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N Jacobsen

Publications and source records attributed to N Jacobsen.

At least 19 recordsLinked to original sources
PubMed2002

Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease.

Darier's disease is a rare autosomal dominantly inherited keratosis.(1) We have previously reported a family in which major affective disorder co-segregated with Darier's disease, consistent with linkage between the Darier gene and a susceptibility locus for affective illness (max lod = 2.1).(2) The Darier gene has been mapped to 12q 23-q24.1 and identified as ATP2A2, a gene encoding SERCA2-a sarcoplasmic/endoplasmic reticulum calcium pump that plays a role in intracellular calcium signalling.(3) A number of groups have reported independent evidence of linkage between bipolar disorder and markers in this region.(4) We here describe a further Caucasian family of European origin in which there is co-occurrence of Darier's disease and major affective disorder including bipolar disorder and report the results of linkage analysis employing genetic markers flanking the Darier's gene. The pedigree includes two individuals with mood disorder from a branch of the family not affected with Darier's disease. However, there is a new mutation in the Darier (ATP2A2) gene in this family and all individuals affected by mood disorder show co-segregation with a haplotype in the region of the Darier's gene (max lod = 3.58). The family provides strong evidence against the Darier-causing mutation itself playing a major role in affective disorder but strongly supports the existence of a bipolar disorder susceptibility gene in the Darier region.

Bipolar Disorder↗
PubMed2001

[Hemorrhagic diarrhea with competing etiologies].

A case history of a 41-year-old woman with bloody diarrhoea is described. A right-sided hemicolectomy was performed and histological findings showed pseudomembranous colitis. The woman was infected with verotoxin-producing E. coli O103:H2. She had taken an overdose of ergotamine and was using a contraceptive containing oestrogen. Each of these have previously been described as being the cause of bloody diarrhoea, but we suggest the combination as the aetiology in the present case.

Adult↗
PubMed2001

Stopped-flow kinetics of locked nucleic acid (LNA)-oligonucleotide duplex formation: studies of LNA-DNA and DNA-DNA interactions.

The locked nucleic acid (LNA) monomer is a conformationally restricted nucleotide analogue with an extra 2'-O,4'-C-methylene bridge added to the ribose ring. Oligonucleotides that contain LNA monomers have shown greatly enhanced thermal stability when hybridized to complementary DNA and RNA and are considered most promising candidates for efficient recognition of a given mixed sequence in a nucleic acid duplex and as an antisense molecule. Here the kinetics and thermodynamics of a series of oligonucleotide duplex formations of DNA-DNA and DNA-LNA octamers were studied using stopped-flow absorption measurements at 25 degrees C and melting curves. The reactions of the DNA octamer 5'-CAGGAGCA-3' with its complementary DNA octamer 5'-TGCTCCTG-3', and with the LNA octamers 5'-T(L)GCTCCTG-3' (LNA-1), 5'-T(L)GCT(L)CCTG-3' (LNA-2) and 5'-T(L)GCT(L)CCT(L)G-3'(LNA-3), containing respectively one, two or three thymidine 2'-O,4'-C-methylene-(D-ribofuranosyl) nucleotide monomers, designated T(L), were studied. In all cases were seen fast second-order association reactions with k(obs)=2x10(7) M(-1)s(-1). At 25 degrees C the dissociation constants of the duplexes obtained from melting curves were: DNA-DNA, 10 nM; DNA-LNA-1, 20 nM; DNA-LNA-2, 2 nM; and DNA-LNA-3, 0.3 nM; thus the greatly enhanced duplex stability induced by LNA is confirmed. Since the association rates were all equal this increase in stability is due to slower rates of dissociation of the complexes.

DNA↗
PubMed2001

Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma.

Excess fatness is frequent after childhood ALL treated without BMT. We measured the whole-body percent fat by dual-energy X-ray absorptiometry and the body-mass index (weight/height(2) (kg/m(2)), BMI) in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4-13). Adjusted for sex and age, the mean BMI was slightly but significantly reduced (0.4 s.d. below predicted) and the whole-body percent fat was significantly increased compared with healthy controls (1.1 s.d. above predicted). Eleven of 25 patients had a percent fat above the 90 percentile of the reference values, which indicates excess fatness. Adjusted for sex and age, a higher percent fat was related to additional cranial irradiation. Controlled for this, the whole-body percent fat seemed to be unrelated to age at BMT, length of follow-up, and previous chemotherapy. Compared with untransplanted ALL survivors treated with cranial irradiation, BMT survivors had significantly reduced BMI but similar whole body percent fat. BMI was a poor measure of body fatness in these patients. In conclusion, survivors of BMT for childhood leukaemia or lymphoma are adipose and slightly underweight and consequently have a substantially reduced lean body mass.

Body Composition↗
PubMed2001

Flow cytometric assessment of lymphocyte subsets, lymphoid progenitors, and hematopoietic stem cells in allogeneic stem cell grafts.

