Hormesis extends the correlation between stress resistance and life span in long-lived mutants of Caenorhabditis elegans.
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Adaptation, Physiological↗
Biomedical subjects
T E Johnson
Publications and source records attributed to T E Johnson.
No effect of albinism on sedative-hypnotic sensitivity to ethanol and anesthetics.
BACKGROUND: Studies using the long-sleep (LS) X short-sleep (SS) (LSXSS) recombinant inbred mice and inbred long-sleep (ILS) by inbred short-sleep (ISS) intercrosses have found genetic linkage between Tyr albinism (c/c) and differential sensitivity to sedative-hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate-limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative-hypnotic sensitivity. METHODS: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics (c/c, Tg(Tyr+)) were backcrossed to ISS (c/c) to compare pigmented (c/c, Tg(Tyr+)) and albino (c/c) mice in the context of an ISS-like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation (c2j) to compare pigmented (c/+) and albino (c/c2j) mice. Pigmented B6 (c2j/+ and +/+) and albino B6 (c2j/c2j) mice were also compared (pentobarbital). RESULTS: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice. CONCLUSION: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself.
Albinism↗
Evidence that the Lore-1 region specifies ethanol-induced activation in addition to sedative/hypnotic sensitivity to ethanol.
BACKGROUND: Low-dose ethanol-induced activation (LDA) and initial sensitivity to alcohol are both predictors of alcohol abuse in human populations. Our hypothesis is that one or more genes specifying hypnotic sensitivity also specify LDA. We tested this hypothesis by using congenic mice derived from the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, which carry an ILS region introgressed onto an ISS background. METHODS: LDA was assessed by assigning mice randomly to receive one of five doses of ethanol ranging from 1.2 to 2.4 g/kg. On day 1, animals were injected with saline and placed in a brightly lit activity monitor for 30 min, after which they were returned to their home cages. On day 2, mice were injected with ethanol (20% w/v), their activity was monitored for a 30-min period, and LDA was determined by subtracting day 1 activity. The blood ethanol concentration of each animal was then assessed at 30 min by retro-orbital collection of 25 microl of blood. RESULTS: Ethanol had a significant effect on the activity of ISS mice, but ILS mice showed no activation at any dose, similar to the activities of the outbred lines. All three congenic strains were activated at several doses. Lore-2 and Lore-5 were not ILS-like (less active than ISS) at any dose. In contrast, ISS.ILS-Lore-1 congenics (carrying an ILS-derived Lore-1 allele on the ISS background) were significantly less activated than the ISS controls at 1.8 and 2.4 g/kg of ethanol. CONCLUSIONS: The Lore-2 and Lore-5 congenic regions do not affect LDA. In contrast, the Lore-1 congenic region carries one or more genes specifying both initial hypnotic sensitivity to ethanol and LDA.
Aging↗
The genetic toxicity of the peroxisome proliferator class of rodent hepatocarcinogen.
Peroxisome proliferators comprise a structurally diverse class of chemicals. Some of the members of this class show evidence of genetic toxicity (most evidently the in vitro clastogen Wyeth 14,643, WY), while others do not (most evidently methyl clofenapate, MCP). When attempting to understand the mechanism of rodent hepatocarcinogenesis of this class of chemicals the possible role of genetic toxicity should be assessed on a class-wide basis, i.e., if just one peroxisome proliferator is shown to be unequivocally inactive as a genetic toxin, genetic toxicity cannot be implicated in the carcinogenic activity of peroxisome proliferators as a class. In an earlier paper, we established MCP as inactive in a range of in vitro and in vivo genetic toxicity assays. However, the top dose level of MCP that could be tested for induction of chromosome aberrations (clastogenicity) in human lymphocytes and CHO cells was limited by the relative insolubility of the test agent in the assay medium. Methyl clofenapate was not toxic up to a dose that produced precipitate, so cannot be directly compared with WY, which induced aberrations only at toxic dose levels. In the present paper, we have evaluated the clastogenicity of the carcinogenic peroxisome proliferator nafenopin (NAF) at dose levels up to those that are toxic to CHO cells, and found no evidence of chromosome aberration induction. These data isolate further the genetic toxicity of WY from other peroxisome proliferators, and increase confidence in the proposal that genetic toxicity does not play a critical role in the hepatocarcinogenicity of peroxisome proliferators.
