Biomedical subjects

J B Rubins

Publications and source records attributed to J B Rubins.

At least 37 records · Page 2Linked to original sources

PubMed1998

Pneumolysin: a multifunctional pneumococcal virulence factor.

Pneumolysin (PLY) is a multifunctional pneumococcal virulence factor that appears to augment intrapulmonary growth and dissemination during the early pathogenesis of Streptococcus pneumoniae infection. Through its cytotoxicity to respiratory epithelium and endothelium, PLY disrupts pulmonary tissue barriers that serve as mechanical pulmonary defenses, thus facilitating S. pneumoniae growth and dissemination. Through direct inhibitory effects on immune and inflammatory cells and by activating complement, PLY inhibits bacterial clearance from the pulmonary interstitium and the blood. Because PLY stimulates local and systemic immune responses and enhances the immunogenicity of S. pneumoniae polysaccharide (PS), PLY-PS conjugates may form the basis for vaccines that not only induce protective and durable immune responses to pneumococcal PS but also generate neutralizing anti-PLY antibodies that can protect the respiratory mucosa from toxin-induced injury.

Antibodies, Bacterial↗

PubMed1998

Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer.

OBJECTIVE: To determine whether measurement of preoperative serum carcinoembryonic antigen concentrations adds useful prognostic data to current preoperative staging of lung cancer by computed tomography, bronchoscopy, and mediastinoscopy. METHODS: A prospective cohort study of 130 consecutive patients was evaluated for suspected lung cancer from July 1991 through December 1992 at a university-affiliated Veterans Affairs Medical Center. Serum concentrations of carcinoembryonic antigen were measured before diagnosis, staging, or resection of cancer. RESULTS: Malignant disease was diagnosed by bronchoscopy, needle biopsy, mediastinoscopy, or resection in 111 of 130 patients. In the 50 patients undergoing resection with curative intent, multivariate analysis indicated that carcinoembryonic antigen was a significant predictor of survival independent of patient age, pathologic stage, histologic type, and tumor size (P=.0357). CONCLUSIONS: Elevated preoperative serum concentrations of carcinoembryonic antigen predict a poor prognosis for lung cancer independent of other conventional staging parameters and have an adjunctive role in the staging of lung cancer.

Adenocarcinoma↗

PubMed1998

Magnitude, duration, quality, and function of pneumococcal vaccine responses in elderly adults.

The suboptimal efficacy of the currently available 23-valent pneumococcal vaccine in the growing population of adults >65 years old may be related to the limited immunogenicity of the vaccine polysaccharides in this group. In this study, the majority of elderly outpatients with stable chronic illnesses generated a vigorous IgG response to seven vaccine serotypes comparable to that of healthy young adults at 1, 3, and 16 months after immunization. Moreover, the quality and function of anticapsular antibodies, measured as avidity and in vitro opsonization, were comparable between elderly and young subjects over time. However, a subset (approximately 20%) of elderly outpatients responded to fewer than two of seven serotypes tested 1 and 3 months after immunization, whereas none of the healthy young adults were such poor responders. Thus, despite the adequate mean immune responses of the elderly as a group, a substantial proportion of elderly persons may have poor responses to the currently available pneumococcal vaccine.

Adult↗

PubMed1998

Do molecular markers predict survival in non-small-cell lung cancer?

Patients with non-small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.

Adult↗

PubMed1998

Lovastatin induces apoptosis in malignant mesothelioma cells.

