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Biomedical subjects

D M Lang

Publications and source records attributed to D M Lang.

At least 19 recordsLinked to original sources
PubMed1998

Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol.

The effects of dietary cholesterol on brain amyloid precursor protein (APP) processing were examined using an APP gene-targeted mouse, genetically humanized in the amyloid beta-peptide (Abeta) domain and expressing the Swedish familial Alzheimer's disease mutations. These mice express endogenous levels of APP holoprotein and abundant human Abeta. Increased dietary cholesterol led to significant reductions in brain levels of secreted APP derivatives, including sAPPalpha, sAPPbeta, Abeta1-40, and Abeta1-42, while having little to no effect on cell-associated species, including full-length APP and the COOH-terminal APP processing derivatives. The changes in levels of sAPP and Abeta in brain all were negatively correlated with serum cholesterol levels and levels of serum and brain apoE. These results demonstrate that secreted APP processing derivatives and Abeta can be modulated in the brain of an animal by diet and provide evidence that cholesterol plays a role in the modulation of APP processing in vivo. APP gene-targeted mice lacking apoE, also have high serum cholesterol levels but do not show alterations in APP processing, suggesting that effects of cholesterol on APP processing require the presence of apoE.

Alzheimer Disease↗
PubMed1998

Identification of reggie-1 and reggie-2 as plasmamembrane-associated proteins which cocluster with activated GPI-anchored cell adhesion molecules in non-caveolar micropatches in neurons.

Neurons are believed to possess plasmalemmal microdomains and proteins analogous to the caveolae and caveolin of nonneuronal cells. Caveolae are plasmalemmal invaginations where activated glycosyl-phosphatidylinositol (GPI)-anchored proteins preferentially assemble and where transmembrane signaling may occur. Molecular cloning of rat reggie-1 and -2 (80% identical to goldfish reggie proteins) shows that reggie-2 is practically identical to mouse flotillin-1. Flotillin-1 and epidermal surface antigen (ESA) (flotillin-2) are suggested to represent possible membrane proteins in caveolae. Rat reggie-1 is 99% homologous to ESA in overlapping sequences but has a 49-amino-acid N-terminus not present in ESA. Antibodies (ABs) which recognize reggie-1 or -2 reveal that both proteins cluster at the plasmamembrane and occur in micropatches in neurons [dorsal root ganglia (DRGs), retinal ganglion, and PC-12 cells] and in nonneuronal cells. In neurons, reggie micropatches occur along the axon and in lamellipodia and filopodia of growth cones, but they do not occur in caveolae. By quantitative electronmicroscopic analysis we demonstrate the absence of caveolae in (anti-caveolin negative) neurons and show anti-reggie-1 immunogold-labeled clusters at the plasmamembrane of DRGs. When ABs against the GPI-anchored cell adhesion molecules (CAMs) F3 and Thy-1 are applied to live DRGs, the GPI-linked CAMs sequester into micropatches. Double immunofluorescence shows a colocalization of the CAMs with micropatches of anti-reggie antibodies. Thus, reggie-1 and reggie-2 identify sites where activated GPI-linked CAMs preferentially accumulate and which may represent noncaveolar micropatches (domains).

Amino Acid Sequence↗
PubMed1998

Retinal axon regeneration in the lizard Gallotia galloti in the presence of CNS myelin and oligodendrocytes.

