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Biomedical subjects

T Gottlieb

Publications and source records attributed to T Gottlieb.

At least 55 records · Page 3Linked to original sources
PubMed1994

Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small-cell lung cancer cells.

As an approach to the rational design of combination chemotherapy involving the anti-cancer DNA topoisomerase II poison etoposide (VP-16), we have studied the dynamic changes occurring in small-cell lung cancer (SCLC) cell populations during protracted VP-16 exposure. Cytometric methods were used to analyse changes in target enzyme availability and cell cycle progression in a SCLC cell line, mutant for the tumour-suppressor gene p53 and defective in the ability to arrest at the G1/S phase boundary. At concentrations up to 0.25 microM VP-16, cells became arrested in G2 by 24 h exposure, whereas at concentrations 0.25-2 microM G2 arrest was preceded by a dose-dependent early S-phase delay, confirmed by bromodeoxyuridine incorporation. Recovery potential was determined by stathmokinetic analysis and was studied further in aphidicolin-synchronised cultures released from G1/S and subsequently exposed to VP-16 in early S-phase. Cells not experiencing a VP-16-induced S-phase delay entered G2 delay dependent upon the continued presence of VP-16. These cells could progress to mitosis during a 6-24 h period after drug removal. Cells experiencing an early S-phase delay remained in long-term G2 arrest with greatly reducing ability to enter mitosis up to 24 h after removal of VP-16. Irreversible G2 arrest was delimited by the induction of significant levels of DNA cleavage or fragmentation, not associated with overt apoptosis, in the majority of cells. Western blotting of whole-cell preparations showed increases in topoisomerase II levels (up to 4-fold) attributable to cell cycle redistribution, while nuclei from cells recovering from S-phase delay showed enhanced immunoreactivity with an anti-topoisomerase II alpha antibody. The results imply that traverse of G1/S and early S-phase in the presence of a specific topoisomerase II poison gives rise to progressive low-level trapping of topoisomerase II alpha, enhanced topoisomerase II alpha availability and the subsequent irreversible arrest in G2 of cells showing limited DNA fragmentation. We suggest that protracted, low-dose chemotherapeutic regimens incorporating VP-16 are preferentially active towards cells attempting G1/S transition and have the potential for increasing the subsequent action of other topoisomerase II-targeted agents through target enzyme modulation. Combination modalities which prevent such dynamic changes occurring would act to reduce the effectiveness of the VP-16 component.

Bromodeoxyuridine↗
PubMed1994

Evaluation of E test as a rapid method for determining MICs for nutritionally variant streptococci.

E test was evaluated as an alternative rapid and simple method of MIC estimation for nutritionally variant streptococci. E test with various media was compared with conventional broth and plate dilution techniques supplemented with 0.001% (wt/vol) pyridoxal hydrochloride (vitamin B6). Of the 14 strains tested with E test, isosensitest agar supplemented with 5% defibrinated horse blood and 0.001% pyridoxal HCl, with and without 0.01% cysteine, gave complete agreement within one twofold-dilution titer of the agar reference method and between 93 and 86% agreement within one twofold-dilution titer of the broth reference method. E test MICs with other media were comparable; however, these were considerably more difficult to interpret. Use of Mueller-Hinton and Columbia-based supplemented agar showed hazy growth and double zoning around the endpoint, respectively. The addition of 0.01% (wt/vol) cysteine to media exhibited no significant effect, and incubation in 5% carbon dioxide (CO2) did not affect MICs.

Agar↗
PubMed1993

Hazards of bacterial contamination of blood products.

Post-transfusion bacterial sepsis is infrequent. It is, however, associated with a high mortality due to septic shock. This reflects the release of endotoxin from gram negative bacteria. Lesser transfusion reactions are usually under-reported. These are frequently caused by gram positive bacteria. Gram positive species such as staphylococci and other skin surface organisms may be cultured from platelets stored at room temperature. Typically, gram negative "psychrophyllic" species which survive storage at 4 degrees C are cultured from stored refrigerated blood implicated in transfusion reactions. These include Yersinia enterocolitica, Pseudomonas fluorescens etc. Bacterial contamination of the blood supply can occur via an endogenous or an exogenous source. Endogenous donor bacteraemia due to Y.enterocolitica may be asymptomatic or may follow an episode of gastroenteritis. Exogenous infections occur through some defect in the usual collection practice. Transfusion-acquired syphilis is now extremely uncommon. In the third world, beside the need for effective screening for viral pathogens, infections with protozoa, in particular plasmodia, trypanosoma and leishmania remain a major obstacle to ensuring safe blood supplies. Prevention of transfusion reactions demands rigorous attention to details of collection, storage, reissuing and infusion of blood products, as well as prompt treatment, testing and reporting of suspected reactions.

Bacteremia↗
PubMed1992

Antimicrobial susceptibility of anaerobic bacteria in Australia.

