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Biomedical subjects

Kenneth Johnson

Publications and source records attributed to Kenneth Johnson.

9 recordsLinked to original sources
PubMed2007

Preventing alcohol-exposed pregnancies: a randomized controlled trial.

BACKGROUND: Prenatal alcohol exposure is a leading preventable cause of birth defects and developmental disabilities in the United States. DESIGN: A randomized controlled trial (2002-2005; data analyzed 2005-2006) of a brief motivational intervention to reduce the risk of an alcohol-exposed pregnancy (AEP) in preconceptional women by focusing on both risk drinking and ineffective contraception use. SETTING/PARTICIPANTS: A total of 830 nonpregnant women, aged 18-44 years, and currently at risk for an AEP were recruited in six diverse settings in Florida, Texas, and Virginia. Combined settings had higher proportions of women at risk for AEP (12.5% overall) than in the general population (2%). INTERVENTIONS: Participants were randomized to receive information plus a brief motivational intervention (n=416) or to receive information only (n=414). The brief motivational intervention consisted of four counseling sessions and one contraception consultation and services visit. MAIN OUTCOME MEASURES: Women consuming more than five drinks on any day or more than eight drinks per week on average, were considered risk drinkers; women who had intercourse without effective contraception were considered at risk of pregnancy. Reversing either or both risk conditions resulted in reduced risk of an AEP. RESULTS: Across the follow-up period, the odds ratios (ORs) of being at reduced risk for AEP were twofold greater in the intervention group: 3 months, 2.31 (95% confidence interval [CI]=1.69-3.20); 6 months, 2.15 (CI=1.52-3.06); 9 months, 2.11 (CI=1.47-3.03). Between-groups differences by time phase were 18.0%, 17.0%, and 14. 8%, respectively. CONCLUSIONS: A brief motivational intervention can reduce the risk of an AEP.

Adult↗
PubMed2006

Structure of the heterotrimeric PCNA from Sulfolobus solfataricus.

PCNA is a ring-shaped protein that encircles DNA, providing a platform for the association of a wide variety of DNA-processing enzymes that utilize the PCNA sliding clamp to maintain proximity to their DNA substrates. PCNA is a homotrimer in eukaryotes, but a heterotrimer in crenarchaea such as Sulfolobus solfataricus. The three proteins are SsoPCNA1 (249 residues), SsoPCNA2 (245 residues) and SsoPCNA3 (259 residues). The heterotrimeric protein crystallizes in space group P2(1), with unit-cell parameters a = 44.8, b = 78.8, c = 125.6 A, beta = 100.5 degrees. The crystal structure of this heterotrimeric PCNA molecule has been solved using molecular replacement. The resulting structure to 2.3 A sheds light on the differential stabilities of the interactions observed between the three subunits and the specificity of individual subunits for partner proteins.

Amino Acid Sequence↗
PubMed2006

A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis.

OBJECTIVE: To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS). METHODS: A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL-12/23 mAb (0.3, 0.75, 1.5, and 3.0 mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration. RESULTS: IL-12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL-12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median Tmax ranged from 9.0 to 16.5 days, and the median T1/2 ranged from 20.2 to 30.9 days. CONCLUSION: Single subcutaneous administrations of IL-12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.

Adult↗
PubMed2006

Glatiramer acetate therapy for multiple sclerosis: a review.

The past decade has witnessed a revolution in the treatment of multiple sclerosis (MS), the most common demyelinating disorder of the human CNS. After being considered as an untreatable disease for more than a century, six disease-modifying treatments have been approved between 1993 and 2006. Glatiramer acetate (GA) is a worldwide drug approved for the treatment of relapsing-remitting MS in 1996. The drug is a synthetic copolymer of four amino acids based on the composition of myelin basic protein, one of several putative autoantigens implicated in the pathogenesis of MS. Three separate double-blind, placebo-controlled trials have established its efficacy in relapsing-remitting MS. Observations from an ongoing study, the longest prospective study in MS therapeutics so far, suggest that the effect of GA in reducing the relapse rate and neurological disability is maintained over a 10-year period. Independent investigators have identified several putative immunological mechanisms of action of GA, with the unique observation of the generation of GA-reactive T-helper 2 (anti-inflammatory) polarised lymphocytes within days to weeks of initiating therapy and sustaining an anti-inflammatory milieu for years in the peripheral immune system and, presumably, in the CNS. Emerging data from immunological and imaging studies quantifying axonal injury in the brain point towards neuroprotective abilities of GA. Combined with its remarkable safety and tolerability, long-term efficacy and neuroprotective effect, GA presents it self as a first-line choice in relapsing-remitting MS, and holds immense promise in developing its potential as a combination therapy in MS, as well as extending its indications to other neurodegenerative diseases.

Glatiramer Acetate↗
PubMed2003

An HIV reverse transcriptase-selective nucleoside chain terminator.

