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Biomedical subjects

S Horowitz

Publications and source records attributed to S Horowitz.

At least 37 records · Page 2Linked to original sources
PubMed1999

Induction of metallothionein and heme oxygenase in rats after inhalation of endotoxin.

Various stress proteins appear to play a role in injury and repair produced by inhaled pollutants. The present study examined the effect of inhaled endotoxin on the expression of the metallothionein and heme oxygenase genes. Rats were exposed to saline or endotoxin aerosols for 3 h and sacrificed up to 3 d following exposure. The significant induction of metallothionein mRNA in both the lung (fourfold increase) and liver (one-fold) were greatest at 3 h and returned to basal levels by 24 h after endotoxin exposure. Similarly, the increase in tissue metallothionein was greater in the lung. In situ hybridization in mice showed large increases in the relative abundance of metallothionein transcripts in epithelial cells of the conducting airways, in surrounding airway tissue, and in the nearby gas exchange region. While an endotoxin-induced significant increase in heme oxygenase mRNA followed a time course similar to that observed for metallo thionein, the relative magnitude was reversed for the lung and liver. Heme oxygenase mRNA was induced greater in the liver (twofold) than in the lung (60% above control). Our findings demonstrate that metallothionein and heme oxygenase are early response genes that are rapidly activated after inhalation of occupationally relevant concentrations of endotoxin.

Animals↗
PubMed1999

Expression of IL-12, IL-10, PGE2, sIL-2R and sIL-6R in seminal plasma of fertile and infertile men.

The involvement of cytokines and other immunoregulatory factors in male infertility is still unclear. In the present study we compared the levels of IL-12, IL-10, PGE2, sIL-2R and sIL-6R in the seminal plasma (SP) of fertile and infertile men. Four groups were included: fertile donors (FERT), infertile men with azoospermia (AZOO), and infertile men with either oligoterato-asthenoazoospermia (OTA), or OTA with genital infection (OTA-INF). Cytokines and cytokine-soluble receptors in semen were evaluated by specific ELISA commercial kits. The levels of IL-12, sIL-2R and sIL-6R were similar in SP of fertile and infertile men. The mean levels of IL-10 in the SP of FERT, OTA and AZOO were 5.6 +/- 0.9, 4 +/- 2.8 and 8 +/- 3.5 pg ml-1, respectively, and did not differ significantly. The mean level of IL-10 in SP from OTA-INF (0.9 +/- 0.5 pg ml-1) was significantly lower than that for FERT (5.6 +/- 1.9 pg ml-1; P = 0.02) and AZOO (8.2 +/- 3.4 pg ml-1; P = 0.05), but not significantly different from that for OTA (3.7 +/- 2.1 pg ml-1). The mean SP level of PGE2 was significantly lower in SP of OTA-INF than FERT (7.67 +/- 2.26 and 19.67 +/- 3.69 micrograms ml-1, respectively; P < 0.02). In conclusion, the seminal plasma from fertile and infertile men contained similar levels of IL-12, sIL-2R and sIL-6R. However, the levels of IL-10 were significantly lower in SP from OTA-INF compared to FERT and AZOO. Our results indicate that specific cytokines and their soluble receptors are involved in the male reproductive system.

Dinoprostone↗
PubMed1999

Therapy of desmoid tumors and fibromatosis using vinorelbine.

In patients with either desmoids or fibromatosis who do not tolerate vinblastine and methotrexate because of neurotoxicity, the combination of vinorelbine and methotrexate can be substituted in most. Patients with the same condition who had not been previously treated with a combination of vinblastine and methotrexate responded well to the combination of vinorelbine and methotrexate, with significantly less neurotoxicity and a similar objective and subjective response rate. Sixty percent of patients had either a substantial partial remission or a complete remission. In no patients did the disease progress while they were receiving this therapy. Symptomatic relief, primarily of pain, occurred in 80% of patients. While minimal neurotoxicity was seen in 16% of these patients, it did not interfere with the completion of therapy. The combination of vinorelbine and methotrexate appears to be active in the treatment of both desmoid tumors and fibromatosis and is associated with significantly less neurotoxicity then that seen with the combination of vinblastine and methotrexate. No long-term toxicity was seen in any patient in this series.

Adolescent↗
PubMed1999

Hyperoxia in cell culture. A non-apoptotic programmed cell death.

Here we discuss the morphological features and our current understanding of the pathways involved in non-apoptotic cell death from O2 toxicity. Preliminary data on hyperoxic signaling indicate that NF-kappa B translocation (and presumptive activation) is not a result of the p42/p44 MAPK pathway, but a likely downstream consequence of activation of the JNK pathway. Our observations suggest the existence of multiple signal transduction pathways in hyperoxia-induced cell death: one involved in the stress response which appears to be NF-kappa B-dependent and another in cell death.

