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Biomedical subjects

B A Johnson

Publications and source records attributed to B A Johnson.

At least 19 recordsLinked to original sources

Odorant molecular length: one aspect of the olfactory code.

Organic acid odorants of differing carbon number produce systematically different spatial patterns of [(14)C]2-deoxyglucose uptake in the glomerular layer of the olfactory bulb. Because increasing carbon number correlates with progressive increases in several molecular features, including hydrophobicity, length, and volume, we determined which of these properties was most associated with systematic changes in the location of an anterior, dorsomedial module responding to fatty acids. We exposed groups of rats to two series of organic acids that each had the same number of carbons, but differed in their hydrocarbon structures. These straight-chained, branched, cyclic, and double-bonded molecules differed independently in hydrophobicity, length, and volume. The only molecular property that was strongly correlated with the location of the module was molecular length, suggesting that this molecular feature is the principal determinant of the chemotopic organization of glomeruli within the module. We also found that distinct hydrocarbon structures produced large differences in spatial patterns of 2-deoxyglucose uptake in posterior parts of the bulb. Even subtly distinct structural isomers evoked posterior responses that differed greatly. The odorant 2-methylbutyric acid evoked much greater uptake in the posterior bulb than did its structural isomer 3-methylbutyric acid (isovaleric acid). These data suggest that posterior portions of the bulb may encode specific steric features of odorant molecules and that some odorant features may have an inherent or acquired greater representation than do others.

Animals↗

Use of systemic agents in the treatment of acne vulgaris.

Effective treatment of acne vulgaris can prevent emotional and physical scarring. Therapy varies according to the severity of the disease. Topical medication is generally adequate in clearing comedonal acne, while inflammatory acne usually requires the addition of oral medication. Systemic antibiotics are used most frequently and can be highly effective. Newer formulations of combined oral contraceptives are also helpful in modulating sebum production in the female patient. Severe nodulocystic acne that does not respond to topical retinoids and systemic antibiotics may be treated with isotretinoin. However, the side effect profile of this medication is extensive, and physicians should be well-versed in its potential adverse effects.

Acne Vulgaris↗

Modular representations of odorants in the glomerular layer of the rat olfactory bulb and the effects of stimulus concentration.

To study the mechanism whereby odorants are encoded in the nervous system, we studied the glomerular-layer activity patterns in the rat olfactory bulb evoked by closely related odorants from different chemical families. These odorants had a common straight-chain hydrocarbon structure, but differed systematically in their functional groups. Neural activity was mapped across the entire glomerular layer by using the ¿(14)C2-deoxyglucose method. Group responses were averaged and compared by using data matrices. The glomerular activity patterns that resulted from this analysis were comprised of modules. Unique combinations of modules were activated by each odorant, demonstrating what may be part of the neural code for odorants. Most of the modules were clustered together in the bulb, perhaps providing for enhanced contrast between related chemicals by means of lateral inhibition. We also determined whether changes in odorant concentration would affect spatial patterns of glomerular activity. Two odorants, pentanal and 2-hexanone, evoked different patterns at increased concentrations, with additional glomeruli being recruited at a great distance from glomeruli in which activity was evoked at lower concentrations. Humans report that both of these odorants change in perceived odor with increasing concentration. Three other odorants (pentanoic acid, methyl pentanoate, and pentanol) did not recruit new areas of glomerular activation with increasing concentration, and humans do not report a changed odor across concentrations of these odorants. The results suggest that changes in modular glomerular activity patterns could underlie altered odor perception across odorant concentrations, and they provide additional support for a combinatorial, spatially based code in the olfactory system.

Animals↗

Treatment of seborrheic dermatitis.

Seborrheic dermatitis is a chronic inflammatory disorder affecting areas of the head and trunk where sebaceous glands are most prominent. Lipophilic yeasts of the Malassezia genus, as well as genetic, environmental and general health factors, contribute to this disorder. Scalp seborrhea varies from mild dandruff to dense, diffuse, adherent scale. Facial and trunk seborrhea is characterized by powdery or greasy scale in skin folds and along hair margins. Treatment options include application of selenium sulfide, pyrithione zinc or ketoconazole-containing shampoos, topical ketoconazole cream or terbinafine solution, topical sodium sulfacetamide and topical corticosteroids.

Dermatitis, Seborrheic↗

Ligand-induced stabilization of PPARgamma monitored by NMR spectroscopy: implications for nuclear receptor activation.

