Biomedical subjects

R Hoekstra

Publications and source records attributed to R Hoekstra.

At least 19 recordsLinked to original sources

PubMed2006

Nitric oxide and neopterin in bipolar affective disorder.

BACKGROUND: There is an increasing interest in the role of nitric oxide (NO) and pterines in the pathophysiology of neuropsychiatric disorders. The results so far show an inconsistent pattern. METHODS: In the present study, neopterin and a measure of NO synthesis in plasma of symptomatic and euthymic bipolar affective patients were compared to those of patients with a major depression and healthy controls. As an index of NO synthesis, the ratio of the amino acids citrulline and arginine (Cit-Arg ratio) was calculated. Neopterin is a bypass product in the synthesis of tetrahydrobiopterin, which is a cofactor of NO synthase. RESULTS: The results indicate that both neopterin and the Cit-Arg ratio are decreased in bipolar affective patients, irrespective of their symptomatic status. In addition, an association between the values of the Cit-Arg ratio and the neopterin level was observed, which is suggestive for a low tetrahydrobiopterin activity. CONCLUSION: NO formation may be endangered in bipolar affective disorder.

Adult↗

PubMed2006

A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors.

BACKGROUND: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination). RESULTS: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine-cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine-cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC). CONCLUSIONS: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine-cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.

Adult↗

PubMed2006

Local spin polarization at surfaces probed by hollow atoms.

The relaxation of hollow atoms produced by slow multiply charged ions impinging on surfaces produces characteristic Auger electron spectra. These spectra, which serve as fingerprints of the interaction, can be used to probe local spin ordering at surfaces by relating changes in the intensities of different spin states to local spin polarization at the surface. The area from which the electrons are captured is of the order of a few Angstrom(2), only. The potential of the method is illustrated by He(2+) and N(6+) ions interacting with a ferromagnetic Ni(110) crystal. From the Auger spectra we determine a spin polarization of approximately 90% at room temperature.

Journal Article↗

PubMed2006

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

Aged↗

PubMed2006

Subnormothermic preservation maintains viability and function in a porcine hepatocyte culture model simulating bioreactor transport.

Bioartificial liver (BAL) systems have been developed to bridge patients with acute liver failure (ALF) to liver transplantation or liver regeneration. Clinical application of BAL systems is dependent on the supportive quality of cells used and direct availability of the whole system. Reliable transport of BAL systems from the laboratory to remote treatment centers is therefore inevitable. Subsequently, preservation conditions play a crucial role during transport of a BAL, with temperature being one of the most determining factors. In this study, we assessed the effect of subnormothermic preservation on freshly isolated porcine hepatocytes cultured in monolayer under oxygenation. Additionally, the effect of the University of Wisconsin (UW) preservation solution was compared with Williams' E (WE) culture medium at 4 degrees C. The control group was cultured for 3 days at 37 degrees C, whereas the transport groups were cultured at 4 degrees C, 15 degrees C, 21 degrees C, or 28 degrees C for 24 h at day 2. All groups were tested each day for cell damage and hepatic functions. Subnormothermic culture (i.e., 15 degrees C to 28 degrees C) for a period of 24 h did not reduce any hepatic function and did not increase cellular damage. In contrast, culture of hepatocytes in WE medium and preservation in UW solution at 4 degrees C significantly reduced hepatic function. In conclusion, freshly isolated porcine hepatocytes can be preserved for 24 h at subnormothermic temperatures as low as 15 degrees C. Future research will focus on the implementation of the AMC-BAL in an oxygenated culture medium perfusion system for transport between the laboratory and the hospital.

Albumins↗

PubMed2005

Liver support therapy: an overview of the AMC-bioartificial liver research.