Animals↗
Recurrent orbital solitary fibrous tumor in a 14-year-old girl.
PURPOSE: To report a case of orbital solitary fibrous tumor in a pediatric patient. METHODS: Case report and review of the literature. RESULTS: A 14-year-old girl presented with a 5-month history of painless proptosis of the left eye. Magnetic resonance imaging revealed a well-circumscribed mass in the anterior superomedial left orbit. The lesion was excised, and histopathologic examination revealed a solitary fibrous tumor. The lesion recurred in the orbit 4 months postoperatively, and histologic examination of the new lesion was consistent with solitary fibrous tumor. CONCLUSION: Based on this case report of orbital solitary fibrous tumor in a pediatric patient, solitary fibrous tumor should be included in the differential diagnosis of pediatric orbital tumors.
Adolescent↗
Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors.
More than 40 mutants in Caenorhabditis elegans have been demonstrated to lead to increased life span (a rigorous, operational test for being a gerontogene) of 20% or more ("Age" mutants). Age mutants alter rate-limiting determinants of longevity; moreover, important genes are identified independent of prior hypotheses as to actual mode of gene action in extending longevity and/or "slowing" aging. Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Three well-studied mutants (age-1, clk-1, and spe-26) alter age-specific mortality rates in characteristic fashions; in age-1 mutants, especially, the changes in mortality rates are quite dramatic. All Age mutants (so far without exception) increase response to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies, as well as random mutagenesis, to identify novel genes increasing the worm's ability to resist stress. Two genes (daf-16 and old-1) yield over-expression strains that are stress resistant and long-lived. A variety of approaches to assess transcriptional alterations associated with increased longevity are underway. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress.
Aging↗
Paralogy and orthology of tyrosine kinases that can extend the life span of Caenorhabditis elegans.
Modification of any one of three transmembrane protein tyrosine kinase (PTK) genes, old-1, old-2 (formerly tkr-1 and tkr-2, respectively), and daf-2 can extend the mean and maximum life span of the nematode Caenorhabditis elegans. To identify paralogs and orthologs, we delineated relationships between these three PTKs and all known transmembrane PTKs and all known mammalian nontransmembrane PTKs using molecular phylogenetics. The tree includes a number of invertebrate receptor PTKs and a novel mammalian receptor PTK (inferred from the expressed-sequence tag database) that have not previously been analyzed. old-1 and old-2 were found to be members of a surprisingly large C. elegans PTK family having 16 members. Interestingly, only four members of this transmembrane family appeared to have receptor domains (immunoglobulin-like in each case). The C-terminal domain of this family was found to have a unique sequence motif that could be important for downstream signaling. Among mammalian PTKs, the old-1/old-2 family appeared to be most closely related to the Pdgfr, Fgfr, Ret, and Tie/Tek families. However, these families appeared to have split too early from the old-1/old-2 family to be orthologs, suggesting that a mammalian ortholog could yet be discovered. An extensive search of the expressed-sequence tag database suggested no additional candidate orthologs. In contrast to old-1 and old-2, daf-2 had no C. elegans paralogs. Although daf-2 was most closely related to the mammalian insulin receptor family, a hydra insulin receptor-like sequence suggested that daf-2 might not be an ortholog of the insulin receptor family. Among PTKs, the old-1/old-2 family and daf-2 were not particularly closely related, raising the possibility that other PTK families might extend life span. On a more general note, our survey of the expressed-sequence tag database suggested that few, if any, additional mammalian PTK families are likely to be discovered. The one novel family that was discovered could represent a novel oncogene family, given the prevalence of oncogenes among PTKs. Finally, the PTK tree was consistent with nematodes and fruit flies being as divergent as nematodes and mammals, suggesting that life extension mechanisms shared by nematodes and fruit flies would be reasonable candidates for extending mammalian life spans.
Amino Acid Sequence↗
Diagnosis and management of allergic fungal sinusitis with orbital involvement.