Animals↗
PubMed1999

Hyperoxia-induced cell death in the lung--the correlation of apoptosis, necrosis, and inflammation.

Prolonged exposure to hyperoxia causes tissue damage in many organs and tissues. Since the entire surface area of lung epithelium is directly exposed to O2 and other inhaled agents, hyperoxia leads to the development of both acute and chronic lung injuries. These pathologic changes in the lung can also be seen in acute lung injury (ALI) in response to other agents. Simple strategies to mitigate hyperoxia-induced ALI might not be effective by virtue of merely reducing or augmenting the extent of apoptosis of pulmonary cells. Identification of the specific cell types undergoing apoptosis and further understanding of the precise timing of the onset of apoptosis may be necessary in order to gain a greater understanding of the connection between apoptosis and tolerance to hyperoxia and ALI. Attention should also be focused on other forms of non-apoptotic programmed cell death.

Animals↗
PubMed1999

Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells.

We have previously demonstrated that the lungs of mice can exhibit increased programmed cell death or apoptosis after hyperoxic exposure in vivo. In this report, we show that hyperoxic exposure in vitro can also induce apoptosis in cultured murine macrophage cells (RAW 264.7) as assessed by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end-labeling, and nucleosomal assays. To further delineate the signaling pathway of hyperoxia-induced apoptosis in RAW 264.7 macrophages, we first show that hyperoxia can activate the mitogen-activated protein kinase (MAPK) pathway, the extracellular signal-regulated kinases (ERKs) p42/p44, in a time-dependent manner as assessed by increased phosphorylation of ERK1/ERK2 by Western blot analyses. Neither the c-Jun NH(2)-terminal kinase/stress-activated protein kinase nor the p38 MAPK was activated by hyperoxia in these cells. Chemical or genetic inhibition of the ERK p42/p44 MAPK pathway by PD-98059, a selective inhibitor of MAPK kinase, and dominant negative mutants of ERK, respectively, attenuated hyperoxia-induced apoptosis as assessed by DNA laddering and nucleosomal ELISAs. Taken together, our data suggest that hyperoxia can induce apoptosis in cultured murine macrophages and that the MAPK pathway mediates hyperoxia-induced apoptosis.

Animals↗
PubMed1999

Elevated concentrations of interleukin-6 in intra-amniotic infection with Ureaplasma urealyticum in asymptomatic women during genetic amniocentesis.

BACKGROUND: Intra-amniotic infection is an important cause of preterm delivery and interleukin-6 (IL-6) determination was recently applied for identification of microbial invasion of the amniotic cavity. Our aim was to determine the levels of IL-6 in culture-positive amniotic fluids at genetic amniocentesis and to evaluate their significance in relation to pregnancy outcome. METHODS: Seven culture-positive and 23 culture-negative amniotic fluids, obtained at 17-19 weeks of gestation, were analyzed for IL-6 levels by an immunoassay (ELISA). Pregnancy outcomes of all 30 women were obtained from the medical charts. RESULTS: The mean level of IL-6 in the culture-negative amniotic fluids was 78+/-206 pg/ml. Among the seven culture-positive, high levels of IL-6 were found only in three amniotic fluids that were culture-positive for Ureaplasma urealyticum (1834, 1342 and 2832 pg/ml). Low levels of IL-6, ranging from zero to 60 pg/ml, were found in four AFs that were culture-positive for Staphylococcus epidermidis (n=3) and Bacillus Gram-positive (n= 1). Adverse pregnancy outcome occurred in the three women who had intra-amniotic infection with U. urealyticum accompanied by high levels of IL-6 (two fetal loss and one preterm delivery at 28 weeks of gestation). The four women with culture-positive but IL-6 negative amniotic fluids, had normal pregnancy outcome and term delivery. Two of the 23 women with culture-negative had preterm delivery, one with high (1000 pg/ml) and one with low (80 pg/ml) levels of IL-6. CONCLUSION: High levels of IL-6 are suggestive of a genuine intra-amniotic infection with urea-plasmas resulting in adverse pregnancy outcome, while culture-positive amniotic fluids with normal IL-6 levels, may suggest a state of contamination.

Amniocentesis↗
PubMed1998

The ftsZ gene as a tool for detection of Mycoplasma fermentans.

