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Biomedical subjects

B Weinberger

Publications and source records attributed to B Weinberger.

At least 19 recordsLinked to original sources
PubMed2006

Capillary condensation and adsorption of binary mixtures.

The adsorption of equimolar binary mixtures of hydrogen-carbon dioxide, hydrogen-methane, and methane-carbon dioxide in porous material models is determined by grand canonical Monte Carlo simulations. The material models have an adsorbent surface similar to that of nanofibers with a herringbone structure. Our main result, which is relevant for hydrogen purification and carbon dioxide capture, is that the adsorption selectivities calculated for the mixtures can differ significantly from those deduced from simulations of the adsorption of pure gases, in particular, when one of the adsorbed gases presents a capillary condensation induced by confinement within the pore network. A comparison of our data is also made with theoretical models used in the literature for predicting the properties of the mixture adsorption.

Journal Article↗
PubMed2001

Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia.

PURPOSE: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. PATIENTS AND METHODS: Patients received ara-C 3 g/m(2)/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/m2/d [corrected]. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. RESULTS: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twenty-one patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m(2) of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P =.04). Daunorubicinol clearance decreased 3.3-fold (P =.016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. CONCLUSION: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

Acute Disease↗
PubMed2001

Urinary thiobarbituric acid-reacting substances as potential biomarkers of intrauterine hypoxia.

BACKGROUND: Currently available clinical tools cannot accurately identify the extent of perinatal hypoxic injuries. During hypoxia, reactive oxygen species cause lipid peroxidation of cell membranes, yielding oxidation products that constitute thiobarbituric acid-reacting substances (TBARS). OBJECTIVE: To see if the concentrations of TBARS excreted in urine would be elevated during the first day of life in term and preterm infants following chronic hypoxia or acute asphyxia. DESIGN: Thiobarbituric acid-reacting substances levels were measured by a spectrophotometric assay in urine samples collected from term and near-term (>/= 34 weeks gestation, n = 22), and preterm (<34 weeks gestation, n = 52) infants on the first day of life. PATIENTS: Infants were admitted to the St Peter's University Hospital (New Brunswick, NJ) neonatal intensive care unit from July 1997 to January 1999. Acute asphyxia was defined as umbilical cord blood pH values less than 7.05, or Apgar scores of less than 5 at 5 minutes. Chronic hypoxia was defined as intrauterine growth retardation or low birth weight (small for gestational age) associated with pregnancy-induced hypertension or reversal of umbilical arterial blood flow. RESULTS: Among term infants, urinary TBARS levels were significantly increased following acute asphyxia (P =.02). Levels of TBARS also tended to be elevated following chronic hypoxia. Urinary TBARS levels in term infants tended to be increased in those requiring mechanical ventilation (P =.05) or delivery room resuscitation (P =.15), as well as in those passing intrauterine meconium (P =.13) or having clinical evidence of hypoxic-ischemic encephalopathy (P =.24). CONCLUSIONS: The results show a correlation between elevated urinary TBARS levels in term and near-term infants, and perinatal hypoxia (as determined by low Apgar scores or umbilical cord blood acidosis). We speculate that TBARS concentrations may be useful as a biomarker for perinatal hypoxic injury in newborns. Further studies are needed to determine whether elevations in TBARS levels are better predictors of the extent of hypoxic injury than existing markers.

Asphyxia Neonatorum↗
PubMed2001

Pharmacologic therapy of persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition characterized by a failure of pulmonary vascular resistance to decrease adequately during the transition to extrauterine life. Inhaled nitric oxide, a vasodilator that acts selectively on the pulmonary circulation, has revolutionized the treatment of this condition. However, inhaled nitric oxide has not proven effective in all patients, particularly those with congenital diaphragmatic hernias or meconium aspiration syndrome. Furthermore, large clinical trials of inhaled nitric oxide have failed to demonstrate significant differences in mortality between nitric oxide-treated and control infants with PPHN. Other therapeutic approaches to PPHN have been limited by a relative lack of specificity for the pulmonary circulation, and have received much less attention. Pharmacologic approaches, including pulmonary surfactants, prostacyclin, endothelin antagonists, Ca(2+)-channel blockers, magnesium sulfate, and tolazoline, have exhibited varying degrees of efficacy in lowering pulmonary vascular pressures in humans and/or animals. A number of these agents are also effective when used in combination. For example, phosphodiesterase inhibitors have been reported to act synergistically with inhaled nitric oxide. Surfactants also appear to be useful in PPHN, particularly in patients with congenital diaphragmatic hernia, when used in combination with other therapies. Surfactant lavage and other novel therapies may also be effective in combination therapy of meconium aspiration syndrome. Further studies should be directed at defining the optimal therapies in specific clinical settings. Validation of multiple therapeutic modalities for PPHN, including inhaled nitric oxide, will allow for rational, combined vasodilator strategies that are specific for the underlying pathophysiology in each patient.