PURPOSE: Allergic fungal sinusitis (AFS) is a noninvasive disease characterized by recurrent sinusitis. This condition is commonly treated with surgical debridement and several months of systemic corticosteroids. The treatment of AFS is examined in this study. METHODS: A retrospective case series of three patients with AFS. RESULTS: All three patients were treated with surgical debridement and less than one month of systemic corticosteroids. The patients then were treated with intranasal corticosteroids and monitored closely. Antifungal therapy was not used. All three patients remained disease-free during follow-up ranging from 12 months to 36 months. CONCLUSIONS: Surgical debridement and systemic corticosteroids for less than four weeks followed by intranasal corticosteroids may provide long-term control of AFS. Additional study is recommended to examine further the optimal treatment for AFS.
Adolescent↗
Molecular genetic mechanisms of life span manipulation in Caenorhabditis elegans.
Aging and a limited life span are fundamental biological realities. Recent studies have demonstrated that longevity can be manipulated and have revealed molecular mechanisms underlying longevity control in the soil nematode Caenorhabditis elegans. Signals from both neurons and the gonad appear to negatively regulate longevity. One tissue-specific signal involves an insulin-like phosphatidylinositol 3-OH kinase pathway, dependent upon the DAF-16 forkhead transcription factor. These signals regulate mechanisms determining longevity that include the OLD-1 (formerly referred to as TKR-1) receptor tyrosine kinase. Interestingly, increased resistance to environmental stress shows a strong correlation with life extension.
Animals↗
Management of patients needing antibiotic prophylaxis in a dental education setting.
The management of antibiotic prophylaxed (ABX) patients at an educational institution was evaluated to identify areas for improvement. Management criteria, reflecting guidelines to prevent oral-induced hematogenous microbial seeding, were pretested and applied to 1,225 record entries of eighty-five patients needing ABX for dental treatment between 1991 and 1996. Seven hundred twenty-two of the visits had 857 management or documentation problems, including no documentation indicating whether or not patients premedicated (n = 281); incomplete, insufficient, or repeated treatment (n = 214); and preventive concerns (n = 172), among others. The proportion of providers' patient visits with one or more management problems differed significantly (p < 0.001) by provider type, as did the distribution of problem categories (documentation, treatment, preventive, and scheduling concerns p < 0.001; compliance issues p < 0.005). Fifty-one percent of postgraduates' and 39 percent of faculty's record entries omitted patients' ABX status. Improved documentation, outcome measures, and patient, faculty and student education are indicated.
Antibiotic Prophylaxis↗
Comparison of two porcine (Sus scrofa domestica) skin models for in vivo near-infrared laser exposure.
BACKGROUND AND PURPOSE: The current safety standards for lasers operating in the 1,400- to 2,000-nanometer (nm) wavelength region are based on only a few observations at specific wavelengths. On the basis of experimental results conducted with Yorkshire pigs (Sus scrofa domestica), these standards may not accurately reflect the potential for laser injury when humans are exposed to these wavelengths. It is our belief that one of the damage mechanisms involved in these laser injuries results from energy absorption by skin pigmentation (melanin), and a more highly pigmented animal model, the Yucatan hairless minipig, may be a more suitable subject for laser exposure studies. METHODS: Skin specimens were collected from Yorkshire pigs and Yucatan minipigs for histologic examination, and the thickness of the epidermis was measured. Epidermal thickness of human skin also was determined, and a qualitative assessment of the melanin content in the epidermal layers was conducted. RESULTS: Mean +/- SD thicknesses of the Yucatan minipig flank and dorsal neck epidermis were 68 +/- 34 and 68 +/- 25 microm, respectively. Thicknesses of the Yucatan minipig skin were closely comparable to the thicknesses of human epidermis from the face (68 +/- 26 microm), neck (65 +/- 24 microm) and arms (68 +/- 21 microm). The Yorkshire pig lacks substantial melanin in the epidermis, whereas the skin of the Yucatan minipig is more similar to that of humans. CONCLUSION: On the basis of epidermal skin thickness measurements and melanin assessment, the flank and dorsal neck of the Yucatan minipig are better suited to laser injury studies than are the Yorkshire pig models of human skin.