Mycoplasma fermentans was reported as a common contaminant of cell cultures, and was shown to either induce or suppress several immunological functions. A strain of M. fermentans was recently isolated from a mouse T-lymphoma cell line, which differs from other M. fermentans strains by its growth characteristics and was designated (in the authors' records) as strain 609. Using the differential display technique (DD), a differentially expressed gene that was identified as the M. fermentans 609 ftsZ gene was isolated. Comparison of the nucleotide sequence of the M. fermentans 609 ftsZ gene to other ftsZ genes showed a 98% homology with Mycoplasma fermentans strain K7 and approximately 50% homology with Mycoplasma pulmonis and Mycoplasma genitalium. Comparison of the putative amino acid sequences of the FtsZ proteins showed similar homology. A polymerase chain reaction (PCR) assay to detect the presence of this ftsZ gene was established; it is a fast and convenient assay to detect infection of cells by the M. fermentans species. This work demonstrates that: (i) DD can be used as a useful technique to identify and isolate mycoplasmal genes from infected cells; and (ii) the ftsZ gene can be a useful marker to distinguish between different species of mycoplasma.

Amino Acid Sequence↗
PubMed1998

Antibodies to mycoplasma fermentans in HIV-positive heterosexual patients: seroprevalence and association with AIDS.

There are conflicting reports concerning the prevalence of Mycoplasma fermentans in HIV-positive patients and its association with AIDS. Serum antibodies to M. fermentans were measured by a modified immunoblotting technique in 48 HIV-positive heterosexual patients and in 30 HIV-negative heterosexual controls. Antibodies to M. fermentans were detected in 19 (40%) of HIV-positive patients and in three (10%) of the HIV-negative controls (P = 0.01). The prevalence of antibodies to Mycoplasma hominis and to Ureaplasma urealyticum was similar in both groups. In the HIV-positive group, 16/19 (84%) M. fermentans-positive patients developed AIDS, compared to eight of 29 (28%) M. fermentans-negative patients (P = 0.0004). The HIV-positive patients with antibodies to M. fermentans had a lower CD4+ cell count and a higher prevalence of antibodies to the other mycoplasma tested (P = 0.007 and P = 0.03, respectively), as compared to the patients without antibodies to M. fermentans. These findings may suggest that the presence of antibodies to M. fermentans indicate an opportunistic infection. Of the 19 M. fermentans-positive patients, 11 were positive on the first examination, and eight became positive during the follow-up period. Seven out of these eight patients developed antibodies to M. fermentans before the development of AIDS. Therefore, the possibility exists that M. fermentans might influence the development of AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1998

Interleukin-1 expression during hyperoxic lung injury in the mouse.

An important component of the pathophysiologic response to hyperoxia (O2) is pulmonary inflammation, although the roles of specific inflammatory mediators during pulmonary O2 toxicity are not completely known. Interleukin-1 (IL-1) is an early inflammatory mediator and is sufficient to elicit many of the responses associated with acute injury. The IL-1 family comprises two bioactive proteins, IL-1alpha and IL-1beta, and their natural antagonist IL-1ra. Here we report studies of IL-1 regulation during hyperoxic lung injury in the adult mouse. When assayed by Northern blot, increases in IL-1beta mRNA were seen after 2 days of hyperoxia. In contrast, IL-1alpha mRNA was barely detectable before 4 days of hyperoxia. To further understand the cellular origin of IL-1beta expression in lungs, in situ hybridization and immunohistochemical analyses were performed. IL-1beta mRNA or protein was not detected in the lungs of unexposed animals. At 3 days, we observed the accumulation of IL-1beta transcripts in pulmonary interstitial macrophages and in a subset of neutrophils, and immunodetectable IL-1beta protein was co-localized in adjacent sections. At 4 days of exposure, IL-1beta transcripts were widespread in lung tissue, but many areas rich in IL-1beta mRNA were devoid of immunodetectable IL-1beta. However, it is not known whether increased synthesis of IL-1beta or the uncoupling of IL-1beta protein and mRNA accumulation has a role in pathophysiology of pulmonary O2 toxicity.

Animals↗
PubMed1998

Successful peer review of courses: a case study.

The authors describe their school's system of peer review for courses, established in 1988 to facilitate faculty evaluation and continual course and curriculum improvement. (The system has been temporarily suspended while the school's new curriculum becomes established.) They explain how the system was created and then report how faculty reviews of courses over the five-year operation of the system compared with students' reviews of the same courses. The faculty and students' ratings were in agreement 75% of the time. When not in agreement, the students' ratings tended to upgrade courses that were not very demanding, had easy grading, and emphasized clinical details, often at the expense of basic concepts and the big picture. The authors then document how the work of the peer review system favorably influenced the transformation of the school's curriculum. They also provide guidelines for the creation and operation of a course review process that uses faculty peers. The authors maintain that the peer review system worked because it was run by a committee of experienced and respected teachers who had been selected by their peers, the other faculty. Additional reasons for its success were that the school's faculty supported and respected the committee and its work, that course directors helped evaluate their courses, and that peer reviewers took their work seriously despite having no remuneration, and the clearly positive impact of the review system on faculty interaction, faculty-student interaction, and the reform of the curriculum.

