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Biomedical subjects

K Carlson

Publications and source records attributed to K Carlson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Long-term follow-up of autologous stem-cell transplantation for follicular and transformed follicular lymphoma.

Despite the fact that follicular lymphomas are both chemo- and radiosensitive, the disease is generally non-curable. These lymphomas often undergo transformation to a more malignant state. In order to improve the prognosis, high-dose treatment with stem cell support has been tested, but its role in the treatment of this disease is still unclear. Fourteen men and eight women with a median age of 45 yr (34-59) were treated with high-dose therapy with autologous stem cell transplantation between 1987 and 1996. The patients were selected to undergo intensive therapy because of an estimated short survival (median < 3 yr), even though they had chemosensitive disease and adequate performance status. Eleven patients' lymphomas had transformed, and the other eleven patients had one or more unfavourable prognostic signs such as advanced stage, bulky disease, multiple relapses, or short remission duration. The conditioning regimen has varied over the period, but BEAC (Becenum, etoposide, cytarabine, cyclophosphamide) or etoposide/cyclophosphamide with or without total body irradiation (TBI) was used in most patients. Nine patients had their stem cells purged. After a median follow-up time of 74 months overall survival was 81% and disease-free survival 72%. One toxic procedure-related death occured. There was no difference in outcome between patients with a transformed lymphoma compared to those without transformation. The patients treated with TBI had a significantly worse outcome. Toxicity was also much higher in TBI-treated patients, including four cases of secondary malignancy (three myelodysplastic syndrome (MDS) cases and one patient with breast carcinoma). This retrospective study, with the longest follow-up time so far reported, shows a promising 6-yr DFS of 72% in a group of follicular lymphoma patients with a bad prognosis. The outcome of patients with transformed lymphoma compared to historical controls is especially encouraging. The high incidence of MDS is worrying. The role of TBI should be questioned because this and other studies have not shown any advantage of using TBI. In the absence of randomised trials the role of high-dose treatment for patients with follicular lymphoma is still not defined.

Adult↗
PubMed2000

The dismal outcome in patients with acute leukaemia who relapse after an autograft is improved if a second autograft or a matched allograft is performed. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

All patients receiving autografts for acute leukaemia in remission between 1 January 1981 and 31 December 1996 and reported to the European Group for Blood and Marrow Transplantation and had a relapse, were included. The patients underwent an allograft (n = 90, group A), were treated with chemotherapy (n = 2584, group B) or received a second autograft (n = 74, group C). The 2-year survival after relapse was 32 +/- 5%, 11 +/- 1% and 42 +/- 6% in groups A, B and C, respectively. In group A, those with an HLA-A, -B and -DR compatible related or unrelated donor had a 2-year survival of 37 +/- 7% compared to 13 +/- 8% for those receiving a graft from an HLA mismatched donor (n = 20). The following factors were associated with better survival in multivariate analyses: an interval from first autograft to relapse >5 months (P < 0.00001), a first autograft performed later than 1991 (P < 0.00001), patient age below 26 years (median, P < 0.002), group B vs HLA mismatches from group A (P = 0.002), group C vs group B (P < 0.005), patients who were not treated with total body irradiation at first autograft (P < 0.02) and patients in first remission at first autograft (P = 0.02). To conclude, the poor outcome in these patients was improved if a second autograft was feasible (P < 0.005), or if an HLA-matched allograft was performed (NS). Bone Marrow Transplantation (2000).

Acute Disease↗
PubMed2000

Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures.

