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Biomedical subjects

R S Young

Publications and source records attributed to R S Young.

At least 19 recordsLinked to original sources
PubMed2002

Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area.

Questions have arisen regarding the risk of developing symptomatic Histoplasma capsulatum infection among patients who undergo transplant-related immunosuppression in areas endemic for histoplasmosis. Our medical center is located in a hyperendemic area for histoplasmosis, where three large outbreaks occurred since 1978. We undertook a retrospective chart review of 137 patients who received allogeneic bone marrow transplant and of 449 patients who received solid organ transplant from January 1994 to December 1996 in order to assess the incidence of active histoplasmosis. Charts were reviewed before and after transplantation for clinical outcomes, H. capsulatum serologies and antigen results, and microbiological and radiological results. After a mean follow-up duration exceeding 16 months, no patient was diagnosed with histoplasmosis. In the absence of an outbreak, histoplasmosis is a rare infection following the immunosuppression of allogeneic bone marrow or solid organ transplantation even in a hyperendemic area. Pre-transplant serologies or chest radiographs consistent with prior infection were not associated with post-transplant histoplasmosis.

Adult↗
PubMed2001

Cytoplasmic signals mediate apical early endosomal targeting of endotubin in MDCK cells.

Endotubin is an integral membrane protein that targets into apical endosomes in polarized epithelial cells. Although the role of cytoplasmic targeting signals as mediators of basolateral targeting and endocytosis is well established, it has been suggested that apical targeting requires either N-glycosylation of the ectoplasmic domains or partitioning of macromolecules into glycolipid-rich rafts. However, we have previously shown that the cytoplasmic portion of endotubin possesses signals that are necessary for its proper sorting into the apical early endosomes. To further define the targeting signals involved in this apically directed event, as well as to determine if the cytoplasmic domain was sufficient to mediate apical endosomal targeting, we generated a panel of endotubin and Tac-antigen chimeras and expressed them in Madin-Darby canine kidney cells. We show that both the apically targeting wild-type endotubin and a basolaterally targeted cytoplasmic domain mutant do not associate with rafts and are TX-100 soluble. The cytoplasmic tail of endotubin is sufficient for apical endosomal targeting, as chimeras with the endotubin cytoplasmic domain and Tac transmembrane and extracellular domains are efficiently targeted to the apical endosomal compartment. Furthermore, we show that overexpression of these chimeras results in their missorting to the basolateral membrane, indicating that the apical sorting process is a saturable event. These results show that cells contain machinery in both the biosynthetic and endosomal compartments that recognize cytoplasmic apical sorting signals.

Animals↗
PubMed2001

Expression of cytolethal distending toxin and hemolysin is not required for pustule formation by Haemophilus ducreyi in human volunteers.

Haemophilus ducreyi makes cytolethal distending toxin (CDT) and hemolysin. In a previous human challenge trial, an isogenic hemolysin-deficient mutant caused pustules with a rate similar to that of its parent. To test whether CDT was required for pustule formation, six human subjects were inoculated with a CDT mutant and parent at multiple sites. The pustule formation rates were similar at both parent and mutant sites. A CDT and hemolysin double mutant was constructed and tested in five additional subjects. The pustule formation rates were similar for the parent and double mutant. These results indicate that neither the expression of CDT, nor that of hemolysin, nor both are required for pustule formation by H. ducreyi in humans.

Adult↗
PubMed2001

Haemophilus ducreyi lipooligosaccharide mutant defective in expression of beta-1,4-glucosyltransferase is virulent in humans.

The lipooligosaccharide (LOS) of Haemophilus ducreyi contains a major glycoform that is immunochemically identical to paragloboside, a glycosphingolipid precursor of major human blood group antigens. We recently identified the gene responsible for the glucosyltransferase activity and constructed an isogenic mutant (35000glu-) deficient in this activity. 35000glu- makes an LOS that consists only of the heptose trisaccharide core and 2-keto-deoxyoctulosonic acid (KDO). For this study, the mutant was reconstructed in the 35000HP (human passaged [HP]) background. Five human subjects were inoculated with 35000HP and 35000HPglu- in a dose-response trial. The pustule formation rates were 40% (95% confidence interval [CI], 13.7 to 72.6%) at 10 sites for 35000HP and 46.7% (95% CI, 24.8 to 69.9%) at 15 sites for 35000HPglu-. The histopathology and recovery rates of H. ducreyi from surface cultures and biopsies obtained from mutant and parent sites were similar. These results indicate that the expression of glycoforms with sugar moieties extending beyond the heptose trisaccharide core is not required for pustule formation by H. ducreyi in humans.

Adult↗
PubMed2001

Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalation.

Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuel-induced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m3 JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE2. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-alpha, and 8-iso-PGF2,, levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice.

Administration, Inhalation↗
PubMed2001

Addressing psychosocial issues and problems of co-morbidity for Native American clients with substance abuse problems: a conference proceedings.

This proceedings consists of five papers presented at a conference titled: Psychosocial Issues and Problems of Co-Morbidity for Native American Clients with Substance Abuse Problems. The conference was held June 2-4, 1999, in Albuquerque New Mexico, and was hosted by the Native American Research and Training Center (NARTC) and the National Center for American Indian and Alaska Native Mental Health Research.

Adult↗
PubMed2000

Proteomic analysis of the renal effects of simulated occupational jet fuel exposure.

We analyzed protein expression in the cytosolic fraction prepared from whole kidneys in male Swiss-Webster mice exposed 1 h/day for five days to aerosolized JP-8 jet fuel at a concentration of 1000 mg/m3, simulating military occupational exposure. Kidney cytosol samples were solubilized and separated via large-scale, high-resolution two-dimensional electrophoresis (2-DE) and gel patterns scanned, digitized and processed for statistical analysis. Significant changes in soluble kidney proteins resulted from jet fuel exposure. Several of the altered proteins were identified by peptide mass finger-printing and related to ultrastructural abnormalities, altered protein processing, metabolic effects, and paradoxical stress protein/detoxification system responses. These results demonstrate a significant but comparatively moderate JP-8 effect on protein expression in the kidney and provide novel molecular evidence of JP-8 nephrotoxicity. Human risk is suggested by these data but conclusive assessment awaits a noninvasive search for biomarkers in JP-8 exposed humans.

Aerosols↗
PubMed2000

Effect of simulating leg length inequality on pelvic torsion and trunk mobility.

Although techniques such as roentgenograms and magnetic resonance imaging can provide definitive information about leg length inequality, they are not easily implemented for screening purposes. Using relative heights of palpated iliac crests as criteria for determining degree of lateral pelvic tilt, we examined the immediate effect of simulating leg length inequality on pelvic torsion and trunk flexion. In seven healthy men and 22 healthy women, 18-28 years of age, a lift of at least 15 mm was placed under either foot to laterally tilt the pelvis 1.2 degrees or more. In eight subjects with pre-existing lateral pelvic tilts of 1.8 degrees or more, a lift was also used to eliminate the tilt. We examined how this tilting affected torsion between the innominates and mobility of the trunk. The innominate contralateral to the lift became more anteriorly rotated than the ipsilateral innominate and lateral flexion of the trunk increased toward the side of the lift. Both of these effects can be associated with clinical leg length inequality, so a lateral pelvic tilt on the order of 1.2 degrees, if encountered in the clinic, should signal the suitability of more extensive examination for possible lower limb asymmetry.

Adolescent↗
PubMed2000

Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.

Adult↗
PubMed2000

Expression of peptidoglycan-associated lipoprotein is required for virulence in the human model of Haemophilus ducreyi infection.

Haemophilus ducreyi expresses a peptidoglycan-associated lipoprotein (PAL) that exhibits extensive homology to Haemophilus influenzae protein 6. We constructed an isogenic PAL mutant (35000HP-SMS4) by the use of a suicide vector that contains lacZ as a counterselectable marker. H. ducreyi 35000HP-SMS4 and its parent, 35000HP, had similar growth rates in broth and similar lipooligosaccharide profiles. 35000HP-SMS4 formed smaller, more transparent colonies than 35000HP and, unlike its parent, was hypersensitive to antibiotics. Complementation of the mutant in trans restored the parental phenotypes. To test whether expression of PAL is required for virulence, nine human volunteers were experimentally infected. Each subject was inoculated with two doses (41 to 89 CFU) of live 35000HP and one dose of heat-killed bacteria on one arm and with three doses (ranging from 28 to 800 CFU) of live 35000HP-SMS4 on the other arm. Papules developed at similar rates at sites inoculated with the mutant or parent but were significantly smaller at mutant-inoculated sites than at parent-inoculated sites. The pustule formation rate was 72% (95% confidence interval [CI], 46.5 to 90.3%) at 18 parent sites and 11% (95% CI, 2.4 to 29.2%) at 27 mutant sites (P < 0.0001). The rates of recovery of H. ducreyi from surface cultures were 8% (n = 130; 95% CI, 4.3 to 14.6%) for parent-inoculated sites and 0% (n = 120; 95% CI, 0.0 to 2.5%) for mutant-inoculated sites (P < 0.001). H. ducreyi was recovered from six of seven biopsied parent-inoculated sites and from one of three biopsied mutant-inoculated sites. Confocal microscopy confirmed that the bacteria present in a mutant inoculation site pustule lacked a PAL-specific epitope. Although biosafety regulations precluded our testing the complemented mutant in humans, these results suggest that expression of PAL facilitates the ability of H. ducreyi to progress to the pustular stage of disease.