Curriculum↗
PubMed1998

An institutionally funded program for educational research and development grants: it makes dollars and sense.

Lack of funding for educational research and a paucity of researchers with academic credibility have been identified as the key issues facing the medical education research enterprise. The authors argue that institutionally supported programs for educational research and development grants can help to address these issues. This report (1) describes the general rationale for having such programs, (2) describes the development of such a program at the University of Wisconsin School of Medicine, and (3) reports the outcome of the first three cycles of awards. The program outcomes include 28 intramurally funded projects, a 200% increase in funds for educational research from local sources other than the medical school, two new grants funded from extramural sources, one peer-reviewed publication, three presentations at national meetings, and six presentations at local meetings. Such a program is an excellent mechanism for demonstrating the administration's support for educational efforts and also provides a way to factor peer review of educational efforts into the faculty promotion process. The authors argue that these two reasons alone are sufficient to justify the development of such programs, although the outcomes at the University of Wisconsin also show compelling added value.

Education, Medical↗
PubMed1998

Synergistic cytotoxicity from nitric oxide and hyperoxia in cultured lung cells.

Exogenous nitric oxide (NO) is being tested clinically for the treatment of pulmonary hypertension in infants and children. In most cases, these patients receive simultaneous oxygen (O2) therapy. However, little is known about the combined toxicity of NO + hyperoxia. To test this potential toxicity, human alveolar epithelial cells (A549 cells) and human lung microvascular endothelial lung cells were cultured in room air (control), hyperoxia (95% O2), NO (derived from chemical donors), or combined hyperoxia + NO. Control cells grew normally over a 6-day study period. In contrast, cell death from hyperoxia was evident after 4-5 days, whereas cells neither died nor divided in NO alone. However, cells exposed to both NO and hyperoxia began to die on day 2 and died rapidly thereafter. This cytotoxic effect was clearly synergistic, and cell death did not occur via apoptosis. As an indicator of peroxynitrite formation, nitrotyrosine-containing proteins were assayed using anti-nitrotyrosine antibodies. Two protein bands, at molecular masses of 25 and 35 kDa, were found to be increased in A549 cells exposed to NO or NO + hyperoxia. These results indicate that combined NO + hyperoxia has a synergistic cytotoxic effect on alveolar epithelial and lung vascular endothelial cells in culture.

Cells, Cultured↗
PubMed1998

Cell-specific expression of fibronectin and EIIIA and EIIIB splice variants after oxygen injury.

Cellular fibronectin (cFN) expression is characteristic of injured tissues. Unlike plasma FN, cFN mRNA often contains the EIIIA or EIIIB domains. We examined the lung cell-specific expression of total cFN mRNA and the EIIIA and EIIIB splice variants in rabbits after acute oxygen injury. By in situ hybridization, control lung had low cFN mRNA. After exposure to > 95% oxygen, mRNAs for total cFN and EIIIA were noted primarily in alveolar macrophages and large-vessel endothelial cells. By 3-5 days recovery, cFN and EIIIA mRNA abundance was increased in alveolar septal cells (i.e., alveolar epithelial, interstitial, or endothelial cells) and in some large-vessel endothelial cells but was low in bronchial epithelial cells. During recovery, EIIIB mRNA was low in alveolar septal cells but was noted mainly in chondrocytes. Immunostaining for EIIIA increased during recovery, paralleling the in situ hybridizations. Because FN may modulate alveolar type II cell phenotype, we investigated type II cell cFN mRNA expression in vivo. During recovery, neither isolated type II cells nor cells with surfactant protein C mRNA in vivo contained FN mRNA. In summary, these data suggest that cFN with the EIIIA domain has a role in alveolar cell recovery from oxygen injury and that type II cells do not express cFN during recovery.

Animals↗
PubMed1998

Intracellular uptake of recombinant superoxide dismutase after intratracheal administration.