Retinal ganglion cell (RGC) axons in lizards (reptiles) were found to regenerate after optic nerve injury. To determine whether regeneration occurs because the visual pathway has growth-supporting glia cells or whether RGC axons regrow despite the presence of neurite growth-inhibitory components, the substrate properties of lizard optic nerve myelin and of oligodendrocytes were analyzed in vitro, using rat dorsal root ganglion (DRG) neurons. In addition, the response of lizard RGC axons upon contact with rat and reptilian oligodendrocytes or with myelin proteins from the mammalian central nervous system (CNS) was monitored. Lizard optic nerve myelin inhibited extension of rat DRG neurites, and lizard oligodendrocytes elicited DRG growth cone collapse. Both effects were partially reversed by antibody IN-1 against mammalian 35/250 kD neurite growth inhibitors, and IN-1 stained myelinated fiber tracts in the lizard CNS. However, lizard RGC growth cones grew freely across oligodendrocytes from the rat and the reptilian CNS. Mammalian CNS myelin proteins reconstituted into liposomes and added to elongating lizard RGC axons caused at most a transient collapse reaction. Growth cones always recovered within an hour and regrew. Thus, lizard CNS myelin and oligodendrocytes possess nonpermissive substrate properties for DRG neurons--like corresponding structures and cells in the mammalian CNS, including mammalian-like neurite growth inhibitors. Lizard RGC axons, however, appear to be far less sensitive to these inhibitory substrate components and therefore may be able to regenerate through the visual pathway despite the presence of myelin and oligodendrocytes that block growth of DRG neurites.

Animals↗
PubMed1998

Exercise-induced bronchospasm in high school athletes via a free running test: incidence and epidemiology.

BACKGROUND: Exercise-induced bronchospasm (EIB) affects up to 35% of athletes and up to 90% of asthmatics. Asthma morbidity and mortality have increased over the past several decades among residents of Philadelphia, PA. It is possible that a simple free running test for EIB may serve as a tool to study the factors contributing to recent trends in asthma, and to screen for asthma in athletes in the urban setting. OBJECTIVES: The purposes of this study were to (1) assess a free running test to screen for EIB, and (2) examine prevalence of and epidemiologic factors associated with EIB in high school athletes. DESIGN: Cross-sectional observational study on the incidence and risk factors for EIB. To validate our method and criteria for the diagnosis of EIB, a repeat test was performed on a portion of the athletes. In a randomized single-blinded fashion, 15 athletes who had demonstrated EIB initially received albuterol or placebo prior to a repeat exercise test. SETTING: Community high school athletic facilities. PARTICIPANTS: We studied 238 male high school varsity football players. INTERVENTION: All athletes underwent an acquaintance session with a questionnaire, followed by a 1-mile outdoor run (6 to 8 mins). MEASUREMENTS: Peak expiratory flow (PEF) measurements were determined prior to and 5, 15, and 30 min after exercise. Heart rates (HRs) and dyspnea scores were measured. EIB was defined as a decrease of 15% in PEF at any time point after exercise. Associations of EIB with demographic factors were assessed by univariate and multivariate analyses. RESULTS: Two hundred thirty-eight athletes participated: 92 European-Americans (EA), 140 African-Americans (AA), 5 Hispanics, and 1 Native American. Mean age was 16+/-1 years. Average HR postexercise was 156+/-24 beats/min. Twenty-four (10%) reported a history of treated asthma. The prevalence of EIB among the remaining 214 athletes was 19 of 214 (9%). The rate of EIB among AA athletes was higher than among EA athletes: (17/126 [13%] AA vs 2/82 [2%] EA, p = 0.01). During the validation portion of the study, the placebo-treated group (n = 7) demonstrated a consistent drop in PEF after exercise on repeat testing, with a 16+/-5% fall in PEF on initial testing and a 14+/-13 drop with placebo. In contrast, the fall in airflow in the albuterol-treated athletes (n = 8) following exercise reversed with albuterol treatment, from a 15+/-6% fall in PEF at initial testing to an increase in PEF of 6+/-9% from baseline following albuterol administration. A history of wheezing (p < 0.001), residence in a poverty area (p < 0.0001), race (p = 0.01), remote history of asthma (p < 0.001), and absolute water content of the air on the day tested (p = 0.04) were significantly associated with EIB. By stepwise regression, EIB was most closely associated with a history of wheezing (p = 0.001) and poverty area residence (p = 0.003). CONCLUSIONS: Our findings indicate a substantial rate of unrecognized EIB exists among urban varsity athletes, and suggest that active screening for EIB, especially for students residing in poverty areas, may be indicated to identify individuals at risk for EIB and asthma.

Albuterol↗
PubMed1997

Guidelines and realities of asthma management. The Philadelphia story.