Anti-Inflammatory Agents↗
PubMed2001

The toxicology of inhaled nitric oxide.

Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.

Animals↗
PubMed2001

Effects of perinatal hypoxia on serum unbound free fatty acids and lung inflammatory mediators.

Cellular injury during tissue hypoxia is due, in part, to reactive intermediates released by activated leukocytes. We found that the inflammatory mediators tumor necrosis factor (TNF)-alpha, IL-6, and IL-1beta are elevated in situ in lung macrophages on day 14 following exposure of rats to intermittent or chronic hypoxia from birth. Because inflammatory mediators can increase lipolysis in adipocytes, we also measured serum unbound free fatty acids (FFAu)--the biologically active compartment of FFA--in rat pups exposed to intermittent or chronic hypoxia. FFAu values were markedly elevated during the first 2 days of life in all rats, displaying an approximately 3-fold decrease from day 2 to day 3. Exposure to chronic hypoxia significantly increased FFAu levels measured on day 13. Since elevated serum FFAu are known to suppress leukocyte activation, we speculate that increased FFAu levels represent a mechanism for attenuating inflammation and tissue injury following sublethal hypoxia in the perinatal period, either physiologically in the immediate newborn period, or as a late response to ongoing hypoxic insult.

Aging↗
PubMed2001

Functional heterogeneity in liver and lung macrophages.

Although initially considered merely "scavenger cells" that participate in immunologic responses only after B and T lymphocytes have performed their biological tasks, more recent evidence suggests that macrophages play a key role in host defense as well as in the maintenance of normal tissue structure and function. For macrophages to perform their biological functions, they must be activated. This involves up-regulation of an array of signaling pathways resulting in altered gene expression and increased biochemical and functional activity. Macrophages have been identified in almost all tissues of the body. However, the basal activity of these cells, as well as their ability to respond to inflammatory mediators, varies considerably with their location. In addition, even within a particular tissue, there is evidence of macrophage heterogeneity. The largest populations of macrophages in the body are located in the liver and lung. Because of the unique attributes of these tissues, hepatic and pulmonary macrophages play essential roles not only in nonspecific host defense but also in the homeostatic responses of these tissues. In this review, the functional and biochemical activities of macrophages localized in the liver and lungs are compared. Evidence suggests that these represent distinct cell populations with unique functions and responsiveness to inflammatory agents.

Animals↗
PubMed2001

Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants.

Potential mechanisms underlying impaired chemotactic responsiveness of neonatal neutrophils were investigated. Two distinct chemoattractants were compared: bacterially derived N-formyl-methionyl-leucyl-phenylalanine (fMLP) and a unique chemotactic monoclonal antibody, designated DL1.2, which binds to a neutrophil antigen with an apparent molecular mass of 120 kDa. Chemotaxis of neutrophils toward fMLP, as well as DL1.2, was reduced in neonates when compared with adult cells. This did not appear to be a result of decreased fMLP receptor or DL1.2 antigen expression by neonatal neutrophils. fMLP, but not DL1.2, induced a rapid increase in intracellular calcium in adult and neonatal cells, which reached a maximum within 30 s. The calcium response of cells from neonates to fMLP was reduced when compared with adult cells, and an unresponsive subpopulation of neonatal neutrophils was identified. NF-kappaB nuclear binding activity induced by fMLP and DL1.2, as well as expression of the p65 NF-kappaB subunit and IkappaB-alpha, was also significantly reduced in neonatal cells, when compared with adult cells. In contrast, although fMLP, but not DL1.2, activated p42/44 and p38 mitogen-activated protein (MAP) kinases in neutrophils, no differences were observed between adults and neonates. Chemotaxis of adult and neonatal neutrophils toward fMLP and DL1.2 was also blocked to a similar extent by inhibitors of phosphatidylinositol 3-kinase, as well as an inhibitor of NF-kappaB. These findings indicate that reduced chemotactic responsiveness in neonatal neutrophils is a result of, at least in part, aberrations in chemoattractant-induced signaling. However, the biochemical pathways mediating this defect appear to be related to the specific chemoattractant.