We have previously demonstrated that recombinant human copper-zinc superoxide dismutase (rhCu,ZnSOD) is rapidly incorporated into cells of airways, respiratory bronchioles, and alveoli after intratracheal administration. The present study examines whether this cellular uptake is specific for rhCu,ZnSOD or whether other proteins are similarly incorporated into lung cells. Twenty-two newborn piglets (2-3 days old, 1.2-2.0 kg) were intubated and mechanically ventilated. Eight piglets received fluorescently labeled recombinant human manganese superoxide dismutase (rhMnSOD), six received fluorescently labeled albumin, two received free (unbound) fluorescent label intratracheally, and two piglets served as untreated controls. To determine whether endogenous surfactant was important in the process of intracellular uptake, four additional piglets were made surfactant deficient by repeated bronchoalveolar lavage and then given rhCu,ZnSOD intratracheally. All animals were killed after 30-60 min. Lung sections were examined blindly by laser confocal microscopy. Similar to our previous observations with rhCu,ZnSOD, intracellular uptake of rhMnSOD and albumin was noted throughout the lung. The free label did not localize intracellularly. The uptake of proteins did not appear to be affected by surfactant deficiency. rhMnSOD administration was associated with a greater than twofold increase in lung MnSOD activity. Data suggest that the cellular uptake of antioxidants and other proteins in the lung may reflect a nonspecific host defense system for clearing proteins from the lumen of airways and alveoli.

Animals↗
PubMed1998

Pulmonary apoptosis in aged and oxygen-tolerant rats exposed to hyperoxia.

Accumulating evidence demonstrates that genotoxic and oxidant stress can induce programmed cell death or apoptosis in cultured cells. However, little is known about whether oxidative stress resulting from the deleterious effects of hyperoxia can induce apoptosis in vivo and even less is known regarding the functional significance of apoptosis in vivo in response to hyperoxia. Using hyperoxia as a model of oxidant-induced lung injury in the rat, we show that hyperoxic stress results in marked apoptotic signals in the lung. Lung tissue sections obtained from rats exposed to hyperoxia exhibit increased apoptosis in a time-dependent manner by terminal transferase dUTP nick end labeling assays. To examine whether hyperoxia-induced apoptosis in the lung correlated with the extent of lung injury or tolerance (adaptation) to hyperoxia, we investigated the pattern of apoptosis with a rat model of age-dependent tolerance to hyperoxia. We show that apoptosis is associated with increased survival of aged rats to hyperoxia and with decreased levels of lung injury as measured by the volume of pleural effusion, wet-to-dry lung weight, and myeloperoxidase content in aged rats compared with young rats after hyperoxia. We also examined this relationship in an alternate model of tolerance to hyperoxia. Lipopolysaccharide (LPS)-treated young rats not only demonstrated tolerance to hyperoxia but also exhibited a significantly lower apoptotic index compared with saline-treated rats after hyperoxia. To further separate the effects of aging and tolerance, we show that aged rats pretreated with LPS did not exhibit a significant level of tolerance against hyperoxia. Furthermore, similar to the hyperoxia-tolerant LPS-pretreated young rats, the nontolerant LPS-pretreated aged rats also exhibited a significantly reduced apoptotic index compared with aged rats exposed to hyperoxia alone. Taken together, our data suggest that hyperoxia-induced apoptosis in vivo can be modulated by both aging and tolerance effects. We conclude that there is no overall relationship between apoptosis and tolerance.

Aging↗
PubMed1998

Increased endothelial cell expression of platelet-endothelial cell adhesion molecule-1 during hyperoxic lung injury.

Lung injury is a frequent consequence of oxygen (O2) therapy administered to newborns and adults with respiratory distress. Acute exposure to hyperoxia results in a well-described pathophysiologic response in the lungs. Because inflammation is an important component of pulmonary O2 toxicity, we have an interest in identifying the inflammatory mediators that increase during hyperoxia. Platelet-endothelial cell adhesion molecule-1 (PECAM-1), a member of the immunoglobulin superfamily that is expressed at the junctions between endothelial cells, is essential to the transendothelial migration of leukocytes. We hypothesized that increased expression of PECAM-1 occurs in pulmonary endothelial cells during hyperoxic lung injury. Adult mice were exposed to 100% O2 for up to 96 h. We analyzed PECAM-1 expression by RNA blot hybridization, in situ hybridization, and immunohistochemistry. A increase in PECAM-1 mRNA was seen as soon as 2 d of hyperoxia relative to unexposed control mice. PECAM-1 mRNA and protein were found in endothelial cells of both large and small arteries. The expression of PECAM-1 in capillary vessels was further confirmed using in situ hybridization at the electron microscope level. This increase in PECAM-1 expression coincided with the appearance of leukocytes in lung tissue. These observations suggest that PECAM-1 expression is a relatively early step in the inflammation cascade, and intervention at this phase may be critical to the prevention of further damage.

Alternative Splicing↗