Nuclear receptors are ligand-dependent transcription factors that are mediators of the action of lipophilic hormones and other endogenous ligands and are the targets of drugs useful in a variety of therapeutic areas. Peroxisome proliferator-activated receptor (PPAR)gamma is a nuclear receptor that, acting as a heterodimer with RXR, mediates a variety of cellular effects including adipocyte-differentiation. Due to its role in modulating insulin sensitivity, it is the target of therapeutically active anti-diabetic agents such as rosiglitazone. We have assigned the chemical shifts of the backbone atoms of the 32 kDa ligand-binding domain of PPARgamma in the presence of bound rosiglitazone. Three-dimensional HNCO spectra of the apo ligand-binding domain (LBD) have less than half the expected number of cross-peaks. The missing cross-peaks are restored upon binding strong agonists such as rosiglitazone. The NMR results indicate that the apo-LBD of PPARgamma is in a conformationally mobile state, and that agonist binding is associated with a marked stabilization of the conformation. Mapping the missing peaks to the 3D X-ray crystallographic structure indicates the region of mobility is extensive and includes the ligand-binding region and the cofactor-binding site. This leads to the conclusion that activation of this nuclear receptor is a result of a population shift of a dynamic ensemble of conformations, rather than a two-state switch from an inactive to an active conformation. Our results have important implications for the mechanisms by which antagonists, partial agonists, and agonists of nuclear receptor function operate.

Amino Acid Sequence↗

Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival.

The immediate early protein tristetraprolin (TTP) is required to prevent inappropriate production of the cytokine TNF-alpha, and is a member of a zinc finger protein family that is associated with RNA binding. TTP expression is induced by TNF-alpha, and evidence indicates that TTP can bind and destabilize the TNF-alpha mRNA. TTP and the closely related TIS11b and TIS11d proteins are evolutionarily conserved, however, and induced transiently in various cell types by numerous diverse stimuli, suggesting that they have additional functions. Supporting this idea, continuous expression of each TTP/TIS11 protein at physiological levels causes apoptotic cell death. By various criteria, this cell death appears analogous to apoptosis induced by certain oncoproteins. It is also dependent upon the zinc fingers, suggesting that it involves action on appropriate cellular targets. TTP but not TIS11b or TIS11d also sensitizes cells to induction of apoptosis by TNF-alpha. The data suggest that the TTP and TIS11 immediate early proteins have similar but distinct effects on growth or survival pathways, and that TTP might influence TNF-alpha regulation at multiple levels.

3T3 Cells↗

Both coactivator LXXLL motif-dependent and -independent interactions are required for peroxisome proliferator-activated receptor gamma (PPARgamma) function.

Nuclear receptor activation is dependent on recruitment of coactivators, including CREB-binding protein (CBP/p300) and steroid receptor coactivator-1 (SRC-1). A three-dimensional NMR approach was used to probe the coactivator binding interface in the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain (LBD). In the presence of a CBP peptide, peaks corresponding to 20 residues in helices 3, 4, 5, and 12 of the LBD were attenuated. Alanine mutants revealed that K301A, V315A, Y320A, L468A, and E471A were required for binding of both CBP and SRC-1 and for cell-based transcription. Several additional amino acids in helix 4 of the PPARgammaLBD were defective with respect to CBP recruitment, but retained relatively normal SRC-1 recruitment. Thus these amino acid residues may be important determinants of specificity for nuclear receptor LBD interactions with discrete coactivator molecules.

Animals↗

Neuropharmacological treatments for alcoholism: scientific basis and clinical findings.

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-D-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate's potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone's reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone's effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.

Acamprosate↗

Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on D-methamphetamine-induced cognitive and physiological changes in humans.

D-methamphetamine is abused for its euphoric effects and stimulatory action on cognitive function. Its abuse can, however, be associated with massive hypertension resulting in strokes, ruptured aneurysms, or myocardial infarction. We examined the utility of isradipine, a dihydropyridine-class calcium channel antagonist, in treating d-methamphetamine induced hypertension and evaluated its effects on cognitive function, both of which are mediated by dopaminergic mechanisms. D-methamphetamine dose-dependently increased all vital signs (systolic, diastolic, and mean arterial pressure, and pulse rate) parameters. Isradipine significantly reduced d-methamphetamine-induced increases in diastolic and mean arterial pressure; however, this potentially beneficial therapeutic effect was offset by a significant reflex rise in pulse rate. D-methamphetamine also improved attention, accuracy of reasoning ability, and performance on computerized cognitive function tasks. D-methamphetamine's cognitive improving effects were not altered significantly by isradipine. Isradipine increased the false responding rate but was without significant effect on any other attentional task, or on reasoning ability, or performance. Isradipine does not appear to enhance cognitive function in healthy humans.

