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Biomedical subjects

P Blum

Publications and source records attributed to P Blum.

At least 19 recordsLinked to original sources
PubMed2006

[Translational research in renal cell cancer. Illustrated by the example of the vascular endothelial growth factor pathway].

For patients with metastatic renal cell cancer (RCC), therapeutic options after cytokine failure are rather limited. There is a considerable need to identify new substances for systemic therapy. Due to upregulation after the loss of a functional von Hippel Lindau gene product, the vascular endothelial growth factor (VEGF) pathway is a promising target for a molecular based therapy. Over the last few years, therapeutic agents have been developed which inhibit this pathway at various levels. Here, we provide an overview of the molecular background and currently used drugs which have entered clinical trials in the setting of metastatic RCC disease. Until now, the results from early clinical trials are very promising, however, the best schedule, dosage, potential combination regimens, as well as long time efficacy, are still to be determined.

Angiogenesis Inhibitors↗
PubMed2004

Post anaesthesia care unit discharge: a clinical scoring system versus traditional time-based criteria.

This prospective cohort analysis compared the efficiency of time-based discharge criteria (Group 1) to a modified clinical scoring system (Group 2), incorporating the assessment of pain and temperature, in the post anaesthesia care unit (PACU). Two consecutive series of patients (n = 292) were assessed following general anaesthesia for various surgical procedures. The time taken for patients to satisfy their respective discharge criteria was recorded as PACU length of stay (LOS). Patient group and other factors that may have influenced PACU-LOS were examined using time-to-event analysis. The raw PACU-LOS was not shown to be different between the two groups (log rank test, P = 0.12). Covariate adjusted estimates were used to compare the two discharge criteria and also to identify other factors influencing PACU-LOS. The Cox regression model was poorly specified and a log-logistic accelerated failure time model was found to be the most parsimonious predictive model. Predictors of decreased PACU-LOS were the treatment group (Group 2 versus Group 1) and the covariate recording anaesthetic airway choice (no endotracheal tube (ETT) versus ETT). Surgical time, as a linear function, intra- and postoperative opioid administration, as well as postoperative antiemetic use were predictors of increased PACU-LOS. Patient age, gender, urgency of surgery, and ASA classification were not predictive of PACU-LOS. Using covariate adjusted estimates, the new PACU discharge criteria, based on the Aldrete's scoring system, was associated with a significantly reduced PACU-LOS in comparison with time-based criteria.

Adult↗
PubMed2004

Barriers to effective perioperative communication in indigenous Australians: an audit of progress since 1996.

This prospective study was designed to elucidate barriers limiting effective perioperative communication between indigenous Australians and anaesthetists, and to identify strategies for improving communication. A questionnaire was used to collect data on 1040 consecutive patients undergoing anaesthesia at Royal Darwin Hospital between February and March 2003. 27.1% of these patients described themselves as Aboriginal. Aboriginal patients were more likely to undergo emergency surgery and were more likely to be classified as ASA 3, 4 or 5 than non-indigenous patients. Communication difficulties were identified in 28.7% of all Aboriginal patients, which was 31 times higher than those in non-Aboriginal patients. The most common reason identified for this was difficulty in speaking English. Only 17.7% of Aboriginal patients presenting to the operating theatre spoke English as their first language. Unfortunately, the anaesthetic team utilized the Aboriginal interpreter service in only a minority of cases. Communication difficulty in indigenous Australians is pervasive and often goes unrecognized. The results suggest that heath care providers may need staff training in cross-cultural communication and that protocols need to be developed within the health care system so that interpreters are called upon automatically early in the admission process.

Adolescent↗
PubMed2003

Treatment of painful peripheral neuroma by vein implantation.

Painful neuromas form on cutaneous nerves as a result of trauma, pressure, stretch or entrapment. Since the earliest descriptions of neuromas, proposed treatments have been met with poor results and controversy. The myriad of treatments described include: simple division of an affected nerve, implantation into muscle or bone, silicon sleeves and caps, repeated injection of steroids, end-to-side neurorrhaphy, medication and vein caps to name a few. Due to encouraging recent reports of treatment of painful neuromas by vein implantation, the authors describe a simple technique to achieve this surgical goal. As veins are readily accessible due to their proximity in the neurovascular bundle, they serve as a ready source for grafting. The advantages include minimisation of trauma to bone and muscle as compared with previous treatment techniques and the relative ease of the method.

Amputation, Surgical↗
PubMed2002

Extremely low vertical-emittance beam in the accelerator test facility at KEK.