BACKGROUND: Guidelines from the National Heart, Lung, and Blood Institute, Bethesda, Md, have encouraged more frequent use of inhaled steroids in asthma management. OBJECTIVES: To determine (1) whether prescription rates for inhaled steroids have increased compared with prescriptions for bronchodilators and (2) significant associations of demographic factors with bronchodilator-inhaled steroid prescription ratios and with rates of inhaled steroid prescriptions. DESIGN: Cross-sectional analysis of monthly bronchodilator and inhaled steroid prescription rates, numbers and types of asthma care providers, and demographic factors. SETTING: Philadelphia, Pa. MEASUREMENTS: Using univariate and multivariate analyses, bronchodilator and inhaled steroid prescription rates were determined for 45 ZIP codes and studied for associations with race and ethnicity, poverty, educational attainment, marital status, gender, total numbers of asthma drug prescriptions, and numbers and types of asthma care providers. RESULTS: Monthly bronchodilator-inhaled steroid prescription ratios increased from July 1991 to June 1993 (P < .001). Prescription rates for inhaled steroids and inhaled bronchodilators declined, but rates for oral bronchodilators (beta-agonists and theophylline) increased. By stepwise multiple regression, higher bronchodilator-inhaled steroid prescription ratios and lower inhaled steroid prescription rates were each significantly associated with ZIP codes in which greater proportions of residents lacked a high school diploma (P < .001); associations that approached statistical significance were found for higher bronchodilator-inhaled steroid ratios and fewer asthma care providers (P = .05) and for lower inhaled steroid prescription rates and lower proportions of asthma specialists (P = .04). CONCLUSIONS: In Philadelphia, a gap exists between optimal asthma drug prescribing and actual prescribing patterns that has widened from July 1991 to June 1993. Underuse of inhaled steroids is most closely associated with lower educational attainment, suggesting that interventions that include addressing the special asthma care needs of a low-literacy population will be required to achieve the goals of the National Asthma Education Program.

Administration, Inhalation↗
PubMed1996

Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a "humanized" Abeta sequence.

The processing of the beta-amyloid precursor protein (APP) in vivo has been characterized in a novel animal model that recapitulates, in part, the APP genotype of a familial form of Alzheimer's disease (AD). A gene-targeting strategy was used to introduce the Swedish familial AD mutations and convert mouse Abeta to the human sequence. The mutant APP is expressed at normal levels in brain, and cleavage at the mutant beta-secretase site is both accurate and enhanced. Furthermore, human Abeta production is significantly increased to levels 9-fold greater than those in normal human brain while nonamyloidogenic processing is depressed. The results on Abeta production extend similar findings obtained in cell culture to the brain of an animal and substantiate Abeta as a etiological factor in Swedish familial AD. These animals provide several distinguishing features over others created by conventional transgenic methodologies. The spatial and temporal expression patterns of human Abeta are expected to be faithfully reproduced because the gene encoding the mutant APP remains in its normal chromosomal context. Thus, the neuropathological consequences of human Abeta overproduction can be evaluated longitudinally in the absence of potential mitigating effects of APP overexpression or presence of the mouse Abeta peptide.

Alzheimer Disease↗
PubMed1996

Modulation of the inhibitory substrate properties of oligodendrocytes by platelet-derived growth factor.

Although growth cones typically collapse after encountering O1/galactocerebroside (GalC)-positive oligodendrocytes, the majority of growth cones traversed oligodendrocytes, which were raised for 8-10 d in medium containing 10 ng/ml platelet-derived growth factor (PDGF). Oligodendrocytes raised 8-10 d in control medium caused growth cone collapse as they normally do, but failed to elicit this response after being transferred to PDGF-containing medium for an additional 8-10 d. The opposite was observed when PDGF-treated oligodendrocytes were brought to control medium. Growth cones collapsed when contacting these cells. Oligodendrocytes also lost their collapse-inducing activity when raised in medium conditioned by astrocytes, known to produce PDGF. Antibody IN-1 is directed against against neurite growth inhibitors (NI), proteins of 35 and 250 kDa on the surface of O1/GalC-positive oligodendrocytes, which are known to elicit growth cone collapse. IN-1 immunoreactivity was markedly reduced in PDGF-treated oligodendrocytes. However, both PDGF-treated and control oligodendrocytes exhibited myelin-associated glycoprotein, proteolipid protein, and myelin basic protein immunoreactivity. This suggests that PDGF-treatment affects NI expression but does not interfere with the expression of advanced myelin marker proteins. Because NI cause growth cone collapse, the loss of collapse-inducing activity by PDGF-treated oligodendrocytes suggests that PDGF regulates, directly or indirectly, the expression of these proteins.