The synthesis of a 2',3'-dideoxynucleoside cytidine analogue, but one that lacks the O2-carbonyl, is described from 2-aminopyridine in an overall yield of 60%. The synthesis of the 2-pyridone C-nucleoside relies upon the use of a Heck-type coupling between an appropriately protected sugar glycal and the 5-iodo derivative of 2-aminopyridone. Upon conversion of the dideoxynucleoside to the corresponding 5'-triphosphate, the analogue ddNTP is observed to be a reasonable substrate with HIV reverse transcriptase (for a template dG residue), but is not a substrate for calf thymus DNA polymerase alpha or for human DNA polymerase beta. With the human mitochondrial DNA polymerase the analogue functions as a poor substrate. The observed polymerase selectivities appear to arise from the absence of the O2-carbonyl, which either results in a destabilized Watson-Crick base pair or represents a critical contact for some polymerases.

Animals↗
PubMed2003

Racial/ethnic diversification in metropolitan and nonmetropolitan population change in the United States: implications for health care provision in rural America.

The diversification of the rural population of the United States provides substantial challenges to the current and to future health care systems in rural areas. Because of a variety of historical, discriminatory, and other factors, minority populations have had lower levels of access to health care in rural as well as urban areas and higher rates of both mortality and morbidity than nonminority populations. Although minority health issues have often been seen as primarily urban issues, this article demonstrates that minority population growth has become a major component of total population growth in rural areas in the past several decades (accounting for nearly 62% of the net growth in the nonmetropolitan population of the United States in the 1980s and for nearly 42% in the 1990s), that future US population growth is likely to be largely a product of minority population growth (nearly 89% of US net population growth from 2000 to 2100 is projected to be due to minority population growth), and that the incidence of diseases and disorders in the US population will come to increasingly involve minority populations (by 2050 roughly 43% of all disease/disorder incidences would involve minority population members). The growth of younger minority populations with disproportionately impoverished socioeconomic characteristics will pose challenges for rural areas and health care systems, which also are likely to face health issues created by disproportionately older populations.

Cultural Diversity↗
PubMed2002

The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons.

Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target. Netrin 1, a bifunctional cue involved in both attracting and repelling axons, is involved in many cell migration and axon pathfinding processes in the CNS. The netrin 1 receptor DCC and its Caenorhabditis elegans homolog UNC-40 have been implicated in directing the guidance of axons toward netrin sources, whereas the C. elegans UNC-6 receptor, UNC-5 is necessary for migrations away from UNC-6. However, a role of vertebrate UNC-5 homologs in axonal migration has not been demonstrated. We demonstrate that the Unc5h3 gene product, shown previously to regulate cerebellar granule cell migrations, also controls the guidance of the corticospinal tract, the major tract responsible for coordination of limb movements. Furthermore, we show that corticospinal tract fibers respond differently to loss of UNC5H3. In addition, we observe corticospinal tract defects in mice homozygous for a spontaneous mutation that truncates the Dcc transcript. Postnatal day 0 netrin 1 mutant mice also demonstrate corticospinal tract abnormalities. Last, interactions between the Dcc and Unc5h3 mutations were observed in gene dosage experiments. This is the first evidence of an involvement in axon guidance for any member of the vertebrate unc-5 family and confirms that both the cellular and axonal guidance functions of C. elegans unc-5 have been conserved in vertebrates.

Animals↗
PubMedDate not supplied

Neurotoxic effects of MDMA ("ecstasy") administration to neonatal rats.

3,4-methylenedioxymethamphetamine damages fine serotonergic fibers and nerve terminals in adult organisms. Developing animals seem to be less susceptible to this effect, possibly due to a lack of drug-induced hyperthermia. We tested this hypothesis by producing hyperthermia in neonatal rats for 2h after each of twice-daily MDMA (10 mg/kg s.c.) or saline injections administered from postnatal days 1-4. Other drug-treated and control litters were maintained at normothermic temperatures following injection. Changes in forebrain serotonergic innervation were assessed at postnatal day 25 (serotonin transporter binding and serotonin levels), postnatal day 60 (serotonin transporter binding), and 9 months of age (serotonin transporter immunohistochemistry). We also determined the influence of MDMA treatment on apoptotic activity by means of immunohistochemistry for cleaved caspase-3 at postnatal day 5. The hippocampus showed significant MDMA-related reductions in serotonergic markers at postnatal day 25 and postnatal day 60. At 9 months, there was no effect of prior MDMA exposure on serotonin transporter-immunoreactive fiber density in the hippocampus; however, significant reductions in fiber density were observed in two neocortical areas and a hyperinnervation was found in the caudate-putamen and nucleus accumbens shell. MDMA treatment also produced a two-fold increase in the number of cleaved caspase-3-immunoreactive cells in the rostral forebrain and hippocampus. All of these effects were completely independent of pup body temperature. These findings demonstrate that neonatal MDMA administration exposure stimulates apoptotic cell death in various forebrain areas and also leads to a long-term reorganization of the forebrain serotonergic innervation. Consequently, offspring of MDMA-using women may be at heightened risk for abnormal neural and behavioral development.

Age Factors↗