Acute liver failure (ALF) is a disease with a mortality of 60-90% depending on the cause. Only high-urgency liver transplantation is able to increase survival compared to standard intensive care therapy. Liver transplantation is hampered by the increasing shortage of organ donors, resulting in a high incidence of patients with ALF dying on the transplantation waiting list. Amongst a variety of liver assist therapies, bioartificial liver (BAL) therapy is marked as the most promising solution to bridge ALF patients to liver transplantation or to liver regeneration, since several BAL systems showed significant improvement of survival time in experimental animals with irreversible ALF. One of these systems has been developed at the Academic Medical Center in Amsterdam, The Netherlands - the AMC-BAL. This overview describes the development of the AMC-BAL based on porcine hepatocytes which was started 10 years ago. Positive results of in-vitro functionality and in vivo safety and efficacy led to a successful phase I study in 12 ALF patients in Italy. However, xenotransplantation legislation in many European countries prohibits the use of porcine hepatocytes in clinically applied BAL systems. The future of the BAL, therefore, resides in the development of a human-derived hepatocyte cell line as biocomponent of BAL systems.

Animals↗

PubMed2005

Bipolar mania and plasma amino acids: increased levels of glycine.

Previous studies have suggested that the N-methyl-d-aspartate (NMDA) glutamate receptor complex is implicated in the pathophysiology of several neuropsychiatric disorders. Especially the glycine coagonist site of this receptor has been proposed as a therapeutic target. It has been hypothesized that the NMDA receptor and the serotonergic system, which function is compromised in affective disorders, are functionally coupled. Furthermore, several studies suggest that peripheral levels of amino acids are associated with psychotic symptomatology. We therefore measured plasma levels of glutamate, glycine, tryptophan and the tryptophan ratio in 20 bipolar-I patients during the manic phase and at remission of symptomatology. Data were compared to a matched group of healthy controls and a group of euthymic bipolar-I patients. During the manic phase, a significant increase of both glutamate and glycine was found, that persisted at remission. Tryptophan and the tryptophan ratio were decreased in manic patients. Subsequent analysis showed that changes in glutamate, tryptophan and tryptophan ratio could be attributed to the use of anticonvulsants. The increased glycine, however, was not related to the use of mood stabilizers. Although the exact relationship between peripheral measures of amino acids, e.g., glycine is not fully clear, the results of this study suggest an involvement of glycine and/or its coagonist site of the NMDA receptor in a manic relapse of patients with a bipolar-I disorder.

Adult↗

PubMed2005

Response of polyatomic molecules to ultrastrong laser- and ion-induced fields.

The exposure of molecules to short, ultrastrong electric fields leads to multiple ionization and a subsequent Coulomb explosion. We present a comparative study where uracil molecules are exposed to fields generated by high-power laser pulses (tau approximately 75 fs, I > 10(16) W/cm2) or swift highly charged ions (0.5 MeV Xe25+) representing a half-cycle pulse of less than 10 fs duration. Molecular dynamics and structural information contained in the fragmentation pathways can be assessed separately. Despite the similar field strengths large differences in fragment kinetic energies are found which are related to field shape and duration with the aid of molecular dynamics simulations.

Journal Article↗

PubMed2005

Assessment and improvement of liver specific function of the AMC-bioartificial liver.

UNLABELLED: The variety of methods for measuring bioactive mass and functionality of bioartificial livers (BAL) is confusing and prevents accurate comparison of reported data. Here we present a comparison of different hepatocyte quantification methods and propose that estimation of cell pellet volume after centrifugation generates a reliable, useful and fast method. In addition a correlation is made between several function tests performed in 26 bioreactors to assess their predictive value. The ammonia eliminating capacity was found to be most predictive for other liver functions, except for lidocaine elimination as a measure of mixed function oxidase activity, which should therefore be determined separately. The oxygen consumption test proved to be an easy and predictive parameter as well. The first generation of our BAL system needed further development to assure optimal treatment of acute liver failure (ALF) patients. Changes in the porcine hepatocyte isolation method and bioreactor loading as well as changes in bioreactor configuration, including use of different materials, resulted in a significantly improved level and maintenance of in vitro BAL function. A fourfold increase in ammonia eliminating capacity, which is only reduced to 75% after seven days of culturing, offers promising prospects for further clinical application. CONCLUSION: The current second generation of our BAL and improvement of hepatocyte isolation and testing protocols have led to a significant increase in the level as well as the maintenance of hepatocyte specific function in our BAL. Finally, consensus on definition of the bioactive mass to be loaded in the bioreactor and insight in the variation and reliability of the functional and metabolic parameters enhances comparison of the different types of bioartificial livers presented in literature.

