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Biomedical subjects

L Johnson

Publications and source records attributed to L Johnson.

At least 37 records · Page 2Linked to original sources
PubMed2003

Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans.

CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.

Acquired Immunodeficiency Syndrome↗
PubMed2003

HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death.

The Bcl-2 oncoprotein is commonly overexpressed in hematological malignancy, where it promotes the survival of neoplastic cells. Recently, a small molecule (HA14-1) was reported to bind the surface pocket of Bcl-2 that mediates antiapoptotic interactions, triggering apoptosis in a Bcl-2-transfected cell line. We investigated the activity of this compound in a panel of malignant hematopoietic cell lines. Consistent with its proposed role as a Bcl-2 inhibitor, HA14-1 was most cytotoxic in lines expressing high levels of Bcl-2. In addition, at lower concentrations (5-12.5 muM), the compound predominantly triggered apoptosis. However, at concentrations two-fold higher than this and above, increasing primary necrosis was observed, suggesting the onset of interactions supplementary to Bcl-2 inhibition. In experiments on primary cells, 25 muM HA14-1 induced extensive apoptosis in acute leukemic blasts, but also suppressed normal hematopoietic colony formation to <50% of baseline. Importantly, low-concentration HA14-1 (5 muM) was nontoxic to normal colony-forming cells, whereas it enhanced the cytotoxicity of the antileukemia drug cytarabine in Bcl-2-positive lymphoblastic leukemia cells. In conclusion, our results indicate that HA14-1 at low concentration selectively triggers apoptosis in malignant hematopoietic cells that overexpress Bcl-2. Agents of this class may have particular utility in combination with cytotoxic chemotherapy drugs.

Apoptosis↗
PubMed2003

Effects of vitamin E supplementation during erythropoietin treatment of the anaemia of prematurity.

AIMS: To evaluate the effects of vitamin E supplementation on haemoglobin concentration and the requirement for transfusion in premature infants treated with erythropoietin and iron. METHODS: Randomised, double blind, placebo controlled trial. Thirty infants </=32 weeks gestation and </=1250 g birth weight, who were defined as stable based on minimal requirements for respiratory support and phlebotomy, and absence of major congenital anomalies were enrolled. All were treated with erythropoietin and iron, and were randomised to receive, in addition, either vitamin E 50 IU/day or placebo for eight weeks or until discharge, whichever came first. RESULTS: Despite higher vitamin E (alpha-tocopherol) levels in the experimental group in weeks 3 (49.0 v 28.1 micro mol/l) and 8 (66.2 v 38.5 micro mol/l), there were no differences in haemoglobin, reticulocyte count, iron concentration, or transfusion requirement. CONCLUSIONS: Oral vitamin E supplementation at 50 IU/day does not increase the response of preterm infants to erythropoietin and iron. Vitamin E obtained through standard nutrition may have been sufficient or higher doses may be required.

Anemia, Neonatal↗
PubMed2002

Release of cytokines and apoptosis in fetal rat Type II pneumocytes exposed to hyperoxia and nitric oxide: modulatory effects of dexamethasone and pentoxifylline.

The response of the fetal rat Type II pneumocyte (FTIIP), the stem cell of the alveolar epithelium, to hyperoxia would be helpful to understand the effects of oxygen-induced injury to the immature lung. In such a scenario, the presence of nitric oxide (NO) may have a protective or detrimental effect. Our goals were to evaluate the release of cytokines and apoptotic cell death in freshly isolated FTIIP (19-day) in the presence of 95% O(2) and/or NO. The effects of dexamethasone and pentoxifylline on the FTIIP cytokine response were also studied. There was no significant difference in the levels of IL-1beta and IL-10 from FTIIP, in room air, hyperoxia and/or NO at 2, 6 and 24 h. However, IL-6 release was significantly higher, when measured over time, after 2, 6 and 24 h of exposure to hyperoxia and NO. Dexamethasone in the presence of hyperoxia and/or NO increased the release of IL-10 at 24 h. There was increased apoptosis in FTIIP exposed to hyperoxia alone and in combination with NO; this was significantly attenuated in the presence of dexamethasone and pentoxifylline. We speculate that the cytoprotective effects of dexamethasone in the immature lung may, in part, be mediated via IL-10.