Malignant mesothelioma causes profound morbidity and nearly universal mortality that is refractory to conventional treatment with aggressive surgery, radiotherapy, or chemotherapy. We report that pharmacologic concentrations of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, induced apoptosis in human malignant mesothelioma cell lines. Mesothelioma cell viability was decreased in a dose-dependent manner by lovastatin (5 to 30 microM). These effects were not reversed by exogenous growth factors or cholesterol, but were reversed by addition of 100 microM mevalonate, confirming that lovastatin affected mesothelioma viability by inhibiting mevalonate synthesis. Lovastatin appeared to decrease mesothelioma viability by inducing apoptosis, as indicated by morphologic changes, histologic evidence of nuclear condensation and degeneration, and flow-cytometric analysis of DNA content. Lovastatin's effects on cell viability were partially reversed in the presence of farnesol, and treatment of mesothelioma cells with a specific farnesyl-protein transferase (FTP) inhibitor decreased cell viability and induced morphologic changes indistinguishable from those caused by lovastatin. In addition, lovastatin-treated cells showed translocation of ras guanosine triphosphate (GTP)-binding proteins from membrane to cytosolic fractions on Western blots, suggesting that lovastatin's effects on mesothelioma were mediated in part by disrupting acylation of GTP-binding proteins. Thus, lovastatin is a commercially available and clinically well-tolerated agent that reduces viability and induces apoptosis of mesothelioma cells, and may provide the basis for adjunctive treatments of patients with mesothelioma.

Alkyl and Aryl Transferases↗

PubMed1997

Invasive pneumococcal disease in the immunocompromised host.

A normal constituent of the human upper respiratory flora, Streptococcus pneumoniae also produces respiratory tract infections that progress to invasive disease at high rates in specific risk groups. The individual factors that contribute to the development of invasive pneumococcal disease in this distinct minority of persons, include immune (both specific and innate), genetic, and environmental elements. Specific defects in host responses may involve age, deficiencies in levels of antibodies and complement factors, and splenic dysfunction. Combinations of these immune defects contribute to the increased rates of invasive pneumococcal disease in patients with sickle cell disease, nephrotic syndrome, neoplasms, and underlying medical conditions such as diabetes and alcoholic liver disease. The number of risk factors are greatest and the rates of invasive disease are highest in patients with HIV-1 infection, which has emerged as a major risk factor for serious S. pneumoniae infection worldwide.

AIDS-Related Opportunistic Infections↗

PubMed1997

Role of gamma interferon in the pathogenesis of bacteremic pneumococcal pneumonia.

Gamma interferon (IFN-gamma) concentrations in blood, but not in lungs, rose significantly at 24 to 48 h after murine pulmonary infection with virulent pneumococci. In contrast, infection with avirulent pneumococcal strains produced minimal rises in serum IFN-gamma concentrations. Compared with that of immunocompetent mice, mortality was appreciably increased after pulmonary infection of IFN-gamma gene knockout mice, suggesting a protective role for IFN-gamma in host response to pneumococcal disease.

Animals↗

PubMed1997

Prostatic meningeal carcinomatosis presenting as delirium tremens.

We report an unusual case of prostatic carcinomatous meningitis and remind clinicians to maintain a high index of suspicion of meningeal involvement when patients with advanced prostatic cancer present with cerebral symptoms, back pain, or neurologic findings. The diagnosis may require repeated cytologic examinations of cerebrospinal fluid, and immunocytochemical stains should be considered to confirm a prostatic source if malignant cells are identified. Androgen ablative therapy may give prolonged remissions, especially in patients with previously untreated tumours.

Aged↗

PubMed1997

Community-acquired pneumonia. Tailoring management of adult patients according to risk category.

A cost-conscious evaluation of CAP in the adult patient requires an initial assessment of the clinical severity and the risks of complicated pneumonia. Initially, most patients should have chest radiography; some authorities also recommend sputum Gram staining and culture, but additional blood testing, culture, and diagnostic procedures are indicated only for patients who have chronically impaired health or clinical evidence of sever infection. Initial empirical antibiotic therapy varies depending on the setting (outpatient, hospitalized patient, critically ill patient). Failure of the patient to respond to empirical antibiotic therapy within 72 hours should direct the clinician to consider unusual or resistant organisms or noninfectious causes of pneumonitis.

Adult↗

PubMed1997

Implication of pneumolysin as a virulence factor in Streptococcus pneumoniae endophthalmitis.