Currently, bone marrow (BM), cord blood (CB), and G-CSF-mobilized peripheral blood progenitor cells (PBPCs) are the most commonly used sources for allogeneic stem cell transplantation (SCT). The aim of this study was to assess the yields and distribution of lymphocyte subsets, lymphocyte progenitors and hematopoietic stem cells (HSC) in each type of allograft by three-color flow cytometry. The yields of CD34(+)CD38(-) HSCs did not differ significantly between BM grafts (2.80 +/- 0.74 x 10(6)) and leukapheresis products (LPs) (1.82 +/- 0.64 x 10(6)), and were lowest in CB grafts (0.21 +/- 0.05 x 10(6)). For most lymphocyte subsets yields were lowest in CB grafts and significantly higher in LPs than in BM grafts. BM grafts, however, contained the highest yields of CD34(+)CD19(+)CD20(-) B cell progenitors and CD19(+)CD20(-) B cells. The relative frequencies of the naive CD45RA(+)CD45RO(-) phenotype among CD4(+) and CD8(high) T cells were highest in CB grafts (P < or = 0.001), and higher in LPs than in BM grafts (P < or = 0.02). The latter finding was in accordance with a preferential G-CSF mobilization of naive T cells relative to the total lymphocyte population (P < or = 0.014). CD3(+)CD8(low) and CD3(+)CD8(low)CD4(-) subsets, which facilitate engraftment in murine transplantation models, demonstrated a tendency towards lower frequencies among T cells in CB grafts and LPs compared to BM grafts. This observation coincided with a significantly reduced mobilization of subsets potentially enriched for facilitating cells as compared to the total lymphocyte population (P < or = 0.036). The CD34(+) compartment of CB grafts contained a significantly higher percentage (12.1%) of CD34(+)CD7(+)CD3(-) T cell progenitors than those of BM grafts (5.1%) and LPs (3.6%). In addition, CB lymphocytes contained the highest fraction of CD3(-)CD16/56(+) NK cells (P < or = 0.013) and almost no CD3(+)CD16/56(+) NKT cells (P < 0.001) compared to adult cell sources. In summary, LPs, CB allografts and BM allografts differ widely with respect to the cellular composition of their lymphocyte compartments, which is partially affected by a varying mobilization efficiency of G-CSF for distinct lymphocyte subsets.

Adult↗
PubMed2000

Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.

The bone mass was measured by dual energy X-ray absorptiometry in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4-13). Results were compared with local data on 463 healthy controls and 95 survivors of childhood ALL treated without BMT. Adjusted for sex and age, the mean whole-body bone mineral content (BMC) and bone mineral areal density were significantly less than in healthy controls (0.8 and 0.5 s.d. less than predicted). The reduced BMC was caused by a significantly reduced height for age, whereas bone area for height and BMC for bone area were similar to controls. Less bone mass tended to be related to additional cranial irradiation and age above 20 years at follow-up. Controlled for this, the whole-body bone mass seemed to be unrelated to previous chemotherapy and endocrine status at follow-up and tended to be only marginally less in BMT patients than in ALL survivors treated without BMT. In conclusion, 8 years after allogeneic BMT for childhood leukaemia or lymphoma, the whole-body bone mass was only slightly reduced and the size-adjusted bone mass (BMC for bone area) was normal. Bone Marrow Transplantation (2000) 25, 191-196.

Adolescent↗
PubMed2000

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.

Actuarial Analysis↗
PubMed1999

Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group.

BACKGROUND: Patients who receive bone marrow transplants have increased risk for new malignant conditions because of several risk factors, including conditioning with radiation and chemotherapy, immune stimulation, and malignant primary disease. The occurrence of and risk factors for malignant neoplasm in long-term survivors must be assessed. OBJECTIVE: To determine the risk and define potential risk factors for new malignant conditions in long-term survivors after marrow transplantation. DESIGN: Retrospective multicenter study. SETTING: Study of the Late Effects Working Party with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. PATIENTS: 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Transplantation was done before December 1985, and patients had survived more than 5 years. MEASUREMENTS: Reports on malignant neoplasms were evaluated, and the incidence was compared to that in the general population. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. RESULTS: Median follow-up since transplantation was 10.7 years (range, 5 to 22.1 years). Malignant neoplasms were seen in 53 patients; the actuarial incidence (+/- SE) was 3.5% +/- 0.6% at 10 years and 12.8% +/- 2.6% at 15 years. The rate of new malignant disease was 3.8-fold higher than that in an age-matched control population (P < 0.001). The most frequent malignant diseases were neoplasms of the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5 patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3 patients). Median age of patients and their donors was 21 years. Malignant neoplasms were more frequent in older patients and in patients with chronic graft-versus-host disease. Older patient age and treatment of chronic graft-versus-host disease with cyclosporine were significant risk factors for new malignant neoplasms after bone marrow transplantation. CONCLUSIONS: The spectrum of neoplasms and immunosuppressive treatment with cyclosporine for chronic graft-versus-host disease as dominant risk factors indicate that immunosuppression is the major cause of malignant neoplasms in patients receiving marrow transplants.