Animals↗
PubMed1996

Biologically active monomeric and heterodimeric recombinant human calpain I produced using the baculovirus expression system.

Calpain I is a heterodimeric protein that is part of a family of calcium-activated intracellular cysteine proteases presumed to play a role in mediating signals transduced by calcium. Expression of bioactive recombinant human calpain I has been achieved using the baculovirus expression system, by either co-infection with two viruses, each expressing one of the subunits, or infection with a single virus containing both subunits. The approximately 80 kDa catalytic subunit exhibited calcium-dependent proteolytic activity when expressed alone or with the approximately 30 kDa regulatory subunit. Baculoviral recombinant calpain I appeared fully active in that the catalytic subunit in unpurified cell extracts exhibited calcium-dependent autocatalytic cleavage at the correct locus. The amount of approximately 80 kDa subunit accumulated at steady state was greatly increased by co-expression of the approximately 30 kDa subunit, suggesting a possible role for enzyme stabilization by the latter subunit. The recombinant human calpain I was purified to near homogeneity and compared with purified native human erythrocyte calpain I. The recombinant and native enzymes had equivalent inhibition constants for structurally diverse calpain inhibitors, identical calcium activation profiles, and similar specific activities, demonstrating the suitability of using the recombinant protein for studies of the native enzyme.

Amino Acid Sequence↗
PubMed1996

Adaptive plasticity of Xenopus glial cells in vitro and after CNS fiber tract lesions in vivo.

Xenopus oligodendrocytes and aspects of their differentiation were analyzed in vitro and in vivo using cell- and stage-specific antibodies. Undifferentiated oligodendrocytes were derived from optic nerves or spinal cords. They divided in vitro, were of elongated shape, were glial fibrillary acidic protein and O4 positive, transiently exhibited several antigens including HNK-1 and L1, and promoted axon growth as do Schwann cells. With forskolin they differentiated and, much like myelin-forming oligodendrocytes in the intact optic nerve and spinal cord, they expressed sets of advanced myelin markers. These advanced myelin markers disappeared from the regenerating optic nerve 4 weeks after lesion. The optic nerve instead was populated by cells with radial processes and somata in the center of the nerve; among them were cells and processes that were O4 positive and that are suspected to represent undifferentiated oligodendrocytes. Where processes of these cells reached to the retinal axons in the nerve's periphery, advanced myelin markers typical of differentiated oligodendrocytes reappeared 8 weeks after lesion. These glial changes did not occur in the absence of retinal axons. Thus, the apparent capability of Xenopus oligodendrocytes to adapt to the transient absence, reappearance, and regenerative state of the axons enables them to contribute to central nervous system fiber tract repair. This occurs in the lesioned optic nerve but not in the spinal cord, where no such glial changes were observed and where axons fail to regenerate.

Adaptation, Physiological↗
PubMed1996

Theophylline improves measurements of respiratory muscle efficiency.

