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T Neff

Publications and source records attributed to T Neff.

18 recordsLinked to original sources
PubMed2005

An optimized workflow for the integration of biological information into radiotherapy planning: experiences with T1w DCE-MRI.

Planning of radiotherapy is often difficult due to restrictions on morphological images. New imaging techniques enable the integration of biological information into treatment planning and help to improve the detection of vital and aggressive tumour areas. This might improve clinical outcome. However, nowadays morphological data sets are still the gold standard in the planning of radiotherapy. In this paper, we introduce an in-house software platform enabling us to combine images from different imaging modalities yielding biological and morphological information in a workflow driven approach. This is demonstrated for the combination of morphological CT, MRI, functional DCE-MRI and PET data. Data of patients with a tumour of the prostate and with a meningioma were examined with DCE-MRI by applying pharmacokinetic two-compartment models for post-processing. The results were compared with the clinical plans for radiation therapy. Generated parameter maps give additional information about tumour spread, which can be incorporated in the definition of safety margins.

Algorithms↗
PubMed2001

Receptor specificity in the self-renewal and differentiation of primary multipotential hemopoietic cells.

To determine whether cytokine-induced signals generate unique responses in multipotential hemopoietic progenitor cells, the signaling domains of 3 different growth factor receptors (Mpl, granulocyte-colony-stimulating factor [G-CSF] receptor, and Flt-3) were inserted into mouse primary bone marrow cells. To circumvent the activation of endogenous receptors, each signaling domain was incorporated into an FK506 binding protein (FKBP) fusion to allow for its specific activation using synthetic FKBP ligands. Each signaling domain supported the growth of Ba/F3 cells; however, only Mpl supported the sustained growth of transduced marrow cells, with a dramatic expansion of multipotential progenitors and megakaryocytes. These findings demonstrate that the self-renewal and differentiation of multipotential progenitor cells can be influenced through distinct, receptor-initiated signaling pathways.

Animals↗
PubMed2001

Evaluation of the FASTSTART mode for reducing start-up delay in syringe pump infusion systems.

OBJECTIVE: The aim of the study was to evaluate the IVAC P7000 FASTSTART mode with regard to start-up performance in a 50-ml infusion syringe at a flow rate of 1 ml.h-1. METHODS: The time from depression of the start button to first fluid flow (T1) and to establishment of a pre-set flow rate (T2) were gravimetrically recorded with and without FASTSTART and with and without priming of the infusion system with a 1-ml fluid bolus prior to connection of the infusion line to the patient. RESULTS: FASTSTART significantly reduced start-up times in the unprimed syringe pump infusion system from (mean [SD]) 9.4 (6.0) to 2.5 (3.5) min for T1 and from 21.8 (9.8) to 9.4 (6.2) min for T2 (all p < 0.001). The greatest improvement in shortening of T1 and T2 was obtained when the system was primed prior to starting (p < 0.0001). After priming the infusion system, FASTSTART shortened T2 by some 50% from 1.4 (1.4) to 0.7 (0.6) min. CONCLUSION: Our data indicate that the FASTSTART procedure is effective and that substantial improvements can be obtained by priming the system prior to starting.

Catheterization, Central Venous↗
PubMed2001

Always flush the sampling port before flushing the arterial cannula in pediatric patients.

BACKGROUND: Blood sampling from arterial lines is a frequent event in anesthesia and critical care. To avoid clot formation, both the stopcock outlet and the cannula must be flushed after sampling. We investigated in a bench experiment whether fluid flow through the cannula is affected by the sequence of flushing procedures. METHODS: Continuity of fluid delivery from a vascular cannula was gravimetrically determined using two different flushing techniques with either a syringe pump flush system or a bag flush system. The procedures comprised first flushing the stopcock towards the cannula and then towards the stopcock sampling outlet or the reverse order. Experiments were repeated in triplicate and two sets for each flushing system at hydrostatic pressures of 37 mm Hg and 74 mm Hg. RESULTS: The main finding of the study was that flushing the stopcock towards the outlet after flushing the cannula resulted in considerable retrograde aspiration volumes and zero flow times, in particular in combination with syringe pump flush systems. At a hydrostatic pressure of 74 mm Hg, the observed zero flow time at the cannula tip amounted to (mean+/-SD) 0.1+/-0.01 min with the bag flush system and 7.7+/-0.5 min with the syringe pump flush system. The related retrograde aspiration volumes were 2.2+/-0.7 microl with the bag system and 30.0+/-2.0 microl with the syringe pump system. No backflow was recorded when the stopcock was first flushed to ambient pressure and then afterwards towards the cannula. CONCLUSION: Opening a flush system to ambient pressure affects the continuity of fluid delivery, particularly when using syringe pump flush systems. After blood sampling, the stopcock outlet should be flushed first followed by cannula flushing.