Adult↗

The accreditation status of student health services at academic medical centers.

BACKGROUND: Student health services (SHSs) on campuses with academic medical centers (AMCs; schools affiliated with teaching hospitals) often provide clinical services (including occupational health services) for students and staff. There are few aggregate data about the accreditation status of these health services. METHOD: A cross-sectional survey of SHSs at the 124 medical schools in the United States was conducted in spring 1999. SHSs were questioned about their accreditation status. RESULTS: One-hundred three SHSs were included in the survey. Forty-seven (46%) of the SHSs were accredited, 30 (64%) through the Joint Commission on Accreditation of Healthcare Organizations, and the remainder through the Accreditation Association of Ambulatory Health Care (AAAHC). The Joint Commission predominated among private SHSs (13/15 [87%]), but public institutions were more evenly divided. Most of the SHSs accredited as freestanding ambulatory care centers were AAAHC accredited (16/27 [59%]). Nearly all the SHSs accredited as satellites of the AMCs were Joint Commission accredited. CONCLUSION: Although fewer than one-half of SHSs at AMCs are accredited either through the Joint Commission or AAAHC, this is a far higher percentage than of accredited SHSs in general (134/1,500 [9%]). The Joint Commission dominates as the accrediting body for SHSs at AMCs largely because of the high-proportion of services accredited as satellites of the AMCs. Although the accreditation process is costly and time-consuming and may appear daunting, SHSs at AMCs should pursue accreditation to ensure quality in health care processes.

Academic Medical Centers↗

A transient assay for regulatory gene function in haemopoietic progenitor cells.

This work aimed to provide a means of assaying directly the effects of transient expression of introduced genes on the survival, proliferation, lineage commitment and differentiation of haemopoietic progenitor cells. For this purpose, we have developed a system that allows isolation of productively transfected, mulitipotent haemopoietic cells within a few hours of the introduction of test genes. We have shown that FDCP-mix cells productively transfected with expression plasmids encoding green fluorescent protein (GFP) differentiate normally and retain colony-forming potential. We constructed an expression vector consisting of a bicistronic cassette in which a GFP marker gene and a test gene are driven from the same promoter. The vector design has been optimized for co-expression and the test gene was shown to be biologically active. The expression profile from a transiently transfected template under different growth conditions reveals that active expression continues for at least 2 d after transfection. The transient transfection of FDCP-mix cells with the vectors described provides a powerful tool for analysis of the immediate early effects of test gene overexpression during haemopoietic differentiation.

Animals↗

Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population.

Subtyping alcoholics may provide a more accurate guide as to the course and character of the disease. Classifications of different ages of onset of problem drinking have so far resulted in categorical inconsistencies. In the past, hospital-based alcoholics have over-represented those most severely ill, and comprehensive evaluations of psychopathology for discriminating between alcoholic subtypes have been infrequent. In a heterogeneous treatment-seeking, outpatient, alcoholic population, we tested the hypothesis that age of onset represents a continuum of disease, and that greater severity of psychopathology is associated with lower ages of onset. Using a standard questionnaire, 253 male and female treatment-seeking alcoholics were stratified according to specific ages of onset: a) < 20 years; b) 20-25 years, and c) > 25 years. These age of onset groups were compared on alcohol severity and craving, family history, childhood behavior, personality, hostility, overt aggression, mood, and social functioning. Symptom severity and age of onset were negatively correlated, and the 20-25-year onset group usually had intermediate scores. The < 20 year onset group was characterized by greater severity of alcohol-related problems, family history, childhood behavioral problems, craving, hostility, antisocial traits, mood disturbance, and poor social functioning. Alcoholics with an earlier age of onset have relatively greater psychopathology than those of later onset. While the preponderance of psychopathology among those in the < 20-year onset group could be conceptualized as a clinical "subtype," such a characterization would not define an entirely homogeneous category. Yet, this clinical characterization would be clinically important if specific age of onset levels were found to be differentially sensitive to pharmacological and/or psychological treatments.

Adult↗

Vitamin D deficiency among older women with and without disability.