Animals↗
PubMed2002

Hyperoxia and nitric oxide reduce surfactant components (DSPC and surfactant proteins) and increase apoptosis in adult and fetal rat type II pneumocytes.

Nitric oxide (NO) alone or in conjunction with hyperoxia can have protective or detrimental effects on the lung. Our hypothesis was that hyperoxia in conjunction with NO would result in increased cellular dysfunction and apoptotic cell death in adult and fetal Type II pneumocytes (TIIP) in a dose-dependent manner. The TIIP were obtained from adult and 19-day fetal rat lungs. The TIIP were then exposed to 100, 200 and 500 micro M of the NO-donor, Glyco-SNAP-2, alone or in conjunction with 95% oxygen for 24 h. While low-dose NO exposure alone did not increase cytotoxicity, in conjunction with hyperoxia, there was a significant dose-dependent increase in apoptotic cell death of adult TIIP as well as fetal TIIP. Choline incorporation into disaturated phosphatidylcholine was markedly decreased in adult TIIP while the fetal TIIP had similar values as controls. However, the mRNAs of surfactant proteins A, B and C as well as iNOS were significantly reduced in fetal TIIP. Exogenous peroxynitrite also increased nitrotyrosine formation in fetal TIIP as did hyperoxia and NO. The effect of hyperoxia and NO could be abrogated with catalase and superoxide dismutase. These findings may have significant clinical implications in the use of NO in premature infants.

Animals↗
PubMed2002

Acts of control in schizophrenia: dissociating the components of inhibition.

BACKGROUND: Inhibitory deficits have been frequently reported in schizophrenia. Such deficits are usually associated with activities of prefrontal cortex and related networks. An understanding of intentional inhibitory control requires knowledge of how actions are planned and initiated and the components involved in stopping these actions. METHODS: Patients with schizophrenia, a psychosis comparison group and a healthy control group participated in a visual choice reaction time (go) task and attempted to inhibit their responses to the go task when an auditory 'stop' signal was heard. RESULTS: Schizophrenia patients demonstrated significantly slower response execution but the estimated speed of inhibition was not significantly different from that of healthy controls. Both patient groups were impaired in their ability to inhibit a response across a range of stop-signal delays. The poorer performance of schizophrenia patients only was related to a difficulty in reliably triggering the inhibitory response. CONCLUSIONS: Impaired response inhibition is not unique to schizophrenia. However, the nature of their problem is markedly different from that of other psychopathological groups. Possible neural mechanisms underpinning difficulties in triggering inhibitory responses and in the voluntary initiation of actions in schizophrenia are considered.

Adult↗
PubMed2002

Methods of ovarian suppression used in the UK.

Ovarian suppression in the management of breast cancer has had a resurgence in the 1990s. In view of the development of luteinizing hormone-releasing hormone (LHRH) analogues and advances in laparoscopic surgery, we wished to determine whether more consultants are considering these methods for achieving ovarian suppression than radiotherapy. A questionnaire was designed to determine the current practice of consultants in the UK and to discover who is involved in making this decision. It was distributed via the Adjuvant Breast Cancer (ABC) trials office to consultants who enter patients into the ABC premenopausal trial. Seventy-four (72%) questionnaires were analysed. The preferred method of treatment was radiotherapy in 60%, surgery in 30% and LHRH analogues in 9%. Seventy-three per cent of consultants were using more than one technique but did not always involve the patient in the decision-making process to determine which treatment modality to use. Radiotherapy techniques used included using bony landmarks for field borders (46%), using a standard field size (20%) or using ultrasound localization (15%).

Journal Article↗
PubMed2002

Use of NHS Direct calls for surveillance of influenza--a second year's experience.