PURPOSE: To determine if pneumolysin, a multifunctional cytotoxin produced by Streptococcus pneumoniae, may be a virulence determinant in the pathogenesis of pneumococcal endophthalmitis. METHODS: Lewis rats (n = 20) were injected intravitreally with purified recombinant pneumolysin at the following doses; 3.9 hemolytic units (HU), 39 HU, 390 HU, 3.9 x 10(3) HU, and 3.9 x 10(4) HU. After 24 hours, eyes were examined clinically and enucleated for histopathologic examination to elucidate the dose-response relationship. To determine the temporal progression of the disease model, a second group of rats (n = 8) were injected intravitreally with 390 HU of pneumolysin. At 6 and 48 hours, eyes were examined clinically and enucleated for histopathology. RESULTS: Eyes injected with pneumolysin demonstrated increasing anterior and posterior segment inflammation in response to increasing doses of administered toxin. The onset of inflammation and tissue damage occurred rapidly, and was maximal at 24 to 48 hours. The clinical and histopathologic changes observed mimicked those of S. pneumoniae endophthalmitis. Histopathologic analysis demonstrated rapid onset of iridocyclitis and vitritis with polymorphonuclear leukocyte influx, inner retinal necrosis, and retinal detachment. Retinal pigment epithelial necrosis and choroiditis were noted at the highest doses administered. Inflamed eyes were shown to be sterile. CONCLUSIONS: Pneumolysin injected intravitreally induces many of the clinical and histopathologic features of pneumococcal endophthalmitis, and may play an important role in the inflammation and tissue damage that occurs in pneumococcal endophthalmitis.

Animals↗

PubMed1996

Rb and p16INK4a expression in resected non-small cell lung tumors.

Inactivation of the cyclin-dependent kinase inhibitor p16INK4a (CDKN2/MTS1) is documented in a wide variety of cancer cell lines and tumors. We have shown that loss of p16INK4a protein expression is a common event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher stage disease. One hundred NSCLC tumors from patients undergoing definitive thoracotomies at a single institution were examined for p16INK4a and retinoblastoma protein (pRB) expression. Abnormal pRB staining was identified in 15% of the tumors, whereas 51% possessed aberrant p16INK4a protein expression. Tumors with aberrant expression of p16INK4a by immunohistochemistry were associated with a significantly worse survival (P=0.04). Additionally, the inverse correlation of pRB and p16INK4a expression previously noted in lung cancer cell lines and tumors was confirmed in this large cohort of patients, with 65% of the tumors demonstrating inverse expression of pRB and p16INK4a (p=0.00019). A statistically significant increase in aberrant p16INK4a expression, as well as inverse expression of p16INK4a and pRB, was seen with increasing pathological stage of disease. These findings establish the prognostic significance (of the absence of p16INK4, in resected NSCLC and confirm the critical importance of disrupting the pathway of cyclin-dependent kinase-mediated phosphorylation of pRB in the molecular oncogenesis and progression of NSCLC.

Adenocarcinoma↗

PubMed1996

Ethanol ingestion reduces antipneumococcal activity of rat pulmonary surfactant.

Because chronic ethanol ingestion decreases pulmonary clearance of Streptococcus pneumoniae in rats, and extracellular antipneumococcal factors in rat surfactant are important in the early clearance of pneumococci from the rat alveolus, the effects of ethanol ingestion on surfactant bactericidal activity were investigated. Normal surfactant from chow-fed rats showed potent anti-pneumococcal activity, even against bacteria growing in nutrient-rich media under favorable conditions. In contrast, surfactant from ethanol-fed rats and from calorie-restricted control-fed rats had significantly reduced antipneumococcal activity compared with surfactant from chow-fed rats. The reductions in surfactant bactericidal activity produced by ethanol ingestion or caloric restriction did not appear to be mediated through changes in either the total amount or the distribution of fatty acids, the antipneumococcal factors in normal surfactant. Rather, ethanol ingestion, and to a lesser extent caloric restriction, produced a surfactant inhibitor of free fatty acids that was partially characterized as a hydrophobic protein.

Alcohol Drinking↗

PubMed1996

Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia.