The p38 MAP kinase inhibitor, SB 242235, was evaluated for its effects on the metabolism of bovine and human cartilage and primary chondrocyte cultures. SB 242235 had no effect on proteoglycan synthesis (PG) in bovine articular cartilage explants (BAC), as measured by [(35)S]-sulfate incorporation into glycosaminoglycans (GAGs). In addition, the compound had no effect on IL-1 alpha-induced GAG release from these cultures. However, there was a potent, dose-dependent inhibition of nitric oxide (NO) release from IL-1 alpha-stimulated BAC with an IC(50)of approximately 0.6 microM, with similar effects observed in primary chondrocytes. The effect on BAC was time dependent, and mechanistically did not appear to be the result of inhibition of protein kinase C (PKC), protein kinase A (PKA) or MEK-1. The effect on NO release in bovine chondrocytes was at the level of inducible nitric oxide synthase (iNOS) gene expression, which was inhibited at similar concentrations as nitrite production. In primary human chondrocytes, IL-1 beta induction of p38 MAP kinase was inhibited by SB 242235 with an IC(50)of approximately 1 microM. Surprisingly, however, treatment of IL-beta-stimulated human cartilage or chondrocytes with SB 242235 did not inhibit either NO production or the induction of iNOS. On the other hand, the natural product hymenialdisine (HYM), a protein tyrosine kinase (PTK) inhibitor, inhibited NO production and iNOS in both species. In contrast to the differential control of iNOS, PGE(2)was inhibited by SB 242235 in both IL-1-stimulated bovine and human chondrocyte cultures. These studies indicate that there are species differences in the control of iNOS by p38 inhibitors and also that different pathways may control IL-1-induced proteoglycan breakdown and NO production.

Animals↗
PubMed2000

Prepubertal growth and growth hormone secretion in children after treatment for hematological malignancies, including autologous bone marrow transplantation.

Prepubertal growth standards were used to assess growth in 20 children who had undergone autologous bone marrow transplantation (ABMT) as part of their treatment for hematological malignancy. Most of the patients (16 of 20) were transplanted after a relapse of their disease. A negative change in height standard deviation score (H-SDS) was seen only in the group of patients (n = 7) who had received both cranial irradiation therapy (CRT) and 7.5-Gy single-fraction total body irradiation (TBI). Height changes in this group were observed from the time of diagnosis. In contrast, the groups of patients conditioned with chemotherapy only (n = 3) or both chemotherapy and TBI, without preceding CRT (n = 10), did not demonstrate a significant loss in H-SDS. Weight related to height demonstrated large individual differences over time. Spontaneous growth hormone (GH) secretion, as measured by a four-point sleep curve, was followed longitudinally and an increasing proportion of patients with low peak levels was seen in all patient groups. In summary, prepubertal growth was suppressed only in patients who received cranial irradiation before ABMT. Despite low GH peak levels, normal prepubertal growth was found in patients with no CRT before ABMT.

Adolescent↗
PubMed2000

Human neuroblastoma cell viability and growth are affected by altered culture conditions.

The effects of differing culture parameters are seldomly investigated, even though they influence the way immortalized cells grow and die. In this study, the changes in total cell number, confluency, membrane permeability, and DNA content were evaluated in SH-SY5Y and IMR-32 human neuroblastoma cells following culture at different seeding densities and media consistencies. These four endpoints were determined using a hemacytometer, phase-contrast microscope, trypan blue (0.4% v/v), and propidium iodide (50 microg/mL), respectively. Both cell lines (SH-SY5Y and IMR-32) responded in a similar manner to changing culture conditions, even though baseline values for all four endpoints were different. Higher seeding densities (19,200 and 38,400 cells/cm2) significantly increased the percent confluency and total cell number over time, but decreased the initial percentage of cells with fragmented (subG1) DNA in both cell lines when compared with lower seeding densities (4800 and 9600 cells/cm2, p < 0.05). Daily media changes significantly increased the percentage of cells in S and G2/M, but decreased the percentage of cells in G0/G1 phase of the cell cycle over time in both cell lines when compared with cultures without media changes (p < 0.05). Results suggest that environmental culture conditions greatly affect cellular mitosis and death. This information may be of particular relevance in the investigation of compounds that act on specific cell-cycle stages, such as antineoplastic agents.

Cell Communication↗
PubMed1999

Organophosphorus compound-induced modification of SH-SY5Y human neuroblastoma mitochondrial transmembrane potential.