A second year's call data to NHS Direct are presented to evaluate their usefulness for influenza surveillance. During the winter of 2000-01, age-group-specific data relating to the 'cold/flu' algorithm were collected from six NHS Direct sites (population coverage: 16 million). The total number of calls was collected from all 23 NHS Direct sites on a daily basis. Despite the winter of 2000-01 having been a season of low activity for influenza in the United Kingdom, NHS Direct data demonstrated a peak in the 'cold/flu' calls as a proportion of the total calls (3.1% [672 'cold/flu' calls] during week 06/01). This coincided with the peak recorded by routine influenza surveillance systems. There was also an earlier peak in the proportion of 'cold/flu' calls (3.3% during weeks 52/00 [789 'cold/flu' calls] and 01/01 [749 'cold/flu' calls]) which may have been due to other respiratory infections, the lack of specificity of the definition of NHS Direct 'cold/flu' calls and an increase in 'out-of-hours' calls to NHS Direct at the time. Despite limitations, the timeliness of NHS Direct data, the total population coverage of the service and the ability to provide local information on 'cold/flu' calls make the call data suitable for further surveillance during the winter of 2001-02. It is hoped that as NHS Direct reaches a 'steady state' in terms of population coverage and uniformity of clinical support systems, it will be possible to begin to construct 'baselines' for the respiratory disease related call data.

Adolescent↗
PubMed2001

Effects of long-term lithium treatment on monoaminergic functions in major depression.

Platelet [14C]serotonin uptake, the density of serotonin transporters and 5HT(2) receptors, and 5HT(2) and alpha(2) receptor function in platelets were investigated in 29 outpatients (15 women and 14 men) diagnosed as having a major affective disorder (21 bipolar and 8 unipolar). The data were compared with data for 26 healthy volunteers matched for age, sex and season. No differences were found in the mean values for the uptake velocity (V(max)) and the affinity (K(m)) of the transport carrier for serotonin between patients and controls. However, female patients had lower V(max) compared to male patients and female control subjects. A positive correlation between plasma lithium and V(max) and a tendency toward a negative correlation between plasma lithium and K(m) was observed. Furthermore, there were no differences in platelet B(max) and K(d) for [3H]paroxetine binding and K(d) for [3H]LSD binding between patients and controls. However, there was an increased number of platelet 5-HT(2) receptors and a difference in serotonin-mediated potentiation of platelet ATP secretion between patients compared to controls, especially in women. The findings in the present study suggest that lithium has a net ameliorating impact on serotonin uptake which may render it resistant to change. They also postulate that the effect of lithium may be attained by a dual influence on postsynaptic serotonergic structures, as it increases both the density and the sensitivity of 5-HT(2) receptors.

Adult↗
PubMed2001

Sexual and drug risk-related behaviours after initiating highly active antiretroviral therapy among injection drug users.

OBJECTIVE: To assess whether initiation of highly active antiretroviral therapy (HAART) is associated with a subsequent resumption of sexual and drug use risk behaviors. METHODS: Within an ongoing prospective study of HIV-seropositive injection drug users (IDUs), a subsample with at least one CD4 cell count < 500 x 106 cells/l after 1996 (when HAART became available) and three consecutive visits were selected for analysis. Patients underwent semi-annual interviews for risk behaviors and reports of medication use. Data from visits immediately prior to and following initiation of HAART for the treated group, and from consecutive visits for the eligible but untreated group were compared using linear growth curve analysis. RESULTS: Of 316 eligible HIV-seropositive IDUs, 133 reported HAART use during the study period; 95% were African American, 76% were male, and median age at enrollment was 34 years. The proportion who reported any sexual activity increased over time from 55 to 61% for the HAART-treated group, but decreased from 67 to 63% in the untreated group (P = 0.03); the respective values for unprotected sex were 18 versus 20% and 36 versus 28% (P = 0.06). In both treated and untreated groups, the proportion injecting drugs declined (P = 0.04), whereas the proportion reporting needle sharing decreased marginally (P = 0.11). However, trends in use of shooting galleries between the groups differed (P = 0.04) increasing slightly from 2.3 to 3% in the treated group while decreasing from 12 to 5% in the untreated group. CONCLUSION: In persons treated with HAART, self-report of high-risk behaviors remained stable or showed some increase. Persons initiating HAART should be counselled to refrain from high-risk behaviors.

Adult↗
PubMed2001

Impact of educational print materials on knowledge, attitudes, and interest in BRCA1/BRCA2: testing among Ashkenazi Jewish women.