Adult↗
PubMed2000

Antecedents and neonatal consequences of low Apgar scores in preterm newborns: a population study.

BACKGROUND: To examine the antenatal and early neonatal correlates of low Apgar scores (<3 and <6 at 1 and 5 minutes) in preterm newborns (23-34 weeks' gestation). OBJECTIVE: The use of Apgar scoring for premature newborns remains widespread, despite controversy regarding its reliability as a measure of morbidity and mortality in the neonatal period. DESIGN: A cohort of 852 preterm newborns born during a 34-month period between 1984 and 1987 was studied. Newborns were stratified into 2 groups by gestational age (23-28 weeks and 29-34 weeks), and data were analyzed, controlling for gestational age in single weeks. SETTING: Two academic and 1 community hospital, which together accounted for 83% of all preterm births in a tri-county area of central New Jersey during the study period. PATIENTS: All premature newborns (birth weight <2000 g and gestational age <35 weeks) born in the participating hospitals during the study period were evaluated. MAIN OUTCOME MEASURES: Antecedents included maternal illness during pregnancy, maternal complications of labor and delivery, and fetal heart rate abnormalities during labor and delivery. Consequences included delivery room resuscitation, abnormal physical findings, diagnoses, and therapeutic interventions in the first 6 to 8 hours of life. RESULTS: Premature newborns with low Apgar scores received more cardiopulmonary resuscitation in the delivery room and in the first 6 to 8 hours of neonatal intensive care. Mortality was significantly increased among newborns with low Apgar scores (54% vs. 26% in the 23- to 28-week stratum, 30% vs 6% in the 29- to 34-week stratum). Newborns with low Apgar scores in the 29- to 34-week stratum more often required intubation, positive pressure ventilation, and umbilical vessel catheterization. Newborns with low Apgar scores had higher rates of bradycardia, pneumothoraces, acidosis, and increased oxygen requirement during the first 6 to 8 hours of life. Maternal illness, complications of labor and delivery;, and fetal heart rate decelerations did not correlate with subsequent Apgar scores of newborns. The presence of severe bradycardia (<90/min) and fetal heart rate accelerations correlated with low Apgar scores in the 29- to 34-week group. CONCLUSION: Low Apgar scores are associated with increased neonatal morbidity and mortality in preterm newborns. Antenatal maternal history, and pregnancy complications are not clearly associated with low Apgar scores. Therefore, the Apgar score is a useful tool in assessing neonatal short-term prognosis and the need for intensive care among preterm newborns.

Apgar Score↗
PubMed1999

Nitric oxide in the lung: therapeutic and cellular mechanisms of action.

Nitric oxide is produced by many cell types in the lung and plays an important physiologic role in the regulation of pulmonary vasomotor tone by several known mechanisms. Nitric oxide stimulates soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in lung smooth muscle cells. The gating of K+ and Ca2+ channels by cyclic GMP binding is thought to play a role in nitric oxide-mediated vasodilation. Nitric oxide may also regulate pulmonary vasodilation by direct activation of K+ channels or by modulating the expression and activity of angiotensin II receptors. Administration of nitric oxide by inhalation has been shown to acutely improve hypoxemia associated with pulmonary hypertension in humans and animals. This is presumably due to its ability to induce pulmonary vasodilation. Inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term and near-term infants with persistent pulmonary hypertension. However, long-term benefits to these infants have been difficult to demonstrate. In other pathologic conditions, such as prematurity and acute respiratory distress syndrome, short-term benefits have not been shown conclusively to outweigh potential toxicities. For example, high-dose inhaled nitric oxide decreases surfactant function in the lung. Inhaled nitric oxide also acts as a pulmonary irritant, causing priming of lung macrophages and oxidative damage to lung epithelial cells. Conversely, protective effects of nitric oxide have been described in a number of pathological states, including hyperoxic and ischemia/reperfusion injury. Nitric oxide has also been reported to protect against oxidative damage induced by other reactive intermediates, including superoxide anion and hydroxyl radical. The dose and timing of nitric oxide administration needs to be ascertained in clinical trials before recommendations can be made regarding its optimal use in patients.