Ammonia↗

PubMed2004

Large animal models of fulminant hepatic failure in artificial and bioartificial liver support research.

Among the large range of organs involved in the field of tissue engineering (skin, blood vessels, cartilage, etc.) the liver has been given broad attention in the last decade. Liver support systems encompassing artificial and bioartificial systems are applied to treat patients with fulminant hepatic failure (FHF) as a bridge to orthotopic liver transplantation or to liver regeneration. To test safety, technical applicability and therapeutic effect of liver support systems, reliable animal models are needed. Due to the complexity of FHF many diverse attempts have been made to develop an adequate animal model to study liver failure, liver regeneration and liver support systems. In this paper an overview is given of the different models and their advantages and disadvantages are discussed. Suggestions are made for the most suitable large animal model to test liver support systems.

Acetaminophen↗

PubMed2003

Charge driven fragmentation of nucleobases.

We studied multiple ionization of single nucleobases by means of slow highly charged ions (Xe(q+), q=5-25). The products of the subsequent fragmentation were studied using high resolution coincidence time-of-flight spectrometry. We observed a strong dependence of the fragment kinetic energies on the initial charge state of the intermediate parent ions as well as on the initial chemical environment of the respective fragment ions within the parent molecule. The data allow us to shed light on the charge distribution within the molecule as well as on the fragmentation dynamics of these intermediate size systems.

DNA Damage↗

PubMed2003

Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours.

A single-agent dose escalating phase I and pharmacokinetic study with Cilengitide, an inhibitor of the integrins alphavbeta3 and alphavbeta5, was performed to determine its safety and toxicity. Cilengitide was administered as a one-hour infusion twice weekly without interruption to patients with histologically- or cytologically-confirmed metastatic solid tumours. Plasma pharmacokinetics were determined at days 1 and 15. 37 patients were enrolled into the study. Dose levels studied were 30, 60, 120, 180, 240, 400, 600, 850, 1200, and 1600 mg/m(2)/infusion. There was no dose-limiting toxicity (DLT). Pharmacokinetics were dose-independent and time-invariant. Apparent terminal half-life ranged from 3 to 5 h. At 120 mg/m(2)/infusion, peak plasma concentrations were attained that optimally inhibited tumour growth in preclinical models. Cilengitide can be safely administered using a continuous twice-weekly infusion regimen. As DLT was not reached, future trials should explore Cilengitide at different doses.

Adult↗

PubMed2003

Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus.

BACKGROUND: We have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting. PATIENTS AND METHODS: Patients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2) every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45-78); median World Health Organization performance status of 1 (range 0-2). RESULTS: Ninety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute-Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively. CONCLUSIONS: This dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising.

Aged↗

PubMed2002

Charge localization in collision-induced multiple ionization of van der Waals clusters with highly charged ions.

Charge localization in multiple ionization and fragmentation of small argon clusters is reported. The processes are initiated by interaction of the neutral cluster with highly charged Xe(q+) (5< or =q< or =25). Products are detected by means of multicoincidence time-of-flight methods. A strong dependence of the fragmentation pattern on the Xe charge state q is observed. In particular, we find evidence for formation of multiply charged atomic Ar(r+) fragment ions up to r = 7. Such high charge states have neither been observed in fission of multiply charged van der Waals clusters nor in ion-induced fragmentation of fullerenes or metal clusters. This hints at fundamentally different excitation and fragmentation dynamics.

Journal Article↗

PubMed2002

Analysis of the wild potato germplasm of the series Acaulia with AFLPs: implications for ex situ conservation.