Adult↗
PubMed2000

Effects of short-term JP-8 jet fuel exposure on cell-mediated immunity.

The U.S. Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to environmental toxicants such as JP-8 may have significant effects on host physiology. Jet fuel exposure has been shown to cause human liver dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss of immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). In the current study, an in-depth analysis of the effects of JP-8 exposure on cellular immunity was performed. Short-term (7 days, 1 h/day), low-concentration (1000 mg/m3) exposures were conducted in mice, and T cell and natural killer (NK) cell functions were analyzed 24 h after the last exposure. The exposure regimen was found to almost completely ablate NK cell function, as well as significantly suppress the generation of lymphokine-activated killer (LAK) cell activity. Furthermore, JP-8 exposure suppressed the generation of cytotoxic T lymphocyte (CTL) cells from precursor T cells, and inhibited helper T cell activity. These findings demonstrate that JP-8 jet fuel exposure has significant detrimental effects on immune functions of exposed individuals. JP-8 jet fuel should be considered a potential and significant immunotoxicant. Chronic exposure to JP-8 may have serious implications to the long-term health of exposed individuals.

Administration, Inhalation↗
PubMed2000

Substance P as prophylaxis for JP-8 jet fuel-induced immunotoxicity.

Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system that persisted for extended periods of time. It was found that administration of aerosolized substance P (SP) was able to protect exposed animals from JP-8-induced immune changes, whereas administration of SP antagonists compounded the deleterious effects ofjet fuel exposure. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure. In the current study, aerosolized SP was analyzed for its potential prophylactic ability to counteract JP-8-induced immunotoxicity. It was observed that concentrations as low as 1 nM were effective in ameliorating the effects of JP-8 exposure on the immune system. SP administered before JP-8 exposure could prophylactically protect both the spleen and thymus from significant organ weight loss, but could not completely restore immune cell numbers to normal, baseline levels. Furthermore, SP treatment could be delayed as long as 1 h postexposure and reverse the effects of jet fuel exposure on immune organ weight loss and immune cell recovery. Significantly, SP could be given 15 min pre-JP-8 exposure but neither 1 nor 6 h pre-JP-8 exposure, and prevent immune dysfunction as measured in mitogenesis assays. However, SP could be delayed up to 6 h post-JP-8 exposure and still almost completely restore immune function. Thus, SP appears able to both prevent and reverse the immunotoxicological effects associated with JP-8 exposure. These results also provide insight into the manner in which JP-8 jet fuel mediates its effects on the immune system.

Animals↗
PubMed2000

Jet fuel-induced immunotoxicity.

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

Animals↗
PubMed1999

Proteomic analysis of simulated occupational jet fuel exposure in the lung.

We analyzed protein expression in the cytosolic fraction prepared from whole lung tissue in male Swiss-Webster mice exposed 1 h/day for seven days to aerosolized JP-8 jet fuel at concentrations of 1000 and 2500 mg/m3, simulating military occupational exposure. Lung cytosol samples were solubilized and separated via large scale, high resolution two-dimensional electrophoresis (2-DE) and gel patterns scanned, digitized and processed for statistical analysis. Significant quantitative and qualitative changes in tissue cytosol proteins resulted from jet fuel exposure. Several of the altered proteins were identified by peptide mass fingerprinting, confirmed by sequence tag analysis, and related to impaired protein synthetic machinery, toxic/metabolic stress and detoxification systems, ultrastructural damage, and functional responses to CO2 handling, acid-base homeostasis and fluid secretion. These results demonstrate a significant but comparatively moderate JP-8 effect on protein expression and corroborate previous morphological and biochemical evidence. Further molecular marker development and mechanistic inferences from these observations await proteomic analysis of whole tissue homogenates and other cell compartment, i.e., mitochondria, microsomes, and nuclei of lung and other targets.

Animals↗
PubMed1999

S-cone contribution to pupillary responses evoked by chromatic flash offset.

On a green or red background, the action spectrum of the pupillary responses evoked following the offset of chromatic test flashes shows a prominent short-wavelength lobe and suggests the contribution from photoreceptors other than the previously inferred M- and L-cones (Kimura & Young, Vision Research (1996). 36, 1543-1550), most likely from S-cones. Systematic changes in the shape of the intensity versus amplitude functions with test wavelengths and in the shape of the short-wavelength lobe with response amplitude criteria suggest an antagonistic interaction involving the short- and longer-wavelength photoreceptors.