Pneumolysin, the major Streptococcus pneumoniae cytotoxin, contributes to the early pathogenesis of invasive pneumococcal pneumonia by facilitating intrapulmonary bacterial growth and invasion into the blood. Pneumolysin is a multifunctional toxin, with distinct cytolytic ("hemolytic") and complement-activation ("complement") activities that have been mapped to several regions of the molecule. To characterize the specific contributions of pneumolysin's hemolytic and complement properties to the pathogenesis of pneumococcal pneumonia, we compared the in vivo effects of type 2 S. pneumoniae mutant strains, which produce pneumolysins deficient in these activities. The absence of either pneumolysin's hemolytic or complement activities rendered mutant strains less virulent than the wild-type strain during pulmonary infection. Pneumolysin's hemolytic activity correlated with acute lung injury and bacterial growth at 3 and 6 h after endotracheal instillation. In contrast, pneumolysin's complement activity correlated with bacterial growth and bacteremia at 24 h after pulmonary infection. Pneumolysin's complement activity was not associated with the degree of alveolar-capillary injury or recruitment of leukocytes during initial pulmonary infection. However, pneumolysin's complement activity inhibited killing of mutant bacteria in an in vitro complement-dependent neutrophil killing assay. Thus, both pneumolysin's hemolytic and complement activities made specific contributions to the early pathogenesis of pneumococcal pneumonia at different stages of infection and by different mechanisms.

Animals↗

PubMed1996

Temporal trends in the prevalence of malignancy in resected solitary pulmonary lesions.

STUDY OBJECTIVE: To determine whether there has been an increase in the prevalence of malignancy among resected, indeterminate solitary pulmonary lesions (SPL) over the past 14 years. DESIGN: A retrospective review of all thoracotomies for indeterminate SPLs from 1981 through 1994. SETTING: A university-affiliated VA Medical Center. PATIENTS: Three-hundred seventy resected indeterminate SPLs (all < or = 6 cm) in 360 patients. MEASUREMENTS AND RESULTS: Virtually all patients were men with an average age of 63 +/- 9 years. The average lesion size was 2.5 +/- 1.4 cm; 71% were 3 cm or less. Overall, 79% of resected lesions were malignant; 94% of these were bronchogenic carcinomas. Granulomas accounted for more than 50% of benign lesions. The proportion of malignant diagnoses increased from 55 to 60% in 1981 to 1983 to 90 to 100% in 1990 to 1994 (p < 0.005). The increasing proportion of malignancy over time was independent of age at time of operation and lesion size. There was no significant difference in survival among patients with a malignant lesion resected in 1981 to 1983 compared with 1990 to 1994. CONCLUSION: We conclude that there has been a striking increase in the prevalence of malignancy among resected indeterminate SPLs over the past 14 years in our institution. We suspect that this trend reflects improvements in our ability to diagnose benign SPLs preoperatively, primarily through the use of CT. Our results should prompt other institutions to review their recent experience with the diagnosis of indeterminate SPLs to provide more timely information to physicians and their patients who are contemplating resection of SPLs.

Adenocarcinoma↗

PubMed1996

Origins of breath nitric oxide in humans.

STUDY OBJECTIVES: Nitric oxide (NO) exists in the human breath, but little is known about its site of origin or enzyme source. The aims of this study were to locate the main site of NO release into human breath and to decide whether the inducible isoform of NO synthase (iNOS) and nasal bacteria contribute to breath NO. DESIGN: Using a chemiluminescence assay, NO levels were measured in air exhaled from the nose, mouth, trachea, and distal airway. The susceptibility of breath NO to treatment with a topical corticosteroid (to inhibit iNOS; intranasal beclomethasone dipropionate for 2 weeks) and with antibiotics (systemic amoxicillin plus clavulanic acid and intranasal bacitracin zinc, 5 to 10 days) was also tested. PARTICIPANTS: Twenty-one healthy subjects, 9 intubated patients, and 7 patients undergoing bronchoscopy. All subjects were nonsmokers free of pneumonia, rhinitis, and bronchitis. MEASUREMENTS AND RESULTS: Breath NO levels, collected in the gas sampling bags, were greater (p < 0.05) in the nose (25 +/- 2 parts per billion [ppb]) than in the mouth (6 +/- 1 ppb), trachea (3 +/- 1 ppb), or distal airway (1 +/- 2 ppb). Similar results were obtained when NO was sampled directly by cannula from nose or mouth during resting breathing. Nasal breath NO signal increased sharply during 30 s of breath-holding. Beclomethasone, but not antibiotics, decreased nasal NO levels without changing oral breath NO. CONCLUSIONS: Most NO in normal human breath derives locally from the nose where it can reach high levels during breath-holding. NO is synthesized, at least in part, by a steroid-inhibitable, nonbacterial, NO synthase, presumably iNOS.

