller populations might differ in other respects that tend to increase rates of nonsynonymous substitution, but here such differences are expected to be slight owing to the relatively recent origins of the island taxa. An examination of changes to apparently "preferred" and "unpreferred" synonymous codons revealed no consistent difference between island and mainland lineages.

Amino Acid Sequence↗
PubMed2001

United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis Study Group and the MRI Analysis Center.

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2,433 +/- 59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

Adult↗
PubMed2001

Molecular systematics of Goniodidae (Insecta: Phthiraptera).

The higher level phylogenetic relationships within the avian feather lice (Insecta: Phthiraptera: Ischnocera) are extremely problematic. Here we investigate the relationships of 1 family (Goniodidae), sometimes recognized as distinct within Ischnocera, using parsimony and likelihood analyses of nuclear and mitochondrial DNA sequences. These data support monophyly for a restricted definition of traditional Goniodidae, but recognition of this family would result in paraphyly of the large heterogeneous family Philopteridae. We show that the New World Chelopistes is not related to other members of Goniodidae, despite similarities in morphology, but rather is the sister taxon to Oxylipeurus. Within Goniodidae, genera are divided into those occurring on Galliformes (the Goniodes complex) and those occurring on Columbiformes (the Coloceras complex). Within the well-sampled Coloceras complex, or Physconelloidinae, several groups are identified. However, traditionally recognized genera such as Coloceras and Phvsconelloides appear to be paraphyletic. Whereas the phylogeny of Goniodidae reflects some aspects of host relationships, biogeography also influences coevolutionary history.

Animals↗
PubMed2001

Novel antineoplastic isochalcones inhibit the expression of cyclooxygenase 1,2 and EGF in human prostate cancer cell line LNCaP.

Experiments were conducted to determine the effects of novel anti-neoplastic isochalcones (DJ compounds), on cyclooxyegenase 1 and 2 (COX-1 and COX-2) enzyme expression in androgen receptor dependent human prostate cancer cell line LNCaP. Results from Western blot analysis and cell flow cytometry showed that DJ52 and DJ53 decreased the steady state levels of COX-1 and COX-2 protein levels in a dose dependent manner. In addition, DJ52 and DJ53 decreased the levels of epidermal growth factor (EGF) in LNCaP cells. In this study, we report that novel isochalcones decreased COX-1, COX-2 and EGF levels as well as LNCaP cellular growth in a dose responsive manner. Our findings indicate that relative decreases in COX-1, COX-2 and EGF expressions might serve as indicators of tumor growth inhibition in prostate neoplasms.

Antineoplastic Agents↗
PubMed2000

Nuclear and mitochondrial genes contain similar phylogenetic signal for pigeons and doves (Aves: Columbiformes).

Molecular systematic studies generally assume that gene trees are reasonable estimates of species trees. We tested the validity of this assumption in the pigeons and doves (Aves: Columbiformes) by comparing phylogenies derived from nuclear (beta-fibrinogen intron 7) and mitochondrial (cytochrome b) genes. Trees derived from the two genes when analyzed separately contained many nodes in common. A partition homogeneity test revealed no significant incongruence between trees derived from the two genes; so, we combined nuclear and mitochondrial data in subsequent phylogenetic analyses. The resulting tree, which was highly resolved and generally well supported, contained a strong biogeographic component. The rate of nucleotide substitution for the nuclear intron was approximately six times slower than that of cytochrome b. This resulted in a much higher consistency index for trees derived from the intron because of the low level of multiple substitution. However, the degree of resolution and support for trees reconstructed from the two genes was similar. We also examined the transition and transversion substitution rates for the genes. Third position transversions for cytochrome b accumulated linearly with intron divergence, suggesting low levels of multiple substitution for third position transversions.

Animals↗
PubMed2000

A phylogenetic study of the malagasy couas with insights into cuckoo relationships.

The avian family Cuculidae (cuckoos) is a diverse group of birds that vary considerably in behaviors of interest to behavioral ecologists, e.g., obligate brood parasitism and cooperative breeding. The taxonomy of this group has historically been relatively stable but has not been extensively evaluated using molecular methods. The goal of this study was to evaluate phylogenetic relationships within the ecologically diverse genus Coua and the placement of Coua among major cuckoo lineages. We sequenced 429 bp of cytochrome b (cyt b) and 522 bp of ND2, both mitochondrial genes, for 26 species of cuckoos spanning 13 genera. We also included the enigmatic hoatzin (Opisthocomus hoazin) and used two Tauraco species as outgroups. ND2 exhibited higher rates of DNA sequence and amino acid substitution than cyt b; however, this did not greatly affect the overall levels of phylogenetic resolution and support provided by these two genes. Combined analyses produced two alternative phylogenies, depending on weighting scheme, both of which were fully resolved and were characterized by high bootstrap support. These phylogenies recovered monophyly for all of the traditional cuckoo subfamilies and indicated, with strong support, that the hoatzin is outside of Cuculidae. Within Coua, an arboreal and a terrestrial clade were identified. In contrast, habitat choice of Coua species did not greatly reflect the phylogeny.

Animals↗
PubMed2000

Genetic and phylogenetic consequences of island biogeography.

Island biogeography theory predicts that the number of species on an island should increase with island size and decrease with island distance to the mainland. These predictions are generally well supported in comparative and experimental studies. These ecological, equilibrium predictions arise as a result of colonization and extinction processes. Because colonization and extinction are also important processes in evolution, we develop methods to test evolutionary predictions of island biogeography. We derive a population genetic model of island biogeography that incorporates island colonization, migration of individuals from the mainland, and extinction of island populations. The model provides a means of estimating the rates of migration and extinction from population genetic data. This model predicts that within an island population the distribution of genetic divergences with respect to the mainland source population should be bimodal, with much of the divergence dating to the colonization event. Across islands, this model predicts that populations on large islands should be on average more genetically divergent from mainland source populations than those on small islands. Likewise, populations on distant islands should be more divergent than those on close islands. Published observations of a larger proportion of endemic species on large and distant islands support these predictions.

Geography↗