Organophosphorus (OP) compounds inhibit mitochondrial enzymes, respiration, and ATP generation, in addition to inducing structural changes such as matrix swelling. This implicates mitochondria as primary subcellular targets for these compounds. In this study, the health and function of cellular mitochondria following OP compound exposure were assessed by evaluating the mitochondrial transmembrane potential (DeltaPsi(m)). This was done by measuring the changes in DeltaPsi(m) in SH-SY5Y human neuroblastoma cells incubated with the cationic fluorochrome, rhodamine 123 (5 microg/ml), and the OP compounds tri-ortho-tolyl phosphate (TOTP), triphenyl phosphite (TPPi), or parathion for 7.5 to 960 minutes. OP compounds (100 microM to 1 mM) induced significant concentration-dependent mitochondrial hyperpolarization with peak maxima occurring at 60 (TOTP, TPPi) or 120 (parathion) min. Following this, the mitochondrial membranes gradually depolarized. Pretreatment with cyclosporin A (500 nM, 30 h), a mitochondrial permeability transition pore (PTP) inhibitor, decreased the hyperpolarization. In contrast, 30-h pretreatment with the muscarinic receptor agonist carbachol (1 mM) significantly increased DeltaPsi(m) and delayed subsequent depolarization. Hyperpolarization and subsequent depolarization of mitochondrial membranes occurred 16 to 24 h prior to a loss of substrate adhesion or an increase in DNA fragmentation, indicating that mitochondria were a primary target in OP compound-initiated cytotoxicity.

DNA Fragmentation↗
PubMed1999

[Umbilical cord blood from unrelated donor. An alternative to bone marrow transplantation].

Unrelated umbilical cord blood (UCB) as a source of haematopoietic stem/progenitor cells has been used for the first time in Sweden for allografting two boys (6 and 11 1/2 years old) with acute leukaemia in complete remission. Double class-II HLA-mismatch UCB units, from the Milan and New York cord blood banks, respectively, were used. Pre-transplant preparation consisted in fractionated total body irradiation in both cases, followed by cytoreductive high-dose cyclophosphamide for the 6-year-old with acute lymphocytic leukaemia (ALL) and fludarabine-melphalan for the 11 1/2-year-old with acute non-lymphocytic leukaemia (ANLL). Despite delayed haematopoietic recovery (probably due to HLA disparity) or reactivated cytomegalovirus infection in one boy, the immediate post-graft course was uneventful and extramedullary toxicity mild in both cases. Only transient acute graft-versus-host disease occurred, and complete donor chimerism was confirmed. Unfortunately, the out-come was unfavourable in both cases, the ANLL patient succumbing on day 96 due to pneumonia followed by multiorgan failure, and the ALL patient on day 140 due to combined medullar and central nervous system relapse. Although UCB transplantation needs further evaluation, it may contribute substantially to successful salvage procedures. Thus the introduction of cord blood banking in Sweden merits consideration.

Blood Banks↗
PubMed1999

Spectral karyotype analysis of T-cell acute leukemia.

Analysis of 15 cases of T-cell acute lymphoblastic leukemia with spectral karyotyping (SKY), which can identify all chromosomes simultaneously, clarified the chromosome rearrangements in 3 cases and confirmed them in 11 others; no abnormal cells were identified in 1 case, which had only 10% abnormal cells. Five of the latter cases had a normal karyotype. Thus, the use of SKY substantially improves the precision of karyotype analysis of malignant cells, which in turn leads to a more accurate assessment of the genotypic abnormalities in those cells.

Adolescent↗
PubMed1999

Pharmacokinetics and consistency of pericardial delivery directed to coronary arteries: direct comparison with endoluminal delivery.