Electron beams with the lowest, normalized transverse emittance recorded so far were produced and confirmed in single-bunch-mode operation of the Accelerator Test Facility at KEK. We established a tuning method of the damping ring which achieves a small vertical dispersion and small x-y orbit coupling. The vertical emittance was less than 1% of the horizontal emittance. At the zero-intensity limit, the vertical normalized emittance was less than 2.8 x 10(-8) rad m at beam energy 1.3 GeV. At high intensity, strong effects of intrabeam scattering were observed, which had been expected in view of the extremely high particle density due to the small transverse emittance.

Journal Article↗
PubMed2002

Posterior femoral cutaneous nerve entrapment neuropathy: operative exposure and technique.

An isolated posterior femoral cutaneous nerve lesion is rare. There have been seven reported cases to date. We report a 51-year-old male with pain in the posterolateral thigh, atypical from the classic anatomical description. Somatosensory evoked potentials were suggestive of a posterior femoral cutaneous nerve lesion. We describe our operative exposure and technique for decompression of the posterior femoral cutaneous nerve and include a comparative anatomical explanation for the unusual area of our patient's pain.

Femoral Nerve↗
PubMed2001

Secreted euryarchaeal microhalocins kill hyperthermophilic crenarchaea.

Few antibiotics targeting members of the archaeal domain are currently available for genetic studies. Since bacterial antibiotics are frequently directed against competing and related organisms, archaea by analogy might produce effective antiarchaeal antibiotics. Peptide antibiotic (halocin) preparations from euryarchaeal halophilic strains S8a, GN101, and TuA4 were found to be toxic for members of the hyperthermophilic crenarchaeal genus Sulfolobus. No toxicity was evident against representative bacteria or eukarya. Halocin S8 (strain S8a) and halocin R1 (strain GN101) preparations were cytostatic, while halocin A4 (strain TuA4) preparations were cytocidal. Subsequent studies focused on the use of halocin A4 preparations and Sulfolobus solfataricus. Strain TuA4 cell lysates were not toxic for S. solfataricus, and protease (but not nuclease) treatment of the halocin A4 preparation inactivated toxicity, indicating that the A4 toxic factor must be a secreted protein. Potassium chloride supplementation of the Sulfolobus assay medium potentiated toxicity, implicating use of a salt-dependent mechanism. The utility of halocin A4 preparations for genetic manipulation of S. solfataricus was assessed through the isolation of UV-induced resistant mutants. The mutants exhibited stable phenotypes and were placed into distinct classes based on their levels of resistance.

Anti-Bacterial Agents↗
PubMed2001

Quercetin cumulatively enhances copper induction of metallothionein in intestinal cells.

Wilson's disease, a genetic copper-overload condition, is currently treated with zinc because of the ability of zinc to induce metallothionein. We are interested in nonmetal chemicals that may alter intestinal copper metabolism and thus help to alleviate copper toxicity. Previously, we have shown that quercetin, a dietary flavonoid, can chelate copper. This study further examined the interaction of quercetin and copper in intestinal epithelial cells. We found that quercetin enhanced metallothoinein induction by copper and the effect was dose dependent. Quercetin also exerted a cumulative effect after repeated exposure. Repeated low-dose treatment (3-10 microM) of cells with quercetin can lead to the same effect on metallothoinein as one higher concentration treatment (100 microM). This property of quercetin is distinct from its chemical interaction with copper, but both can contribute to a reduction of copper toxicity. Among other flavonoids tested, two other copper chelators, catechin and rutin, did not increase copper induction of metallothionein, whereas genistein, an isoflavone that does not interact with copper chemically, increased copper induction of metallothionein. The effect of quercetin on copper metabolism is unique. Quercetin decreased zinc-stimulated metallothionein expression and had no effect on the cadmium induction of metallothionein. The clinical application of our observation needs to be explored.

Cadmium↗
PubMed2000

Autohydrolysis of plant polysaccharides using transgenic hyperthermophilic enzymes.