Animals↗
Median effective dose determination and histologic characterization of porcine (Sus scrofa domestica) dermal lesions induced by 1540-nm laser radiation pulses.
BACKGROUND AND PURPOSE: Light amplification by stimulated emission of radiation (laser) systems operating in the so-called "eye safe" region are gaining widespread use in industry, medicine, and military applications. This research effort was geared to study the effects of laser tissue interaction on human skin by using in vivo porcine skin as an animal model. The goals of the study were to determine the median effective dose (ED50) for 1540-nm laser exposures, to evaluate the Yorkshire pig and the Yucatan mini-pig as animal models for laser exposure, and to characterize laser-induced skin lesions histologically. METHODS: A 1540-nm wavelength laser was used to expose multiple sites on the flanks of 10 pigs, using 0.8-ms pulses, ranging from 7 to 96 joules (J)/cm2. Single pulses were delivered to the flank of Yorkshire and Yucatan pigs in a grid pattern. Exposure sites were evaluated immediately after exposure and at 1 hour and 24 hours for presence of gross lesions. Representative biopsy specimens were collected from lesion sites for histologic evaluation at the 24-hour endpoint. RESULTS: The ED50 for the two breeds differed in the amount of energy required to induce dermal lesions. Grossly, lesions in each breed were well demarcated and pale gray to brightly erythematous. Microscopically, lesions had epidermal layer damage as cellular swelling and nuclear pyknosis, loss of cellular detail, and coagulation necrosis at the dermal layer. CONCLUSIONS: Findings suggest the presence of a different mechanism of laser-tissue damage in these two breeds. Photo-thermal mechanism appears to induce the skin lesions in the Yorkshire pig, whereas photo-thermal and photochemical mechanisms appear to be involved in lesion formation in the Yucatan mini-pig. All data obtained in this study will become part of database used by the American National Standards Institute (ANSI) to recommend laser safety standards for the occupational health and safety programs (OHSP), which will be used by industry and the military to base and update their current OHSP.
Animals↗
The RNA polymerase III-recruiting factor TFIIIB induces a DNA bend between the TATA box and the transcriptional start site.
TFIIIB, the RNA polymerase III-recruiting factor of Saccharomyces cerevisiae, may be assembled upstream of the transcriptional start site, either through the interaction of its constituent TATA-binding protein (TBP) with a strong TATA-box, or by means of the multisubunit assembly factor, TFIIIC. Missing nucleoside interference analysis of TFIIIC-dependent TFIIIB-DNA complex formation revealed enhanced complex formation at 0 degreesC when the DNA is missing nucleosides in two broad 7-10 bp regions centered around base-pairs -17 and -3 relative to the transcriptional start site; no effect of missing nucleosides was evident at 20 degreesC. The implication of these results for required DNA flexure in TFIIIC-mediated TFIIIB-DNA complex formation was pursued in a TFIIIC-independent context, using DNA with a suboptimal 6 bp TATA box (TATAAA). A unique missing nucleoside at the downstream end of the TATA box, corresponding to the position of one of two TBP-mediated DNA kinks, significantly enhances TBP-DNA complex formation. In contrast, TFIIIB displays a broad preference for missing nucleosides within an approximately 15 bp region immediately downstream of the TATA box. Consecutive mismatches (4-nt loops), either at the sites of TBP-mediated DNA kinking at both ends of the TATA box or within the identified region where missing nucleosides promote TFIIIB-DNA complex formation, also result in enhanced and specific TFIIIB assembly; 4-nt loops further downstream do not lead to preferential placement of TFIIIB. We conclude that TFIIIB induces an additional DNA deformation between the TATA box and the start site of transcription that is likely to be more extended than the sharp kinks generated by TBP.
Base Sequence↗
Sino-orbital aspergillosis in acquired immunodeficiency syndrome.