Blood Specimen Collection↗
PubMed2001

Start-up delays of infusion syringe pumps.

BACKGROUND: We performed a bench experiment to investigate the extent of start-up delays in fluid delivery for four different syringe pumps after initially placing the infusion syringe in the syringe pump. METHODS: Pump performance was determined at an infusion rate of 1 ml.h-1 with and without a fluid bolus delivered by the infusion pump prior to connecting the infusion line to the simulated patient. RESULTS: The time (mean +/- SD) from starting the pump up to first fluid delivery (t1) differed considerably between pumps (from 6.75 +/- 4.4 to 57.2 +/- 28.6 min) as did the time to steady state fluid delivery (t2) (from 19.6 +/- 9.3 to 76.3 +/- 29.0 min). Applying an initial bolus of 2 ml before connecting the line to the simulated patient practically eliminated the delay in fluid delivery (t1 ranging from 0.3 +/- 0.1 to 1.1 +/- 0.8 min). This manoeuvre also reduced the time to steady flow delivery (t2 from 6.0 +/- 3.1 to 11.1 +/- 4.3 min, P<0.001) and minimized the differences between syringe pumps. CONCLUSIONS: Syringe pump design affects start-up delay times because of free play of the syringe. These delays can be eliminated by a start-up bolus of 2 ml prior to connecting the infusion line to the patient.

Equipment Design↗
PubMed2000

Syringe size and flow rate affect drug delivery from syringe pumps.

PURPOSE: To evaluate the effect of syringe size and infusion rate on drug delivery after vertical displacement of syringe pumps. METHODS: Four syringes (10 ml, 20 ml, 30 ml, 50 ml) were studied at three infusion speeds (2 ml x hr(-1), 1 ml x hr(-1) and 0.5 ml x hr(-1)). Fluid delivery was measured gravimetrically using an electronic balance. Aspiration volume (amount of fluid retracted into the syringe-infusion line assembly) and zero-drug delivery time (time between the lowering of the syringe pump and reattainment of the initial weight) were determined after lowering the syringe pump 130 cm or 50 cm. Then, infusion bolus was measured after elevating the pump to its initial position. Syringe compliance was calculated from the occlusion release bolus at an occlusion pressure of 300 mmHg. RESULTS: Zero-drug delivery time, aspiration volume and infusion bolus increased with syringe size (P < 0.0001). At 0.5 ml x hr(-1), a zero-drug delivery time of 29.7 +/- 0.6 min was recorded for the 50 ml syringe and 5.5 +/- 0.15 min for the 10 ml syringe. As infusion rates increased, zero-drug delivery times decreased following a 1/x ratio. Zero-drug delivery time highly correlated with calculated syringe compliance (Pearson's r = 0.97, P < 0.001), which was closely related to syringe plunger area (R2 = 0.93, P < 0.001). CONCLUSIONS: Vertical displacement of syringe pumps causes flow irregularities which correlate directly with syringe size and indirectly with infusion rate. Extreme vertical maneuvering of syringe pumps should be avoided. Infusion rates > or = 1 ml x hr(-1) and low-compliant, small syringes are recommended when highly concentrated drugs are administered.

Humans↗
PubMed2000

[The effect of air within the infusion syringe on drug delivery of syringe pump infusion systems] .