BACKGROUND: Vitamin D deficiency is associated with bone loss and bone fractures, and the identification of vulnerable populations is important to clinical practice and public health. OBJECTIVE: The objectives of this study were to determine the prevalence of vitamin D deficiency and to examine associated risk factors for vitamin D deficiency in older women. DESIGN: We measured serum concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1, 25(OH)(2)D], intact parathyroid hormone (PTH), osteocalcin, and ionized calcium in women aged >/=65 y who were participating in the Women's Health and Aging Study I, an observational study of women representing the approximately one-third most disabled women living in the community, and women aged 70-80 y who were participating in the Women's Health and Aging Study II, an observational study of women among the two-thirds least disabled women living in the community in Baltimore. RESULTS: The women were classified into 4 domains of physical disability. Among 371 women with 0 or 1 domain of disability and 682 women with >/=2 domains of disability, 6.2% and 12.6%, respectively, had vitamin D deficiency [serum concentrations of 25(OH)D < 25 nmol/L]. In univariate analyses, risk factors for vitamin D deficiency included increasing age, black race, low educational level, high body mass index, high triceps skinfold thickness, increasing level of disability, winter season, and elevated creatinine concentration. In multivariate models, black race had a strong association with vitamin D deficiency when other risk factors were adjusted for. CONCLUSIONS: Vitamin D deficiency, a preventable disorder, is a common and important public health problem for older disabled women living in the community; black women are at higher risk than are white women.

Aged↗

Preclinical mobility disability predicts incident mobility disability in older women.

BACKGROUND: Physical disability and dependency are serious, and frequent, adverse health outcomes associated with aging and resulting from chronic disease. Reasoning has suggested that there might be a preclinical, intermediate phase of disablement which might develop in parallel with progression of underlying disease and precede and predict disability. Definition of this stage could provide a basis for screening and early intervention to prevent disability. The objective of this study was to determine preclinical functional predictors of incident mobility difficulty and provide evidence for a preclinical stage of disability. METHODS: A prospective, population-based cohort study was carried out in Baltimore, Maryland, with two evaluations 18 months apart. The participants were 436 community-dwelling women, 70-80 years of age at baseline, not cognitively impaired, and reporting difficulty in no areas, or only one area, of physical function (primarily mobility), who were participating in the Women's Health and Aging Study II. Participants were recruited from a population-based, age-stratified random sample. Incident mobility disability was studied in the subset without such disability at baseline. The main outcome measure was self-reported incident difficulty walking 1/2 mile or climbing up 10 steps. RESULTS: At baseline, 69.3% of the cohort reported no difficulty with mobility. After 18 months, 16.0 and 11.7% of this group reported incident difficulty walking 1/2 mile or climbing up 10 steps, respectively. Those reporting baseline task modification due to underlying health problems, our measure of preclinical disability, were at three- to fourfold higher odds of progressing to difficulty than were those without such modification. In multivariate logistic regression analyses, this self-report measure, task modification without difficulty, and objective measures of performance were independently and jointly predictive of incident mobility difficulty. Specifically, for incident difficulty walking 1/2 mile, self-reported task modification odds ratio (OR) = 3.67, walking speed (.5 m/s difference) OR = 2.16; for incident difficulty climbing up 10 stairs, OR for task modification = 3.84, for stair climb speed (1/3 step/s difference) = 2.08 (95% CI did not include 1 for any). Covariates, age, living alone, number of chronic diseases, depression score, knee strength, and balance by functional reach, were not significant predictors in either model. CONCLUSIONS: Two indicators of functional changes in older women without mobility difficulty, self-report of modification of method of doing a task in the absence of difficulty and performance measures, are independent and strong predictors of risk of incident mobility disability. The self-report measure provides substantial strength in predicting risk of incident disability across the full range of performance, and may identify a vulnerable point at which other risk factors act to cause transitions to disability. Together, the preclinical indicators identify a subset of high-functioning older women who are at high risk of mobility disability, and provide a potential basis for screening for disability risk and targeting interventions to prevent mobility disability.

Activities of Daily Living↗

Integration of student-health physicians into U.S. medical schools and their affiliated teaching hospitals.