OBJECTIVE: To describe the clinical features, causes, imaging characteristics, treatment, and outcome of patients with the acquired immunodeficiency syndrome (AIDS) and sino-orbital aspergillosis. DESIGN: Records of 5 patients were reviewed. Results of imaging and histopathologic examinations and clinical courses of the patients were studied. RESULTS: There were 3 women and 2 men (mean age, 34.0 years). All had received a diagnosis of AIDS, and mean CD4+ cell count was 0.014 x 10(9)/L (14 cells/mm3). Computed tomographic scanning exhibited heterogeneous, enhancing sino-orbital soft tissue lesions with bony erosion, and magnetic resonance imaging disclosed soft tissue masses hypointense on T1- and T2-weighted images. The infection involved 1 or more paranasal sinuses, with extension into the right orbit in 3 patients and into the left orbit in 2. Patients were treated with aggressive surgical debridement and intravenous antifungal agents. In addition, local irrigation of amphotericin B was performed in 3 patients. Aspergillus fumigatus was found to be the cause in all 5 patients. Intracranial extension developed in 4 patients, and all subsequently died. The 2 longest surviving patients were the only ones being treated with protease inhibitors. Three patients had a history of frequent marijuana smoking. CONCLUSIONS: Sino-orbital aspergillosis is a progressive, relentless, and usually fatal opportunistic infection of advanced AIDS. Patients are first seen with long-standing headache and proptosis with minimal external inflammatory signs. Marijuana smoking may increase the risk for development of sino-orbital aspergillosis in these patients. Aggressive surgical and medical treatment, combined with newer combination therapies using protease inhibitors, may improve the longevity of these patients.
AIDS-Related Opportunistic Infections↗
Nasolacrimal duct obstruction and orbital cellulitis associated with chronic intranasal cocaine abuse.
OBJECTIVE: To report the association of acquired nasolacrimal duct obstruction and orbital cellulitis in patients with a history of chronic intranasal cocaine abuse. METHODS: Retrospective, consecutive case series. Results of imaging, histopathologic examinations, and clinical courses of these patients were studied. RESULTS: Five women and 2 men (mean age, 41 years) with a history of chronic intranasal cocaine abuse (mean, 11 years; range, 5-20 years) presented with epiphora and in some cases acute onset of periorbital pain, edema, and erythema associated with fever. The suspicion of intranasal cocaine abuse was made on anterior rhinoscopy with the detection of an absent nasal septum and inferior turbinate. Computed tomographic and magnetic resonance imaging findings in 4 patients included extensive bony destruction of the normal orbital wall architecture, opacification of the sinuses, and the presence of an intraorbital tissue mass. Histopathologic examination of the nasolacrimal duct in 2 patients and of the orbital mass in a third patient revealed marked chronic inflammation with fibrosis causing secondary nasolacrimal duct obstruction. Six patients were treated with systemic antibiotics followed by dacryocystorhinostomy in 3 patients, and a pericranial flap to insulate the exposed orbit in 1 patient. CONCLUSIONS: Chronic intranasal cocaine abuse can result in extensive bony destruction of the orbital walls with associated orbital cellulitis, and should be included in the differential diagnosis of acquired nasolacrimal duct obstruction. Anterior rhinoscopy is very helpful in establishing the correct diagnosis in these patients.
Administration, Intranasal↗
Identification of peak bone mass QTL in a spontaneously osteoporotic mouse strain.
The whole genome scan for quantitative trait loci (QTLs) specifying peak bone mass was performed with the F2 intercrosses of SAMP6, an established murine model of senile osteoporosis, exhibiting a significantly lower peak bone mass, and SAMP2, exhibiting a higher peak bone mass. Cortical thickness index (CTI), a parameter of bone mass of femurs, was measured in 488 F2 progeny at 4 months of age, when the animals attained peak bone mass by microphotodensitometry. Genetic markers were typed at 90 loci spanning all chromosomes except the Y. By interval mapping of 246 male F2 mice, two loci were identified with significant linkage to peak bone mass, one on Chromosome (Chr) 11 and another on Chr 13, with a maximum lod score of 10.8 (22.2% of the total variance) and 5.8 (10.0%), respectively. Another locus on the X Chr was suggestive of a QTL associated oppositely with a low peak bone mass to the SAMP2 allele. This association was consistent with the distribution of peak bone mass in the F1 and F2. These findings should be useful to elucidate the genetics of osteoporosis.
Animals↗
Factors influencing entrepreneurial dietitians in the use of the computer as a professional tool.
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Adult↗