Application of highly concentrated short-acting vasoactive drugs in the critically ill patient requires precisely working syringe pump systems for continuous intravenous drug delivery. We performed a bench study to investigate the consequences of small amounts of air entrapped within a 50-ml infusion syringe. In particular we studied the effect of entrapped air on drug delivery after moderate vertical displacement of the pump by 50 cm (e.g. in preparation for transport) and the effect on the time required to trigger the pressure alarm after occlusion of the infusion line. At a flow rate of 1 ml/h, lowering the syringe pump prolonged the zero-drug delivery time from (mean +/- SD) 4.1 +/- 0.8 min (without air) to 6.2 +/- 0.9 (with 1 ml air) and to 13.1 +/- 0.9 min (with 2 ml of air, p < 0.001 for all comparisons). Entrapping of 2 ml of air within the syringe resulted in a 2.6-fold prolongation of the occlusion alarm time after accidental occlusion of the infusion line and a 3-fold increase of the resulting infusion bolus after occlusion. Enclosed air within infusion syringes considerably affects the syringe compliance. It increases the susceptibility of constant drug delivery to vertical displacement of syringe pumps and impairs the occlusion alarm function. Therefore, any air in syringe of infusion pump systems should be carefully removed. To avoid infusion boluses of short-acting vasoactive drugs after accidental occlusions, the occluded infusion line should be released to ambient pressure first.

Air↗
PubMed2000

Influence of infusion line compliance on drug delivery rate during acute line loop formation.

OBJECTIVE: To determine whether infusion line compliance contributes to irregular drug delivery during vertical displacement of syringe pumps. DESIGN: Five different commercially available infusion lines were studied at infusion rates of 0.5, 1.0, and 1.5 ml/h. Zero drug delivery time was measured after acute line loop formation (70 cm) using an electronic balance. Compliance of each infusion line was calculated using a pressure transducer and measurement of the occlusion release bolus at 300 mmHg occlusion pressure. Finally, the influence of infusion line compliance on drug delivery during acute lowering of the syringe pump was studied using low- and high-compliance infusion lines. RESULTS: Acute line loop formation resulted in zero drug delivery time from 5.1 +/- 1.5 to 44.0 +/- 6.8 s at flow rates of 0.5 ml/h. Increased flow rates significantly reduced loop-induced flow variability. A close correlation was found between zero drug delivery time and calculated infusion line compliance at 0.5 ml/h (linear regression R2 = 0.79). Lowering of the syringe pump 50 cm prolonged zero drug delivery time from 295.8 +/- 20.7 s with the low-compliance tube to 463.3 +/- 24.0 s with the high-compliance infusion line. CONCLUSIONS: Infusion line compliance contributes to irregular drug delivery associated with vertical displacement of syringe pumps. Siphoning of the infusion line during patient care should be avoided, and flow rates of 1 ml/h or higher are recommended. Low-compliance infusion lines are indicated whenever highly short-acting vasoactive drugs at low delivery rates are administered.

Child↗
PubMed2000

The effects of syringe plunger design on drug delivery during vertical displacement of syringe pumps.

Fluid delivery from four types of commercially available 50-ml syringes was measured using an electronic balance at an infusion rate of 1 ml.h(-1). Retrograde aspiration volume and zero-drug delivery time were recorded after lowering the syringe pump by 50 cm. Syringe compliance was calculated from the volume of bolus released after occlusion at 100 mmHg. Zero-drug delivery times differed significantly between syringes, ranging from [mean (SD)] 3.26 (0.40) min to 6.38 (0.56) min (F = 55.5, d.f. = 3/20, p < 0.0001). Syringe compliance correlated well with aspiration volume (Pearson r(2) = 0.92, p < 0.001) and zero-drug delivery time (r(2) = 0.90, p < 0.001). Syringe design affected the internal syringe compliance. All syringes were associated with potentially relevant zero-drug delivery times after moderate vertical displacement. To minimise this risk, vertical displacement of syringe pumps delivering highly vasoactive drugs should be avoided.

Compliance↗
PubMed2000

Impact of infusion line compliance on syringe pump performance.

To determine the impact of infusion line compliance on the time to occlusion alarm (occlusion time) and the size of the subsequent occlusion release bolus, we studied three different infusion lines in combination with a 50-ml and 10-ml syringe. The mean occlusion time of the 50-ml syringe amounted to 20.3 +/- 0.28 min and increased to 26.2 +/- 0.19 min with the infusion with the infusion line yeielding the largest compliance (P<0.0001). The mean occlusion time of the 10-ml syringe was 2.5 +/- 0.75 min and showed a 2.7-fold variation with the three infusion lines (2.6+/-0.08, 5.6 +/- 0.28 and 6.9 +/- 0.35 min, respectively; P<0.0001). Occlusion times correlated strongly to be calculated estimated compliance of the syringe-infusion line assembly (Pearson's r=0.998, P<0.0001). Infusion line compliance has an important impact on time to occlusion, particularly when using small, low compliant infusion pump syringes.