To determine the effect of theophylline on respiratory muscle efficiency (RME), 12 normal subjects were given theophylline vs placebo in a double-blind, randomized crossover protocol. Spirometry, resting energy expenditure, minute ventilation, RME and oxygen cost of breathing were measured at baseline, after taking theophylline, and after placebo. RME was calculated by dividing the added work required to breathe through a threshold load by the added energy consumed during loaded breathing. Oxygen cost of breathing was calculated by dividing the increase in oxygen consumption induced by breathing an air/carbon dioxide mixture by the associated increase in minute ventilation. RME increased from 3.3 +/- 1.6% at baseline to 7.9 +/- 3.2% after theophylline (p < 0.01) but did not change significantly after placebo (4.8 +/- 2.4%). Oxygen cost of breathing decreased from 3.9 +/- 2.4 mL O2 per liter at baseline to 1.7 +/- 0.7 mL O2 per liter after theophylline (p < 0.05) but did not change significantly after placebo (2.8 +/- 1.3 mL O2 per liter). Theophylline use was also associated with an 18% increase in minute ventilation (p < 0.01) and a 15.7% increase in resting energy expenditure (p < 0.01). Theophylline improves measured RME and reduces oxygen cost of breathing in normal subjects. These effects are offset by increases in resting energy expenditure and minute ventilation.

Adult↗
PubMed1996

Patellar resurfacing versus retention in total knee arthroplasty.

We studied 40 patients in whom the patella was not severely deformed and who were undergoing primary total knee arthroplasty (TKA) for osteoarthritis by one surgeon using one type of prosthesis. They were randomly allocated either to have the patella retained or resurfaced with a cemented, all-polyethylene component regardless of the state of the patellar articular cartilage. Apart from removal of osteophytes, no surgery was undertaken on the retained patellae. All 38 surviving patients were evaluated at three years using the HSS knee score and a new, specifically designed Patellar score (maximum score of 30). No TKA was revised, but two patients in the resurfacing group had a further unrelated procedure. The mean HSS and Patellar scores at follow-up were 89 and 28 in the patellar retention group and 83 and 26 in the patellar resurfacing group. Statistically significant lower scores for both were recorded in women and in heavier patients. Stair-climbing ability was significantly better in the retention group. Although there were no complications related to patellar resurfacing, in the medium term we did not find any significant benefit from resurfacing the patella during TKA for osteoarthritis if it was not severely deformed.

Aged↗
PubMed1995

Gender risk for anaphylactoid reaction to radiographic contrast media.

BACKGROUND: Female predominance has been reported previously in series of anaphylaxis cases; however, no definite precedent has been established for greater risk of anaphylactoid reaction caused by contrast media infusion on the basis of gender. OBJECTIVE: This study was designed to determine whether greater risk for anaphylactoid reaction caused by intravenous contrast media infusion exists in association with female gender. METHODS: Rates of anaphylactoid and severe anaphylactoid reaction, according to gender, were determined in a sample of 5264 consecutive patients receiving conventional radiocontrast media during performance of computed tomography. RESULTS: Of 80 adverse reactions caused by contrast media infusion, 73 (1.39%) were classified as anaphylactoid in nature. Among 5191 patients who received intravenous contrast media without experiencing an anaphylactoid reaction, there were 2642 male patients (51%) and 2549 female patients (49%); reactors included 22 male patients and 51 female patients (odds ratio = 2.40, 95% confidence interval = 1.42-4.10, p < 0.0005). Female patients also comprised 21 of 22 cases of severe anaphylactoid reaction (odds ratio = 21.77, 95% confidence interval = 3.13-435.12, p < 0.0005). CONCLUSION: Greater risk for anaphylactoid and severe anaphylactoid reaction exists in association with female gender. Further studies are needed to identify mechanisms that can explain this risk. The importance of these findings for cost-effective use of lower osmolality contrast media need to be determined.

Anaphylaxis↗
PubMed1995

Anaphylactoid and anaphylactic reactions. Hazards of beta-blockers.

Studies have demonstrated greater hazards associated with anaphylaxis in patients receiving beta-blockers. Serious anaphylaxis is more frequent. Evidence suggests this occurs via modulation of adenylate cyclase, which can influence release of anaphylactogenic mediators. Treatment of anaphylaxis in patients exposed to beta-blockers is complicated because therapeutic administration of epinephrine (adrenaline) may be ineffective or promote undesired alpha-adrenergic and vagotonic effects. Risk reduction efforts should be considered for patients receiving beta-blockers who are prone to experience anaphylaxis.