Administration, Inhalation↗
PubMed1999

Autotransplants in men with breast cancer. ABMTR Breast Cancer Working Committee. Autologous Blood and Marrow Transplant Registry.

The purpose of this study was to determine the outcome of high-dose therapy with autologous hematopoietic stem cell support (autotransplants) in men with breast cancer. We studied 13 men receiving autotransplants for breast cancer and reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) by 10 centers. Six men had stage 2 breast cancer, four had stage 3, and three had metastatic breast cancer. Of twelve tumors tested, all were estrogen receptor positive. Median age at transplant was 50 years. The most common conditioning regimen was cyclophosphamide, thiotepa and carboplatin (n = 5); the remaining eight men received other alkylator-based regimens. Three men received bone marrow, eight received blood stem cells, and two received both for hematopoietic support. All patients had hematopoietic recovery. There were no unexpected regimen-related toxicities. Of 10 men receiving autotransplants as adjuvant therapy, three relapsed 3, 5 and 50 months post-transplant and died 16, 19 and 67 months post-transplant. Seven of 10 are disease-free with median follow-up of 23 months (range 6-50 months). Of three men treated for metastatic breast cancer, one had progressive disease and two recurrent disease at 6, 7 and 16 months post-transplant. In conclusion, results of autotransplants for male breast cancer appear similar to those reported for women receiving autotransplants for breast cancer.

Adult↗
PubMed1998

Inhaled nitric oxide primes lung macrophages to produce reactive oxygen and nitrogen intermediates.

Inhaled nitric oxide is a selective pulmonary vasodilator used for the treatment of pulmonary hypertension. The potential adverse effects of inhaled nitric oxide are unknown and represent the focus of the present studies. Whereas inhalation of nitric oxide (10 to 100 ppm, 5 h) by Balb/c mice had no effect on the number or type of cells recovered from the lung, a dose-related increase in bronchoalveolar lavage protein was observed, suggesting that nitric oxide induces alveolar epithelial injury. To determine if this was associated with altered alveolar macrophage activity, we quantified production of reactive oxygen and nitrogen intermediates by these cells. Interferon-gamma, alone or in combination with lipopolysaccharide (LPS), induced expression of inducible nitric oxide synthase (iNOS) protein and nitric oxide production by alveolar macrophages. Cells from mice exposed to 20 to 100 ppm nitric oxide produced significantly more nitric oxide and expressed greater quantities of iNOS than cells from control animals. Superoxide anion production and peroxynitrite generation by alveolar macrophages were also increased after exposure of mice to nitric oxide. This was correlated with increased antinitrotyrosine antibody binding to macrophages in histologic sections. Taken together, these data demonstrate that inhaled nitric oxide primes lung macrophages to release reactive oxygen and nitrogen intermediates. Increased production of these mediators by macrophages following inhalation of nitric oxide may contribute to tissue injury.

Administration, Inhalation↗
PubMed1997

Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

PURPOSE: To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS: Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS: Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION: The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Adult↗
PubMed1994

Development of the ability to make IgG and IgA in newborns and infants.

An understanding of the ontogeny of the human immune system may provide clues for methods to stimulate the immune response of neonates and young infants at an earlier age than is now possible. Knowledge of normal changes in immune response over time is necessary to evaluate infants for immunodeficiency.

Antibody Specificity↗
PubMed1983

Silicone lymphadenitis secondary to implant degeneration.

The principal objective(s) of this presentation is to report a case of lymphadenitis secondary to implant degeneration. A review of the literature on the history and development of the silicone implant and the durability of the silicone elastomer is presented. A case report with radiologic and histologic documentation is also presented. Silicone lymphadenitis is a rare occurrence and the authors believe they have reported the first case to occur in the lower extremity.

Adult↗