Compliance↗
PubMed2000

Do antisiphon valves reduce flow irregularities during vertical displacement of infusion pump systems?

Vertical displacement of syringe pumps may cause irregular drug delivery due to hydrostatic pressure changes in the infusion line. The extent of flow fluctuations depends on the internal compliance of infusion lines, syringes and syringe pumps. We evaluated whether pressure regulation by antisiphon valves (ASV) reduces the flow variation during vertical displacement of 50 ml standard syringes and infusion pumps. An infusion assembly comprising a standard 50 ml BD Plastipak or a 50 ml Fresenius syringe, with syringe pump and 2 m low compliance infusion line was used for in vitro measurement of fluid delivery. The assembly was tested without ASV, and with two ASVs of differing operating pressure (ASV:75: valve opening pressure = 75 mmHg; ASV:155, 155 mmHg). Retrograde aspiration volume, zero-drug delivery time and valve opening bolus were determined after lowering the syringe pump by 50 cm. After elevating the syringe pump to its initial position the ensuing infusion bolus was recorded. Without an antisiphon valve the observed zero-drug delivery times after lowering the syringe pump were (mean +/- SD) 2.4 +/- 0.2 min using the BD Plastipak syringe and 4.09 +/- 0.55 min using the Fresenius syringe. Introduction of the antisiphon valve prolonged the zero drug delivery time 58% (ASV:75) and 88% (ASV:155) in the BD Plastipak syringe assembly and 43% (ASV:75) and 81% (ASV:155) in the Fresenius syringe assembly (P < 0.001). Antisiphon valves worsen flow irregularities caused by vertical displacement of syringe pumps and when used with delivery of concentrated inotropic drugs at low infusion rates, they may aggravate haemodynamic consequences of inconstant drug delivery.

Infusion Pumps↗
PubMed1999

Marrow sensitization to 5-fluorouracil using the ligands for Flt-3 and c-Kit.

In vivo administration of c-kit ligand (KL) expands early hemopoietic progenitors and stem cells and sensitizes clonogenic progenitors to 5-FU-mediated cell death. Studies were performed to determine whether the in vivo administration of Flk-2/Flt-3 ligand (FL) is also capable of sensitizing progenitors to 5-FU. Mice were treated with FL (100 micrograms/kg every 12 hours for a total of 3 doses), KL (50 micrograms/kg, same schedule) or both, either alone or in combination with 5-FU (a single 125 mg/kg injection 3 hours before the last dose of cytokine). Femurs and spleens were harvested 48 hours following the last dose of cytokine, and the total numbers of mononuclear cells and colony forming unit cells (CFU-C) per femur and spleen were determined. Statistically significant increases in the number of CFU-C per femur were observed in response to FL, KL and FL + KL. In the spleen, statistically significant increases in CFU-C were observed only with the FL + KL combination. 5-FU alone produced marked reductions in CFU-C both in the femur and in the spleen. In the femur, 5-FU-mediated reductions in CFU-C were enhanced 3- to 30-fold in the presence of concomitant KL, FL or KL + FL administration. Surprisingly, the combination of KL + FL was no more effective in sensitizing marrow CFU-C to 5-FU than was KL alone, suggesting that CFU-C that are capable of surviving the KL/5-FU combination cannot be driven into cell cycle by FL. The effects of concomitant cytokine/5-FU administration in the spleen contrasted sharply with those observed in the femur, as FL, KL and FL + KL all failed to enhance 5-FU-mediated reductions in CFU-C. The ability of FL + KL to stimulate CFU-C expansion in the spleen combined with the inability of this cytokine combination to augment 5-FU-mediated progenitor toxicity in the spleen supports the contention that cytokine-mobilized progenitors are not in cycle. FL's capacity to specifically sensitize marrow to the effects of cytotoxic drugs may have applications in bone marrow transplant conditioning regimens.

Animals↗
PubMed1997

Cytokine prestimulation as a gene therapy strategy: implications for using the MDR1 gene as a dominant selectable marker.