Adrenergic beta-Antagonists↗
PubMed1995

Reevaluation of the growth-permissive substrate properties of goldfish optic nerve myelin and myelin proteins.

To determine whether optic nerve myelin of goldfish carries mammalian-like neurite growth inhibitory proteins which can be neutralized by the antibody IN-1, myelin fractions of fish optic nerves were used as substrates for fish retinal ganglion cell axons and rat dorsal root ganglia (DRG). Axonal growth was monitored and compared with that of IN-1 treated preparations. Growth of fish retinal axons and rat DRG neurites was substantial on goldfish optic nerve myelin and no improvement was observed with IN-1. In contrast, rat CNS myelin allowed only poor growth, and number of axons and length of DRG neurites increased significantly with IN-1. In addition, proteins of fish optic nerve myelin and bovine CNS myelin were extracted, reconstituted in liposomes and applied to growth cones. When goldfish myelin proteins in liposomes were seeded onto growth cones, 77% of fish and 89% of rat DRG growth cones continued to elongate, and the proportion of elongating fish growth cones (80%) did not significantly change when liposomes were pretreated with IN-1. But 73% of fish and 93% of rat growth cones collapsed with liposomes containing proteins from bovine CNS myelin. Upon IN-1 treatment, only 24% of fish growth cones collapsed. Thus, axon growth in vitro indicates that goldfish optic nerves, which permit successful axon regeneration in vivo, lack mammalian-like neurite growth inhibitors which are neutralized by IN-1.

Animals↗
PubMed1995

CNS myelin and oligodendrocytes of the Xenopus spinal cord--but not optic nerve--are nonpermissive for axon growth.

In vitro assays reveal that myelin and oligodendrocytes of the Xenopus spinal cord (SC) are--unlike corresponding components of the optic nerve/tectum (OT)--nonpermissive substrates for regenerating retinal axons. The number of growth cones that crossed SC oligodendrocytes is low but increases significantly (four- to fivefold) in the presence of the antibody IN-1, in which case their numbers are similar to the number of growth cones (approximately 60%) that cross OT oligodendrocytes with or without IN-1. IN-1 neutralizes neurite growth inhibitors (NI) of rat CNS myelin, indicating that mammalian-like NI are associated with Xenopus SC myelin and oligodendrocytes but not with the OT. IN-1 immunocytochemistry on sections supports this view: SC myelin was stained with IN-1, whereas OT myelin and PNS myelin were not.

Animals↗
PubMed1994

Patterns of asthma mortality in Philadelphia from 1969 to 1991.

BACKGROUND: The rate of mortality from asthma has increased substantially in the United States since 1978. We analyzed the patterns of the rates of death from asthma in Philadelphia between 1969 and 1991. METHODS: The rates of death from asthma were analyzed and compared with trends in the concentrations of major air pollutants: ozone, carbon monoxide, nitrogen dioxide, particulate matter (particles < 10 microns in diameter), and sulfur dioxide. Univariate and multivariate analyses were used to study the rates of death from asthma from 1985 to 1991 and their association with race, poverty, sex, and other factors. RESULTS: The rate of death from asthma decreased from 1.68 per 100,000 people in 1969 to 0.68 per 100,000 in 1977, but then increased to 0.92 per 100,000 in 1978 and 2.41 per 100,000 in 1991. Between 1965 and 1990, the concentrations of major air pollutants declined substantially. From 1985 to 1991, 258 people were identified for whom asthma was the primary cause of death. According to multivariate analysis, the rates of death from asthma from 1985 to 1991 were significantly higher in census tracts with higher percentages of blacks (P = 0.032), Hispanics (P = 0.013), female residents (P < 0.001), and people with incomes in the poverty range (P < 0.001). CONCLUSIONS: The rates of death from asthma have increased in Philadelphia, whereas concentrations of major air pollutants have declined. The rates are highest in census tracts with the highest percentages of poor people and minority residents, particularly blacks. Public health efforts should target urban areas where the risk of death from asthma is highest.

Adolescent↗