BACKGROUND AND HYPOTHESIS: Pharmacologic modulation of the contents of the pericardial space has been shown to influence the response of coronary arteries to balloon injury. Endoluminal (EL) local delivery of various drugs into coronaries has been found to be limited by short residence time, as well as by highly variable deposited agent concentration. We hypothesized that compounds placed into the pericardial space (P) would penetrate into coronary tissue with greater consistency than seen after EL delivery and provide for prolonged coronary exposure to agents. METHODS AND RESULTS: 125I-labeled basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), albumin, or 131I-labeled diazeniumdiolated albumin (NONO-albumin) were delivered as model/therapeutic proteins into the porcine pericardial space (n = 15 pigs) or into coronaries using an EL delivery catheter (n = 48 arteries). In subjects receiving 125I-labeled proteins, the delivery target or mid-regions of the left anterior descending (LAD) and left circumflex (LCx) arteries were harvested at 1 h or 24 h for gamma-counting and autoradiography, and fractional intramural delivery (FID) or retention measured as percent agent in 100 mg artery/agent in infusate for both time points. In the animals receiving 131I-labeled NONO-albumin, serial gamma imaging was employed to evaluate the rate of redistribution in individual animals following either pericardial or endoluminal delivery. At 1 h, FID values ranged from 0.00064 to 0.0052% for P delivery (median 0.0022%), and from 0.00021 to 6.7 for EL delivery (median 0.27%). At 24 h, FID values ranged from 0.00011 to 0.003 for P delivery (median 0.0013), and from 0.0002 to 1.4 for EL delivery. The estimated T1/2 for bFGF redistribution from the vascular tissue was 22 h (P) and 7 h (EL), respectively, while the directly determined T1/2 values for NONO-albumin redistribution from the delivery region were 22.2 h (P) and 2.5 h (EL). CONCLUSIONS: These data show that pericardial fluid contents can access coronary arteries with intramural concentrations which typically vary by 10-15-fold, while EL delivery results in a remarkably wide intramural concentration range with up to 33,000-fold variability. The apparent redistribution rate is more rapid following EL delivery, possibly due to sustained diffusive tissue loading from the pericardial space. Pericardial delivery appears to offer substantial advantages over EL administration with respect to residence time and reproducibility.

Albumins↗
PubMed1999

The utility of tissue transglutaminase as a marker of apoptosis during treatment and progression of prostate cancer.

PURPOSE: To determine the extent of cell proliferation and apoptosis during treatment and progression of prostate cancer and to determine whether staining for tissue transglutaminase is a better histological marker than TUNEL for neoadjuvant androgen ablation treatment of localized prostate cancer. MATERIALS AND METHODS: Immunocytochemistry techniques were used on archival prostate tissue from four groups of men: 14 men with BPH, 18 men with untreated, localized prostate cancer, 21 men with localized prostate cancer who received neoadjuvant hormone therapy prior to prostatectomy and 18 men with metastatic androgen-independent prostate cancer. Cell proliferation was evaluated by staining for the Ki67 nuclear antigen, and apoptosis was evaluated by staining for DNA fragmentation (TUNEL technique) and tissue transglutaminase (tTG). Image analysis was used to quantitate the results. RESULTS: TUNEL staining increased by 37% in localized prostate cancer compared with BPH, with a further increase of 43% seen after neoadjuvant therapy, although variation was such that neither was statistically significant. In androgen-independent cancer, TUNEL staining was decreased compared with neoadjuvant hormone treated cancer (p = 0.02). Staining for tTG was not increased in untreated prostate cancer compared with BPH; however, staining more than doubled after neoadjuvant therapy, compared with untreated prostate cancer (p = 0.04). Staining for tTG was markedly decreased in androgen-independent cancer (p = 0.07 compared with BPH and p = 0.0004 compared with neoadjuvant hormone treated cancer). Ki67 immunoreactivity did not significantly change in localized prostate cancer, either before or after neoadjuvant therapy, compared with BPH, but it more than doubled in androgen-independent prostate cancer (p = 0.07 compared with BPH and p = 0.05 compared with untreated prostate cancer). CONCLUSIONS: This study shows that cell proliferation increases and apoptosis decreases as prostate cancer progresses to androgen independence, and, that of the markers used in this study, tissue transglutaminase most accurately reflects the anticipated effect of neoadjuvant hormone therapy on localized prostate cancer. An assessment of these parameters provides a valuable tool for appraising new prostate cancer therapies.

Apoptosis↗
PubMed1999

Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation.