The wild potato germplasm of the series Acaulia maintained at the Centre for Genetic Resources, The Netherlands, currently consists of 314 accessions. This collection comprises seed samples of the species Solanum acaule (ssp. acaule, ssp. aemulans, ssp. palmirense and ssp. punae) and Solanum albicans collected from South America. In order to validate taxonomic classification, to investigate the extent of redundancy and to study the distribution of genetic diversity across the collection area, the entire collection was analysed with two AFLP primer pairs on two plants per accession. Within the entire sample a total number of 130 polymorphic bands were scored for the two primer pairs. An UPGMA cluster analysis grouped the majority of plants according to the species and subspecies. A total number of 16 misclassifications were identified, including four cases that did not seem to belong to the series Acaulia. Two accessions were found to consist of plants of different AFLP clusters. AFLP data also allowed the taxonomic classification of the subspecies of 97 accessions that previously were described as S. acaule only. For 126 accessions the two individuals studied displayed identical AFLP profiles. Forty six of these 126 accessions shared their profiles with both or single plants of other accessions. These were all tested for identical profiles for a third primer pair, resulting in 15 duplication groups consisting of a total number of 22 accessions and 14 single plants. Analyses of molecular variance (AMOVA) were performed to examine the distribution of genetic variation. Comparison of geographic distances between the collection site of plants and the number of AFLP polymorphisms revealed no consistent relationship between geographic distance and genetic diversity. AFLP analysis appeared to be an efficient method to verify taxonomic classification and to identify redundancies in the wild germplasm of the series Acaulia. Implications of the results for the ex situ conservation of wild potato germplasm are discussed.

Journal Article↗

PubMed2002

Recent developments on human cell lines for the bioartificial liver.

Most bioartificial liver (BAL) devices contain porcine primary hepatocytes as their biological component. However, alternatives are needed due to xenotransplantation associated risks. Human liver cell lines have excellent growth characteristics and are therefore candidates for application in BAL devices. Tumour-derived cell lines HepG2 and C3A express a variety of liver functions, but some specific liver functions, like ammonia detoxification and ureagenesis are insufficient. Immortalised human hepatocytes might offer better prospects. The balance between immortalisation and transformation with dedifferentiation of cells seems controllable by conditional immortalisation and/or the use of telomerase as immortalising agent. Another promising approach will be the use of embryonic or adult human stem cells. Rodent stem cells have been directed to hepatic differentiation in vitro, which might be applicable to human stem cells. However, both functionality and safety of immortalised human liver cell lines and differentiated stem cells should be improved before successful use in BAL devices becomes reality.

Animals↗

PubMed2002

Phase I clinical trial with the AMC-bioartificial liver.

UNLABELLED: Recently a bio-artificial liver (BAL) system has been developed at the Academic Medical Center (AMC) of Amsterdam to bridge patients with acute liver failure (ALF) to orthotopic liver transplantation (OLT). After successful testing of the AMC-BAL in rodents and pigs with ALF, a phase I study in ALF patients waiting for (OLT) was started in Italy. We present the safety outcome of the first 7 patients aged 21-56 years with coma grade III or IV The total AMC-BAL treatment time ranged from 8 to 35 hours. Three patients received 2 treatments with two different BAL's within three days. Six of the 7 patients were successfully bridged to OLT. One patient showed improved liver function after two treatments and did not need OLT. No severe adverse events of the BAL treatment were noted. CONCLUSION: Treatment of ALF patients with the AMC-BAL is a safe and feasible technique to bridge the waiting time for an adequate liver-graft.

Adult↗

PubMed2001

Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression.

Biopterin, neopterin and the large neutral amino acids (LNAA), i.e. phenylalanine, tyrosine, tryptophan, isoleucine, leucine and valine were measured in plasma of 20 severely depressed inpatients before and after a course of electroconvulsive therapy (ECT). These patients showed a significantly lower plasma biopterin concentration at baseline in comparison with healthy controls. After treatment an increase in biopterin was found, which was statistically significant in the depressed patients with psychotic features. The plasma phenylalanine-tyrosine ratio, which previously increased, normalised after ECT. Mean tryptophan concentration was lower in depressed patients than in normal controls. The patients who responded to ECT showed an increase in the tryptophan concentration and its ratio (tryptophan/LNAA) after treatment. Our results suggest that ECT increases biopterin, which probably results in synthesis of amino acids, especially tyrosine. Furthermore, ECT seems to increase cerebral tryptophan availability because of less tryptophan catabolism parallel with biopterin activation. More research is required to see if biopterin could be useful as a biological marker for the depressive state in this subgroup of patients, because this compound seems to play an important role in the etiology and treatment of depression.

Adult↗