BACKGROUND: The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals. Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population. Furthermore, previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population. The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge, attitudes, and interest in testing among Ashkenazi Jewish women from the general population. METHODS: After a baseline telephone interview, participants were randomized to receive either genetic testing educational print materials (n = 195 women) or general breast cancer education control materials (n = 196 women). One month after receiving these materials, the authors reassessed knowledge, attitudes, and interest in BRCA1/BRCA2 gene testing. RESULTS: Relative to the breast cancer education control materials, the genetic testing education materials led to increased knowledge, increased perception of the risks and limitations of testing, and decreased interest in obtaining a BRCA1/BRCA2 mutation test. CONCLUSIONS: These data indicate that preliminary print education can be used to educate low-risk individuals about BRCA1/BRCA2 genetic testing. This approach may be used to educate low-risk individuals about the benefits and risks/limitations of BRCA1/BRCA2 testing, so that they can make informed decisions about whether to pursue genetic counseling.

BRCA2 Protein↗
PubMed2001

Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases.

Adolescent↗
PubMed2001

Sex differences in risk factors for hiv seroconversion among injection drug users: a 10-year perspective.

BACKGROUND: Injection drug use directly or indirectly accounts for nearly half the annual human immunodeficiency virus (HIV) infections in the United States. Prospective studies that investigate both sexual and parenteral HIV risks among injection drug users (IDUs) are needed. We studied factors for HIV seroconversion among male and female IDUs in Baltimore, Md. METHODS: The HIV-negative IDUs (1447 male and 427 female) were recruited into a prospective study from 1988 to 1989 or in 1994. Participants underwent semiannual HIV tests and surveys through December 1998. Poisson regression was used to identify risk factors for HIV seroconversion, stratified by sex. Behaviors were treated as time-dependent covariates that varied at each semiannual period. RESULTS: Subjects were primarily African American (91%), and median age at enrollment was 35 years. Incidence of HIV was 3.14 per 100 person years (95% confidence interval, 2.78-3.53) and did not significantly differ by sex. Younger age independently predicted HIV seroconversion for both men and women. Among men, factors that independently predicted HIV seroconversion were the following: less than a high school education, recent needle sharing with multiple partners, daily injection, and shooting-gallery attendance. The incidence of HIV was double for men recently engaging in homosexual activity and cocaine injection. Among women, the incidence of HIV was more than double for those recently reporting sexually transmitted diseases. CONCLUSIONS: The incidence of HIV remained high among IDUs in Baltimore over the past decade. Risk factors for HIV seroconversion differed markedly by sex. Predominant risks among men included needle sharing and homosexual activity; among women, factors consistent with high-risk heterosexual activity were more significant than drug-related risks. Human immunodeficiency virus interventions aimed at IDUs should be sex-specific and incorporate sexual risks.

Adolescent↗
PubMed2001

Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure.

BACKGROUND: Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. METHODS AND RESULTS: LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg. kg(-1). d(-1) PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116+/-11 micromol/L) reduced in vitro LV myocardial MMP-2 activity by approximately 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P</=0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443+/-12 versus 563+/-33 mL, P</=0.05) and increased further by 13 months (899+/-64 mL, P</=0.05). LV myocardial MMP-2 activity was increased by approximately 2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678+/-28 mL, P</=0.05). CONCLUSIONS: MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.

Animals↗
PubMed2001

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.

About 30% of human tumours carry ras gene mutations. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas ( approximately 70-90% incidence), colon ( approximately 50%) and lung ( approximately 25-50%). To construct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Alleles↗
PubMed2001

The design and testing of a force feedback dental simulator.

The Iowa Dental Surgical Simulator is a haptic simulator to train dental students in the haptic skills of dentistry. The initial design emphasizes the detection of carious lesions. This work describes the software and implementation of the prototype system, the design tradeoffs' and the technical issues associated with haptic and graphics subsystems. The work also describes the current system performance, including a formal evaluation by practicing dentists and performance measures. A discussion of the limitations of the current system is followed by an analysis of opportunities to improve the quality of the simulator. The results should be of interest to designers of medical haptic simulation systems and other simulation designers.

Biophysical Phenomena↗
PubMed2001

Small animal bronchoscopy.

Bronchoscopy is a useful diagnostic and therapeutic tool in veterinary medicine. The increased availability of fiberoptic technology and video-endoscopy has enhanced recognition of the benefits gained from visualization of the lower airways in animals with lower respiratory tract disease. Specimens retrieved from the lower airway during bronchoscopy have greater diagnostic capacity, and a better understanding of the pathophysiology of disease is provided through application of bronchoscopy to animals with respiratory tract disease.

Animals↗