Twenty-five patients with multiple myeloma received bone marrow grafts (n = 24) or peripheral blood stem cells (n = 1) from twin donors. The outcome was compared in a case-matched analysis to 125 patients who underwent autologous transplantation, and 125 who underwent allogeneic transplantation. Seventeen patients (68%) receiving twin transplants entered complete remission, which was not significantly different from that of autologous (48%) or allogeneic (58%) transplants. The median overall and progression-free survival for the twins was 73 and 72 months, respectively. The overall survival tended to be better (73 vs 44 months) and the progression-free survival was significantly better (72 vs 25 months) than with autologous transplantation and both were significantly better than with allogeneic transplantation. Three of 17 patients who entered complete remission following transplantation had relapsed at follow-up. This relapse rate was significantly lower than following autologous transplantation and similar to the relapse rate with allogeneic transplantation. Only two twins died of transplant-related toxicity. Six further patients died of progressive or relapsing disease. Syngeneic transplantation in multiple myeloma appears to be the treatment of choice if a twin donor is available. A lower relapse risk than in autotransplantation may be due to reinfusion of malignant cells in some patients treated with this modality or to the presence of a graft-versus-myeloma effect in some syngeneic transplants.

Adult↗
PubMed1999

Linear reduction of clonal cells in stem cell enriched grafts in transplanted multiple myeloma.

In 30 patients with multiple myeloma who were scheduled for peripheral blood stem-cell transplantation, a quantitative analysis of the stem cells following enrichment by anti-CD34 was carried out. To detect the cells of the specific myeloma clone, polymerase chain reaction (PCR) was performed using unique allele-specific oligo primers for the immunoglobulin heavy chain rearrangement. The clonogenic cells before and after stem-cell enrichment, were quantified by a limiting dilution assay and a highly sensitive semi-nested PCR combined with a real-time quantitative PCR. In order to accomplish a statistically adequate end-point analysis, a large number of PCR analyses (40 per sample) were performed. By this technique the lowest detection limit observed was one myeloma cell per 106 cells. Myeloma cells were detected in 29/30 samples from the CD34-enriched fraction. The CD34 selection procedure resulted in a median 28-fold enrichment of CD34+ haemopoietic precursor cells. The stem-cell selection reduced the median concentration of clonal cells per million total cells by half, with a highly significant linear relationship between the number of myeloma cells before and after stem cell enrichment. The median depletion of clonal cells by the overall procedure was 2.15 log units, corresponding to a reduction of the total quantity of clonal cells reinfused into the patients by at least 99.3%. We conclude that CD34+ cell enrichment led to a reliable tumour cell depletion of the order of 2 log, which may not be sufficient since the total number of tumour cells in the leukapheresis product was 7.2 log (median).

Adolescent↗
PubMed1999

Sequence-specific cleavage by bacteriophage T4 endonuclease II in vitro.

The 136 codon (408 bp) denA gene encoding endonuclease II (Endoll) of bacteriophage T4 was unambiguously identified through sequencing and subsequent cloning. Endoll prepared from cloned DNA through coupled in vitro transcription-translation nicked and cut DNA in vitro in a sequence-specific manner. In vitro (and in vivo), the bottom strand was nicked between the first and second base pair to the right of a top-strand CCGC motif shared by favoured in vitro and in vivo cleavage sites; top-strand cleavage positions varied. To the right of the cleavage position, favoured in vitro sites lacked a sequence element conserved at favoured in vivo sites. In pBR322 DNA, the sites cleaved in vivo as previously described were also cleaved in vitro, but in vitro additional sites were nicked or cleaved and the preference for individual sites was different. Also, different from the in vivo reaction, nicking was more frequent than ds cutting; in many copies of a ds cleavage site, only the bottom strand was nicked in vitro. A model is discussed in which sequential nicking of the two strands, and different factors influencing bottom-strand nicking and top-strand nicking, can explain the differences between the in vitro and the in vivo reaction.

Bacteriophage T4↗
PubMed1999

Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study.

Early cardiac complications after autologous bone marrow transplantation (ABMT) were recorded for 49 children with haematological malignancies. There was no procedure-related mortality and only two cases of early post-transplant cardiac complications of clinical relevance, both of which were reversible. For 35 long-time survivors (median follow-up 7 y) serial evaluations before and after ABMT included ECG, chest radiography, echocardiography and equilibrium radionuclide ventriculography (RVG). One patient had frequent supraventricular ectopic beats after ABMT, a finding not previously noted. The mean left ventricular diastolic diameter (LVDD) was 104% of expected before ABMT (95% confidence interval 99-110). During the first year post-transplant LVDD was about 110% of expected, but thereafter normalization occurred. The mean shortening fraction before ABMT was 31% (CI 29-34), compared with the mean value of 34% for healthy children in our laboratory, and it ranged between 29% and 33% during the follow-up period. Mean left ventricular ejection fraction determined by RVG was 65% (CI 61-69) and mean right ventricular ejection fraction was 46% (CI 43-49) before ABMT, and they did not change during follow-up. It is encouraging that these heavily pre-treated children could be autografted without serious cardiac complications or deterioration in myocardial performance in a 5-10-y prospect, but longer follow-up is needed for a final evaluation.