Commercial bioprocessing of plant carbohydrates, such as starch or cellulose, necessitates the use of commodity enzyme additives to accelerate polysaccharide hydrolysis. To simplify this procedure, transgenic plant tissues constitutively producing commodity enzymes were examined as a strategy for accelerating carbohydrate bioprocessing. Hyperthermophilic glycosyl hydrolases were selected to circumvent enzyme toxicity, because such enzymes are inactive at plant growth temperatures and are therefore physiologically benign. Transgenic tobacco lines were established that produced either a hyperthermophilic alpha-glucosidase or a beta-glycosidase using genes derived from the archaeon Sulfolobus solfataricus. Western blot and immunoprecipitation analyses were used to demonstrate the presence of recombinant enzymes in plant tissues. Transgenic enzyme levels exhibited an unusual delayed pattern of accumulation while their activities survived plant tissue preservation. Transgenic plant protein extracts released glucose from purified polysaccharide substrates at appreciable rates during incubation in high-temperature reactions. Glucose was also produced following enzymatic treatment of plant extracts enriched for endogenous polysaccharides. Direct conversion of plant tissue into free sugar was evident using whole plant extracts of either transgenic line, and could be significantly accelerated in a synergistic manner by combining transgenic line extracts.

Blotting, Western↗
PubMed1999

Polypeptide flux through bacterial Hsp70: DnaK cooperates with trigger factor in chaperoning nascent chains.

A role for DnaK, the major E. coli Hsp70, in chaperoning de novo protein folding has remained elusive. Here we show that under nonstress conditions DnaK transiently associates with a wide variety of nascent and newly synthesized polypeptides, with a preference for chains larger than 30 kDa. Deletion of the nonessential gene encoding trigger factor, a ribosome-associated chaperone, results in a doubling of the fraction of nascent polypeptides interacting with DnaK. Combined deletion of the trigger factor and DnaK genes is lethal under normal growth conditions. These findings indicate important, partially overlapping functions of DnaK and trigger factor in de novo protein folding and explain why the loss of either chaperone can be tolerated by E. coli.

Bacterial Proteins↗
PubMed1999

Extragenic pleiotropic mutations that repress glycosyl hydrolase expression in the hyperthermophilic archaeon Sulfolobus solfataricus.

The hyperthermophilic archaeon Sulfolobus solfataricus employs a catabolite repression-like regulatory system to control enzymes involved in carbon and energy metabolism. To better understand the basis of this system, spontaneous glycosyl hydrolase mutants were isolated using a genetic screen for mutations, which reduced expression of the lacS gene. The specific activities of three glycosyl hydrolases, including an alpha-glucosidase (malA), a beta-glycosidase (lacS), and the major secreted alpha-amylase, were measured in the mutant strains using enzyme activity assays, Western blot analysis, and Northern blot analysis. On the basis of these results the mutants were divided into two classes. Group I mutants exhibited a pleiotropic defect in glycosyl hydrolase expression, while a single group II mutant was altered only in lacS expression. PCR, Southern blot analysis, comparative heterologous expression in Escherichia coli, and DNA sequence analysis excluded cis-acting mutations as the explanation for reduced lacS expression in group I mutants. In contrast lacS and flanking sequences were deleted in the group II mutant. Revertants were isolated from group I mutants using a lacS-specific screen and selection. These revertants were pleiotropic and restored glycosyl hydrolase activity either partially or completely to wild-type levels as indicated by enzyme assays and Western blots. The lacS mutation in the group II mutant, however, was nonrevertible. The existence of group I mutants and their revertants reveals the presence of a trans-acting transcriptional regulatory system for glycosyl hydrolase expression.

Archaeal Proteins↗
PubMed1999

Bacterial growth state distinguished by single-cell protein profiling: does chlorination kill coliforms in municipal effluent?

Municipal effluent is the largest reservoir of human enteric bacteria. Its public health significance, however, depends upon the physiological status of the wastewater bacterial community. A novel immunofluorescence assay was developed and used to examine the bacterial growth state during wastewater disinfection. Quantitative levels of three highly conserved cytosolic proteins (DnaK, Dps, and Fis) were determined by using enterobacterium-specific antibody fluorochrome-coupled probes. Enterobacterial Fis homologs were abundant in growing cells and nearly undetectable in stationary-phase cells. In contrast, enterobacterial Dps homologs were abundant in stationary-phase cells but virtually undetectable in growing cells. The range of variation in the abundance of both proteins was at least 100-fold as determined by Western blotting and immunofluorescence analysis. Enterobacterial DnaK homologs were nearly invariant with growth state, enabling their use as permeabilization controls. The cellular growth states of individual enterobacteria in wastewater samples were determined by measurement of Fis, Dps, and DnaK abundance (protein profiling). Intermediate levels of Fis and Dps were evident and occurred in response to physiological transitions. The results indicate that chlorination failed to kill coliforms but rather elicited nutrient starvation and a reversible nonculturable state. These studies suggest that the current standard procedures for wastewater analysis which rely on detection of culturable cells likely underestimate fecal coliform content.

Antibodies, Bacterial↗
PubMed1999

Coordinate transcriptional control in the hyperthermophilic archaeon Sulfolobus solfataricus.