Adult↗

PubMed1996

Etiology and prognostic significance of eosinophilic pleural effusions. A prospective study.

STUDY OBJECTIVE: To determine the diagnostic and prognostic significance of eosinophilic pleural effusions. DESIGN: A prospective cohort study of patients undergoing thoracentesis between September 1990 and September 1995. SETTING: A university-affiliated VA Medical Center. PATIENTS: Four hundred seventy-six consecutive patients. MEASUREMENTS AND RESULTS: Eosinophilic pleural effusions were identified in 44 of the 476 patients (9.2%). Malignancy was diagnosed as frequently in eosinophilic as in noneosinophilic effusions (20.5% vs 20.1%). The only diagnoses that were significantly associated with eosinophilic effusions were idiopathic (25% vs 8%; p = 0.001) and postthoracic surgery (11% vs 3%; p = 0.023). Median survival was 7.7 months for those with a noneosinophilic effusion compared to 16.8 months for those with eosinophilia (p = 0.017). This difference in survival persisted after adjustment for age and diagnosis. CONCLUSIONS: We conclude that malignancy is as prevalent among eosinophilic as noneosinophilic pleural effusions. However, the survival of patients with pleural fluid eosinophilia may be better than that of patients with noneosinophilic effusions.

Adult↗

PubMed1996

Specific and effective interaction of a guanine nucleotide analogue with small G proteins.

G proteins are molecular switches that use a cycle of GTP binding and hydrolysis to regulate a wide variety of cellular biochemical processes. Because the functional state of these proteins is allosterically determined by bound guanine nucleotides, a nucleotide analogue with protein specificity might have pharmacological or biochemical value. The binding of [alpha-32P]GTP to four small G proteins immobilized on nitrocellulose was competed by a series of analogues with modifications at multiple sites. One analogue, N2-(p-n-butylphenyl)guanosine 5'-(beta,gamma-difluoromethylene)triphosphate, had a approximately 40-fold higher affinity for one small G protein than for two of the others. Systematic analysis of each modification in the synthetic nucleotide revealed that specificity was conferred by the carbon substitution in the beta,gamma-phosphoanhydride bond. These observations were then extended to purified proteins of known sequence in solution by filtration binding studies with H-ras and rab5. Ras was 9-fold more discriminant between guanosine-5'-(beta,gamma-difluoromethylene)triphosphate and guanosine-5'-O-(3-thiotriphosphate) than was rab5, and the Q79L GTPase-defective mutant of rab5 was 6-fold more discriminant than wild-type rab5. Guanosine-5'-(beta,gamma-difluoromethylene)triphosphate protected a 20-kDa fragment of rab5 from tryptic proteolysis with greater efficacy than guanosine-5'-O-(3-thiotriphosphate) or guanosine-5'-(beta,gamma-imido)triphosphate despite its lower affinity, and GMP stabilized a conformation indistinguishable from apo-rab5. These results identify a synthetic guanine nucleotide analogue with differential affinity for closely related G proteins, determine the atomic substitution in the analogue that confers specificity, demonstrate discrimination by the analogue between wild-type and a point-mutant G protein, and establish efficacy of the analogue in inducing conformational change of a target protein disproportionate to the affinity of the interaction.

Amino Acid Sequence↗

PubMed1995

Colonic medication bezoar from extended-release nifedipine and procainamide.

We report an unusual case of a primary colonic bezoar composed of extended-release formulations of nifedipine and procainamide. Although these bezoars are rare, the increasingly frequent application of extended-release delivery systems to other commonly prescribed medications may increase the incidence of such bezoars in vulnerable patients. Clinicians should be aware of this potential problem when prescribing these medications, and have a high index of suspicion when painful or refractory constipation occurs.

Aged↗