A major obstacle to stem cell gene therapy is the extremely low efficiency of stem cell transduction. In vivo selection is a strategy for enriching a minor population of genetically modified bone marrow cells through the introduction of a drug resistance gene, followed by subsequent administration of the corresponding cytotoxic drug in vivo. Achieving persistent effects from in vivo selection is expected to require selection at the level of stem cells or, minimally, selection at the level of progenitors. Major limitations to in vivo selection are the nonhematologic toxicities of the cytotoxic drugs used and the resistance of stem cells and progenitors to killing by most cytotoxic agents. Experiments were performed in mice to evaluate whether the drugs used for selection in combination with multiple drug resistance gene 1 (MDR1) could have an enhanced effect on clonogenic progenitors if preceded by administration of the cytokine, stem cell factor (SCF). Single doses of taxol, navelbine, or vinblastine produced 10-fold reductions in the total number of mononuclear cells per femur, indicating a significant depletion of nonclonogenic precursor cells. However, for each of these agents, clonogenic progenitors, assayed as colony-forming unit cells and day-12 spleen colony-forming units, were relatively spared. Administration of SCF before taxol, navelbine, or vinblastine completely abrogated the progenitor-sparing phenomenon, because clonogenic progenitors were depleted as effectively as nonclonogenic precursor cells. Furthermore, the administration of SCF before drug administration allowed the dosages of taxol and vinblastine to be reduced by more than half, while retaining reductions in progenitor numbers that were unachievable using very high doses of the cytotoxic drug alone. Doxorubicin administration resulted in a 30- to 40-fold depletion in progenitors that was not significantly altered by preceding SCF administration. These results suggest that previous observations of in vivo selection using MDR1 gene transfer followed by taxol administration may have resulted from selection at the level of relatively mature, nonclonogenic precursor cells. Furthermore, these data suggest that cytokine prestimulation may be a useful strategy for improving the selection of drug-resistant clonogenic progenitors and, possibly, stem cells in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Stem cell gene therapy, position effects and chromatin insulators.

Low efficiency of gene transfer is the main obstacle for a clinically effective gene therapy at the level of the pluripotent hematopoietic stem cell. Another important aspect of stem cell gene therapy, the actual expression of the transduced genes, has only been investigated adequately in very few studies, mainly for globin genes. Transcriptional silencing and position effects due to negative effects of surrounding chromatin on the expression of randomly integrated vector sequences may seriously jeopardize the success of current gene therapy strategies, even if transduction efficiency can be significantly improved. We propose the incorporation of chromatin insulators in the design of gene therapy vectors to overcome the problem of position effects. Chromatin insulators are protein-binding DNA elements that lack intrinsic promoter/enhancer activity but shelter genes from transcriptional influence of surrounding chromatin. The best characterized insulators are from Drosophila. We hypothesize that the important cellular function of chromatin organization is evolutionarily conserved and that human homologs to Drosophila insulator binding proteins such as the suppressor of Hairy-wing exist and can be cloned. Using these putative proteins, it should be possible to identify corresponding minimal binding sites with insulator activity. The design and incorporation of effective chromatin insulator sequences in the next generation of gene therapy vectors should lead to improved and more predictable expression of therapeutic transgenes and constitute an important step toward clinically effective gene therapy.

Animals↗
PubMed1997

Prone postioning and low-volume pressure-limited ventilation improve survival in patients with severe ARDS.