Color Perception↗
PubMed1999

Expression of sialylated or paragloboside-like lipooligosaccharides are not required for pustule formation by Haemophilus ducreyi in human volunteers.

The lipooligosaccharide (LOS) of Haemophilus ducreyi, the etiologic agent of chancroid, chemically and immunologically resembles human glycosphingolipid antigens. To test whether LOS that contains paragloboside-like structures was required for pustule formation, an isogenic mutant (35000HP-RSM2) was constructed in losB, which encodes D-glycero-D-manno-heptosyltransferase. 35000HP-RSM2 produces a truncated LOS whose major glycoform terminates in a single glucose attached to a heptose trisaccharide core and 2-keto-3-deoxyoctulosonic acid. Five human subjects were inoculated with 35000HP and 35000HP-RSM2 in a dose-response trial. For estimated delivered doses (EDDs) of >/=25 CFU, the pustule formation rates were 80% for 35000HP and 58% for 35000HP-RSM2. Preliminary data indicated that a previously described Tn916 losB mutant made a minor glycoform that does not require DD-heptose to form the terminal N-acetyllactosamine. If 35000HP-RSM2 made this glycoform, then 35000HP-RSM2 could theoretically make a sialylated glycoform. To test whether sialylated LOS was required for pustule formation, a second trial comparing an isogenic sialyltransferase mutant (35000HP-RSM203) to 35000HP was performed in five additional subjects. For EDDs of >/=25 CFU, the pustule formation rates were 30% for both 35000HP and 35000HP-RSM203. The histopathology and recovery rates of H. ducreyi from surface cultures and biopsies obtained from mutant and parent sites in both trials were similar. These results indicate that neither the expression of a major glycoform resembling paragloboside nor sialylated LOS is required for pustule formation by H. ducreyi in humans.

Adult↗
PubMed1999

Emerging epidemic of type 2 diabetes in youth.

This review considers the epidemiologic evidence of an increasing incidence of type 2 diabetes in youth, the classification and diagnostic issues related to diabetes in young populations, pathophysiologic mechanisms relevant to the increasing incidence, the role of genetics and environment, and the community challenge for prevention and treatment. Type 2 diabetes in youth has been recognized to be frequent in populations of native North Americans and to comprise some 30 percent of new cases of diabetes in the 2nd decade of life, largely accounted for by minority populations and associated with obesity. Among Japanese schoolchildren, type 2 diabetes is seven times more common than type 1, and its incidence has increased more than 30-fold over the past 20 years, concomitant with changing food patterns and increasing obesity rates. The forms of diabetes seen in children and youth include typical type 1, occurring in all races; type 2, seen predominantly in minority youth; atypical diabetes, seen as an autosomal dominantly transmitted disorder in African-American populations; and maturity-onset diabetes of the young (MODY), seen rarely and only in Caucasians. Of the nonautoimmune forms of diabetes seen in youth, only type 2 diabetes is increasing in incidence. Proper classification requires consideration of onset (acute/severe versus insidious), ethnicity, family history, presence of obesity, and if necessary, studies of diabetes related autoimmunity. Insulin resistance predicts the development of diabetes in Pima Indians, in offspring of parents with type 2 diabetes, and in other high-risk populations. African-American children and youth have greater insulin responses during glucose tolerance testing and during hyperglycemic clamp study than do whites. There is also evidence of altered beta-cell function preceding the development of hyperglycemia. Of particular interest is the evidence that abnormal fetal and infantile nutrition is associated with the development of type 2 diabetes in adulthood. The thrifty phenotype hypothesis states that poor nutrition in fetal and infant life is detrimental to the development and function of the beta-cells and insulin sensitive tissues, leading to insulin resistance under the stress of obesity. The thrifty genotype hypothesis proposes that defective insulin action in utero results in decreased fetal growth as a conservation mechanism, but at the cost of obesity-induced diabetes in later childhood or adulthood. The vast majority of type 2 diabetes in adults is polygenic and associated with obesity. Monogenic forms (MODY, maternally transmitted mitochondrial mutations) are rare, but are more likely to appear in childhood. Linkage studies of the common polygenic type 2 diabetes have emphasized the heterogeneity of the disorder. The prevention and treatment of type 2 diabetes in children and youth is a daunting challenge because of the enormous behavioral influence, difficulty in reversing obesity, and typical nonadherence in this age-group. The emerging epidemic of type 2 diabetes in the pediatric population, especially among minorities whose proportion in the U.S. population is increasing, presents a serious public health problem. The full effect of this epidemic will be felt as these children become adults and develop the long-term complications of diabetes.

Adolescent↗