The existence of a global gene regulatory system in the hyperthermophilic archaeon Sulfolobus solfataricus is described. The system is responsive to carbon source quality and acts at the level of transcription to coordinate synthesis of three physically unlinked glycosyl hydrolases implicated in carbohydrate utilization. The specific activities of three enzymes, an alpha-glucosidase (malA), a beta-glycosidase (lacS), and an alpha-amylase, were reduced 4-, 20-, and 10-fold, respectively, in response to the addition of supplementary carbon sources to a minimal sucrose medium. Western blot analysis using anti-alpha-glucosidase and anti-beta-glycosidase antibodies indicated that reduced enzyme activities resulted exclusively from decreased enzyme levels. Northern blot analysis of malA and lacS mRNAs revealed that changes in enzyme abundance arose primarily from reductions in transcript concentrations. Culture conditions precipitating rapid changes in lacS gene expression were established to determine the response time of the regulatory system in vivo. Full induction occurred within a single generation whereas full repression occurred more slowly, requiring nearly 38 generations. Since lacS mRNA abundance changed much more rapidly in response to a nutrient down shift than to a nutrient up shift, transcript synthesis rather than degradation likely plays a role in the regulatory response.

Culture Media↗
PubMed1998

Roles of DnaK and RpoS in starvation-induced thermotolerance of Escherichia coli.

DnaK is essential for starvation-induced resistance to heat, oxidation, and reductive division in Escherichia coli. Studies reported here indicate that DnaK is also required for starvation-induced osmotolerance, catalase activity, and the production of the RpoS-controlled Dps (PexB) protein. Because these dnaK mutant phenotypes closely resemble those of rpoS (sigma38) mutants, the relationship between DnaK and RpoS was evaluated directly during growth and starvation at 30 degrees C in strains with genetically altered DnaK content. A starvation-specific effect of DnaK on RpoS abundance was observed. During carbon starvation, DnaK deficiency reduced RpoS levels threefold, while DnaK excess increased RpoS levels nearly twofold. Complementation of the dnaK mutation restored starvation-induced RpoS levels to normal. RpoS deficiency had no effect on the cellular concentration of DnaK, revealing an epistatic relationship between DnaK and RpoS. Protein half-life studies conducted at the onset of starvation indicate that DnaK deficiency significantly destabilized RpoS. RpoH (sigma32) suppressors of the dnaK mutant with restored levels of RpoS and dnaK rpoS double mutants were used to show that DnaK plays both an independent and an RpoS-dependent role in starvation-induced thermotolerance. The results suggest that DnaK coordinates sigma factor levels in glucose-starved E. coli.

Adaptation, Biological↗
PubMed1998

Molecular characterization of the alpha-glucosidase gene (malA) from the hyperthermophilic archaeon Sulfolobus solfataricus.

Acidic hot springs are colonized by a diversity of hyperthermophilic organisms requiring extremes of temperature and pH for growth. To clarify how carbohydrates are consumed in such locations, the structural gene (malA) encoding the major soluble alpha-glucosidase (maltase) and flanking sequences from Sulfolobus solfataricus were cloned and characterized. This is the first report of an alpha-glucosidase gene from the archaeal domain. malA is 2,083 bp and encodes a protein of 693 amino acids with a calculated mass of 80.5 kDa. It is flanked on the 5' side by an unusual 1-kb intergenic region. Northern blot analysis of the malA region identified transcripts for malA and an upstream open reading frame located 5' to the 1-kb intergenic region. The malA transcription start site was located by primer extension analysis to a guanine residue 8 bp 5' of the malA start codon. Gel mobility shift analysis of the malA promoter region suggests that sequences 3' to position -33, including a consensus archaeal TATA box, play an essential role in malA expression. malA homologs were detected by Southern blot analysis in other S. solfataricus strains and in Sulfolobus shibatae, while no homologs were evident in Sulfolobus acidocaldarius, lending further support to the proposed revision of the genus Sulfolobus. Phylogenetic analyses indicate that the closest S. solfataricus alpha-glucosidase homologs are of mammalian origin. Characterization of the recombinant enzyme purified from Escherichia coli revealed differences from the natural enzyme in thermostability and electrophoretic behavior. Glycogen is a substrate for the recombinant enzyme. Unlike maltose hydrolysis, glycogen hydrolysis is optimal at the intracellular pH of the organism. These results indicate a unique role for the S. solfataricus alpha-glucosidase in carbohydrate metabolism.

Amino Acid Sequence↗