PURPOSE: To determine whether physicians in the student health services (SHSs) at U.S. medical schools and their affiliated teaching hospitals, referred to here as academic medical centers (AMCs), have unique opportunities for integration into AMCs that do not exist for physician-faculty at SHSs on purely academic campuses. METHOD: A survey of SHS offices at the 124 U.S. medical schools was conducted in the spring of 1999. The questionnaire asked about the reporting relationships of the SHS within the AMC, whether the student-health physicians had academic appointments within the AMC, and whether these physicians participated in the AMC's clinical services, administration, research, or teaching activities. RESULTS: There were 116 (94%) responses (not all responses were complete and eight were excluded because their campuses offered no formal SHS). Approximately half of the SHSs (52/107, 49%) reported to their AMCs. Student-health physicians with career-track appointments were more likely to be found at SHSs reporting to AMCs (35/58, 60%) than at SHSs reporting solely to a division of student affairs (20/58, 34%). Having a career-track appointment increased the likelihood of the student-health physicians' attending on the wards (34/59, 58%), seeing private patients in an AMC's faculty practice (40/59, 68%), participating in administrative activities for an AMC (50/56, 89%), and participating in research activities (36/57, 63%). CONCLUSIONS: Student health services that reported to their AMCs were more likely to have faculty with career-track appointments, and these appointments were more likely to result in the integration of student-health physicians into their AMC's clinical services, administration, and research activities. Career-track appointments, however, had no influence on whether teaching activities occurred within the SHS. Fully integrating student-health physicians into the AMC's activities enhances outcomes for both the SHS and its AMC.

Academic Medical Centers↗

Pulmonary arterial smooth muscle cells modulate cytokine- and LPS-induced cytotoxicity in endothelial cells.

Cytokines and lipopolysaccharide (LPS) are known to be injurious to vascular endothelial cells (ECs), but the influence of adjacent vascular smooth muscle cells (SMCs) on this injury is unknown. Exposure of cultured rat (RPMECs) or human (HPMECs) pulmonary microvascular ECs on tissue culture plastic to a mixture of cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) and LPS (cytomix) resulted in a significant increase in (51)Cr release to 35-40%. When unstimulated RPMECs were cocultured with cytomix-pretreated rat pulmonary microvascular SMCs (RPMSMCs) there was an increase in (51)Cr release to 8.4%, which was nitric oxide dependent. However, when RPMECs or HPMECs were stimulated in direct contact with their respective SMCs, rather than a further increase in cytomix-induced injury (e.g., >35-40%), (51)Cr release decreased to <10%. This cytoprotection was fully reproduced with fixed RPMSMCs, and partially reproduced by plating HPMECs on gelatin. These data show that the direct toxicity of a cytokine and endotoxin mixture on cultured ECs can be reduced by contact with vascular smooth muscle.

Animals↗

Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells.

Actin released from damaged cells after a variety of tissue injuries appears to be involved in multiple organ dysfunction syndrome. Under experimental conditions, when the quantity of actin present in plasma is made to exceed the protective capacity of the actin-scavenging mechanism, microembolism and pulmonary vascular angiopathy have been noted in rats. It remains to be determined whether this injury is a result of a direct toxic effect or occurs indirectly via platelet activation or fibrin interactions. We examined the effect of sera from patients with adult respiratory distress syndrome (ARDS), as well as G-actin added to normal serum, on the viability, morphology, and function of cultured sheep pulmonary artery endothelial cells (SPAEC). Both patient sera and normal sera to which actin was added were toxic in the cell culture model; this toxicity could be abrogated, at least partially, by preincubation with gelsolin, which is known to complex with actin. A significant portion of the toxicity of sera from patients with ARDS was sensitive to heat (56 degrees C), suggesting an important role of complement. Sera from patients with ARDS were shown to contain filaments of F-actin by immunoblot and rhodamine phalloidin staining after ultracentrifugation. Thus, saturation of the actin-scavenging system by addition of exogenous G-actin to plasma produces direct pulmonary endothelial cell injury. Furthermore, plasma from patients with ARDS secondary to bacterial pneumonia is toxic to SPAEC, and a small but significant contributory role of actin is apparent in these studies.

Actins↗

Topical therapy for acne vulgaris. How do you choose the best drug for each patient?

Although management of acne is sometimes difficult, primary care physicians can offer a number of treatment plans to patients with this skin condition. Comedonal acne usually responds to topical keratolytics, such as salicylic acid, benzoyl peroxide, adapalene, and tretinoin. Inflammatory acne is usually treated with topical therapy plus a systemic antibiotic. Nodulocystic acne generally requires an 8-week course of systemic antibiotics. If the nodulocystic acne does not improve, minocycline or isotretinoin may be needed. Topical therapy is often helpful in the long-term management of nodulocystic acne. New products are available that deliver topical agents in novel ways that decrease skin irritation. With the proper tools and instructions in use, most patients have significant improvement in their acne.

Acne Vulgaris↗