Adolescent↗
PubMed1999

Evaluation of bone disease in multiple myeloma: a comparison between the resorption markers urinary deoxypyridinoline/creatinine (DPD) and serum ICTP, and an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios.

Markers of bone metabolism were measured in 73 newly diagnosed myeloma patients and in age-matched controls. Correlations to bone disease on X-rays and survival were performed. In urine deoxypyridinoline/creatinine (DPD) and in serum carboxyterminal pyridinoline cross-linked telopeptide of type I collagen (ICTP), procollagen type I carboxy-terminal extension peptide (PICP) and osteocalcin were analyzed. The ratios DPD/osteocalcin and ICTP/osteocalcin were calculated. Skeletal X-ray findings were divided into no, limited and extensive bone involvement. DPD and ICTP levels were significantly elevated in patients compared to controls. Levels increased with advancing skeletal involvement. Serum osteocalcin was elevated in patients without visible bone disease. The level decreased with more advanced bone involvement. The finding of significantly elevated osteocalcin and ICTP levels in patients without bone involvement on X-rays indicates that bone markers might reflect bone disease better than X-rays in untreated myeloma patients. Ratios between bone resorption and bone formation markers added no further information on bone disease or survival. Only ICTP had prognostic value with an inverse correlation between serum levels and survival.

Aged↗
PubMed1998

Endonuclease II of coliphage T4: a recombinase disguised as a restriction endonuclease?

EndoII shares with restriction endonucleases the property of cleaving foreign DNA while leaving the endonuclease-encoding genome intact, ensuring the survival of one DNA species in the cell. In addition, in vivo EndoII cleaves a specific DNA sequence and cleavage is context dependent. These context effects extend over at least 1000 bp, largely limiting cleavage to once within this distance. Like homing endonucleases, in vivo EndoII recognizes a long, asymmetric and degenerate consensus sequence which has two distinct parts. Recognition of one part of the consensus sequence involves base-specific bonds, and recognition of the other involves sequence-dependent helical structure. EndoII fulfills an obvious short-term survival role in ensuring the dominance of phage DNA in an infected cell, but may also have a long-term evolutionary role, producing gene-size fragments of foreign DNA to be enrolled in the phage genetic repertoire.

Bacteriophage T4↗
PubMed1997

A novel mechanism of virus-virus interactions: bacteriophage P2 Tin protein inhibits phage T4 DNA synthesis by poisoning the T4 single-stranded DNA binding protein, gp32.

P2 prophages have been known to inhibit DNA replication and growth of T-even phages. We show here that this inhibition is due to poisoning of the T-even single-stranded DNA binding protein gp32 by the product of the nonessential P2 tin gene. Synthesis of Tin protein from a gene cloned in a multicopy plasmid is necessary and sufficient to completely prevent de novo DNA replication and growth of wild-type T2 or T4 phage. We isolated more than 20 independent mutants that render T-even phages resistant to poisoning by the P2 Tin protein. In all of these mutants, which we call asp, Asp codon 163 of gene 32 is changed to a Gly or Asn codon. The mutant alleles are recessive; i.e., when wild-type and asp mutants coinfect the same host cells, most DNA replication is poisoned by P2 Tin protein. To explain our results, we propose that the P2 Tin protein interacts with T-even gp32 at position 163 and distorts the helical filament of gene 32 protein on single-stranded DNA. Thereby Tin protein inhibits either assembly or function, or both, of the T4 replisome. The inhibition of late gene expression by P2 Tin protein may be an indirect consequence of inhibition of DNA replication.

Bacteriophage P2↗