The susceptibilities of 900 clinical isolates of anaerobic bacteria to 14 antimicrobial agents were determined by an agar dilution technique. Chloramphenicol, imipenem and metronidazole were found to be active against virtually all of the strains; only a single Bacteroides fragilis isolate was resistant to both imipenem and metronidazole. The addition of clavulanic acid to amoxycillin and ticarcillin potentiated the activities of these agents against all anaerobes including members of the B. fragilis group. Ampicillin/sulbactam and clindamycin were the next most active agents, 91 and 89% of isolates respectively being susceptible. Seventy-three per cent of the bacteria tested were susceptible to cefoxitin and 65% to cefotetan, with the MICs of almost 50% of the isolates clustering between 16 and 32 mg/L. There was also clustering around the breakpoint (64 mg/L) of piperacillin. Azithromycin exhibited poor activity against the B. fragilis group; only 18% of isolates were susceptible to < or = 4 mg/L. However, 92% of non-B. fragilis Bacteroides group strains were susceptible to this agent. We conclude that imipenem, metronidazole, chloramphenicol, ticarcillin/clavulanate, co-amoxiclav and, to a lesser extent, ampicillin/sulbactam are suitable as empirical therapy for infections caused by anaerobic bacteria.

Anti-Bacterial Agents↗
PubMed1992

Nursing research in the VA system. A consortium approach.

Five Veterans' Administration Medical Centers formed a consortium to promote nursing research. Consortium arrangements focusing on research are reviewed based on the literature, the consortium's experience, and a survey of 171 VA facilities. Consortiums are suggested for multisite facilities, such as city, state, proprietary, and religious hospital systems, to increase the quality and quantity of nursing research where institutional mechanisms for overcoming the difficulties of meeting and sharing information are already in place.

Hospitals, Veterans↗
PubMed1991

The role of viruses and atypical organisms in the pathogenesis of adult pneumonia in Papua New Guinea.

The role of viruses and atypical organisms in pneumonia is well known in western populations, yet very little documentation is available about their role in pneumonia in developing countries. In a study of 175 adults with community-acquired pneumonia in Papua New Guinea, serological methods were used to assess this issue. Five patients had high influenza A titres suggestive of recent infection. Adenovirus titres rose significantly in one patient with Haemophilus influenzae pneumonia, whilst no evidence of past or recent infection was found in the remainder of patients when tested for all pathogens. Bacterial cultures revealed the continued predominance of Streptococcus pneumoniae in the pathogenesis of pneumonia in this population. We conclude that viruses and atypical organisms (including Mycoplasma and Legionella) play a very limited role in this setting.

Adenovirus Infections, Human↗
PubMed1989

A sorting signal for the basolateral delivery of the vesicular stomatitis virus (VSV) G protein lies in its luminal domain: analysis of the targeting of VSV G-influenza hemagglutinin chimeras.

When synthesized in polarized epithelial cells, the envelope glycoproteins hemagglutinin of influenza and G of vesicular stomatitis virus are targeted to the apical and basolateral plasma membranes, respectively. To determine which portions of these transmembrane proteins contain information necessary for their sorting, the behavior of two different G-hemagglutinin chimeric polypeptides, consisting of all or nearly all the luminal portion of the vesicular stomatitis virus G protein linked to C-terminal segments of influenza hemagglutinin that included its transmembrane and cytoplasmic domains, was studied in MDCK cells transformed with the corresponding cDNAs. Both chimeras were transported from the endoplasmic reticulum to the Golgi apparatus and from there to the cell surface with the same rapid kinetics as the intact G protein. By using a cell surface immunoprecipitation assay with monolayers cultured on permeable filters that allows the recovery of labeled protein molecules present in each cell surface domain, it was found that both chimeric proteins as well as the intact G protein were delivered almost exclusively to the basolateral surface. This polarized distribution of the polypeptides did not change during a subsequent 90-min chase period, although during this time a large fraction of the glycoprotein molecules underwent degradation. In addition, a small fraction of the cell surface-associated glycoprotein molecules shed their ectoplasmic segments into the basolateral compartment, apparently as a result of a proteolytic cleavage. Immunofluorescence on transverse frozen sections and immunoelectron microscopy revealed a prominent accumulation of the chimeric polypeptides in the lateral cell membranes, with lesser amounts on the basal and apical surfaces. These results indicate that information specifying the basolateral transport of the G glycoprotein is located within the first 426 N-terminal amino acids of its ectoplasmic portion.

Amino Acid Sequence↗
PubMed1989

Community-acquired Acinetobacter pneumonia.

We describe the first case report of community-acquired Acinetobacter pneumonia in Australia. Well recognised risk factors for this entity (alcoholism, diabetes mellitus and chronic lung disease) were present in our patient. His pneumonia ran a fulminant course, with death occurring within 24 hours of presentation to hospital. Whilst rare, this infection is being described with increasing frequency, particularly in developing countries including Papua New Guinea.

Acinetobacter Infections↗
PubMed1987

Nonpolarized secretion of truncated forms of the influenza hemagglutinin and the vesicular stomatitus virus G protein from MDCK cells.

The demonstration that the envelope glycoproteins G of vesicular stomatitus virus and hemagglutinin of influenza virus synthesized in polarized epithelial cells transfected with the corresponding genes are effectively segregated to the basolateral or apical plasma membrane domains, respectively, implies that the information determining this segregation resides within the structures of the proteins themselves. To localize the sorting information within these proteins, the polarity of secretion of truncated hemagglutinin and G glycoproteins secreted from confluent monolayers of MDCK cells transformed with vectors containing the corresponding truncated cDNAs was examined. It was found that, even though the transformed cells continued to secrete a major endogenous glycoprotein exclusively from the apical surface, the modified viral glycoproteins were secreted in a nonpolarized fashion from both sides of the monolayers. These observations suggest that important information for the sorting of the viral glycoprotein is contained within their membrane anchoring or cytoplasmic segments or that, if sorting signals are luminally located, these signals must be present in a conformation that is not attainable when the polypeptides are not attached to the membrane.

Animals↗