STUDY OBJECTIVES: Investigating the effect of low-volume pressure-limited ventilation and repeated prone positioning on the short-term course and outcome in patients with severe ARDS. SETTING: Level 1 trauma center of a university hospital. PATIENTS: Twenty-five patients suffering from ARDS with a lung injury score (LIS) > or = 2.5 admitted consecutively to our ICU from January 1992 to December 1994. METHODS: Mechanical ventilation with peak inspiratory pressure limitation to 35 mbar, irrespective of hypercapnia and prone positioning to achieve adequate oxygenation. SCORING AND MEASUREMENTS: Patient assessment with LIS, APACHE (acute physiology and chronic health evaluation) II score, injury severity score, and multiple organ failure score. Blood gas analyses and estimation of static compliance were repeated at least every 4 h during the treatment period. PaO2/FIO2 (fraction of inspired oxygen) ratio, alveolo-arterial oxygen difference, and intrapulmonary shunt were calculated according to standard equations. The best values taken from each 4-h period during the investigation were used to evaluate the best possible performance of the lung within this interval and to investigate the entire course. RESULTS: Mean predicted mortality based on the APACHE II score was 35.4+/-15.2%. Three of the 25 patients (12%) died. However, none was related to respiratory failure. No pneumothorax occurred. Sixteen patients, lacking any contraindication for prone positioning, responded positively to this change in position, each to a different individual degree. CONCLUSION: We assume that our low mortality in patients with severe ARDS might be due mainly to low-volume pressure-limited ventilation and prone positioning. This simple strategy seems to allow successful treatment for patients with severe ARDS.

APACHE↗
PubMed1996

The hematological effects of folate analogs: implications for using the dihydrofolate reductase gene for in vivo selection.

Previous studies have shown that dihydrofolate reductase (DHFR) gene transfer protects marrow from methotrexate (MTX)-mediated toxicity; however, MTX treatment in vivo has not convincingly been shown to enrich DHFR-transduced progenitors or stem cells. Experiments were performed to better characterize the hematological effects of MTX, and maneuvers were tested with the aim of improving the utility of MTX as an agent for in vivo selection. Progenitors were assayed as colony forming unit cells in culture (CFU-C) and in the spleens of irradiated mice (day 11 CFU-S). A single injection of MTX at doses up to 250 mg/kg (more than three times the LD10) failed to reduce CFU-C numbers significantly in the femur or spleen assayed 1-3 days later. However, consistent declines in the number of mononuclear cells per femur reflected a significant depletion of nonclonogenic precursor cells. Preceding administration of pegylated stem cell factor (SCF), 100 micrograms/kg per day, increased CFU-C killing by a single dose of 5-fluorouracil (5-FU) 15- to 65-fold in the femur, and 5- to 15-fold in the spleen, consistent with previous reports. In contrast, despite preceding SCF administration there was no significant progenitor killing by MTX. Similar results were obtained using a second folate analog, trimetrexate. These results suggest that the mechanism by which folate analogs exert their hematological toxicity is through the depletion of relatively mature, nonclonogenic precursor cells, and not by killing progenitors. This information is relevant to the use of DHFR in gene therapy protocols, and suggests that folate analogs are poorly suited agents for selection at the level of clonogenic progenitor cells in vivo.

Animals↗
PubMed1996

Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine.

Genes that confer cellular resistance to cytotoxic agents have potential applications both for marrow protection following cancer chemotherapy and as dominant selectable markers for the selection of genetically modified hematopoietic cell populations in vivo. Cytidine analogues, including cytosine arabinoside (Ara-C), 2',2'-difluorodeoxycytidine (gemcitabine), and other drugs represent a clinically important class of chemotherapeutic agents for which no drug resistance gene has yet been described. Studies were performed to determine whether forced expression of a gene encoding the enzyme cytidine deaminase can confer resistance to cytosine arabinoside (Ara-C) and gemcitabine in vitro. A pooled population of NIH3T3 cells overexpressing cytidine deaminase from a retroviral construct based on the LXSN-vector (LCDSN) demonstrated a 4.5-fold increased resistance to Ara-C based on the 50% inhibitory concentration (ID50) and a 3.7-fold increased resistance to Ara-C based on the 80% inhibitory concentration (ID80) relative to cells transduced with a control vector. In the hemopoietic cell line CCRF-CEM, the same retroviral construct conferred a 2.1-fold increased resistance to Ara-C by ID50 and a 3.0-fold increased resistance to Ara-C by ID80 relative to cells transduced with a control vector. CEM cells transduced with LCDSN were also resistant to gemcitabine (2.4-fold by ID50 and 2.5-fold by ID80). Furthermore, Ara-C-resistance could be completely reversed in LCDSN-transduced CEM cells by a specific inhibitor of cytidine deaminase, tetrahydrouridine (THU). Expression of the transgene was confirmed by RNase-protection assay and by an enzyme activity assay. These results provide the first direct evidence that forced expression of cytidine deaminase confers cellular resistance to Ara-C and gemcitabine.

3T3 Cells↗