Adolescent↗
PubMed1999

Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group.

Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P =.01) and hemorrhagic cystitis (32% v 10%, P =.003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the busulfan-treated group versus 47% in the TBI group (P =.05). Death from GVHD was more common in the busulfan group (22% v 3%, P <.001). Obstructive bronchiolitis occurred in 26% of the busulfan patients but in only 5% of the TBI patients (P <.01). Complete alopecia developed in 8 busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group (P <.001). Cataracts occurred in 5 busulfan-treated patients and 16 TBI patients (P =.02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively (P =.004). Leukemia-free survival (LFS) in patients with early disease was 68% in busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the busulfan group versus 49% in the TBI group (P <.01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively.

Adolescent↗
PubMed1999

Eleven trinucleotide repeat loci that map to chromosome 12 excluded from involvement in the pathogenesis of bipolar disorder.

The hypothesis that one or more genes containing expanded trinucleotide repeats contribute to the pathogenesis of bipolar disorder has received support from three independent studies demonstrating that bipolar patients tend to have larger CAG/CTG repeat expansion detection products than controls. In an attempt to identify the specific expanded CAG/CTG locus or loci which are associated with bipolar disorder, we determined repeat size at CAG/CTG loci mapping to candidate regions for bipolar disorder. Recent linkage studies suggest the existence of a bipolar susceptibility gene on chromosome 12q23-q24.1 in the region of the Darier's disease (DAR) gene. In this study we report our findings from 11 loci which map to chromosome 12, including CAG repeat polymorphisms within the genes SCA2 and ASH1. We conclude that all of these loci are excluded as candidates for CAG/CTG repeat expansion in bipolar disorder.

Ataxins↗
PubMed1999

Reactions of beta-carotene with cigarette smoke oxidants. Identification of carotenoid oxidation products and evaluation of the prooxidant/antioxidant effect.

Recent intervention trials reported that smokers given dietary beta-carotene supplementation exhibited an increased risk of lung cancer and overall mortality. beta-Carotene has been hypothesized to promote lung carcinogenesis by acting as a prooxidant in the smoke-exposed lung. We have examined the interactions of cigarette smoke with beta-carotene in model systems. Both whole smoke and gas-phase smoke oxidized beta-carotene in toluene to several products, including carbonyl-containing polyene chain cleavage products and beta-carotene epoxides. A major product of the reaction was identified as 4-nitro-beta-carotene, which was formed by nitrogen oxides in smoke. Both cis and all-trans isomers of 4-nitro-beta-carotene were detected. The hypothesis that smoke-driven beta-carotene autoxidation exerts prooxidant effects was tested in a liposome system. Lipid peroxidation in dilinoleoylphosphatidylcholine liposomes exposed to gas-phase smoke was modestly inhibited by the incorporation of 0.1 mol % beta-carotene. Both the lipid soluble antioxidant alpha-tocopherol and the water soluble antioxidant ascorbate were oxidized more slowly by gas-phase smoke exposure in liposomes containing beta-carotene. These data indicate that beta-carotene exerts weak antioxidant effects against smoke-induced oxidative damage in vitro. It is unlikely that a prooxidant effect of beta-carotene occurs under biologically relevant conditions or is responsible for an increased incidence of lung cancer observed in smokers who consume beta-carotene supplements.

Animals↗
PubMed1999

Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

Calcium-Transporting ATPases↗
PubMed1999

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood.

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Adolescent↗
PubMed1999

Single leukapheresis products collected from healthy donors after the administration of granulocyte colony-stimulating factor contain ten-fold higher numbers of long-term reconstituting hematopoietic progenitor cells than conventional bone marrow allografts.

Cytokine-mobilized peripheral blood progenitor cells (PBPCs) have been used successfully for hematopoietic reconstitution following allogeneic transplantation. The ease of harvest, the faster engraftment and the high yield of CD34+ cells have made this source of hematopoietic progenitor cells (HPCs) an attractive alternative to bone marrow (BM). In the present study we compared the engraftment potential of conventional BM allografts and single leukapheresis products (LPs) collected from healthy donors following the administration of granulocyte colony-stimulating factor (G-CSF). For this, lineage-committed and primitive HPCs were assessed by flow cytometry and by colony- and cobblestone area-forming cell (CFC, CAFC) assays. Mean numbers of CD34+ cells in LPs (n = 11) were similar to that of BM grafts (n = 12) (278+/-57 vs 227+/-34 x 10(6) CD34+ cells). The frequencies of CFCs, week 5 CAFCs and week 8 CAFCs were 1.6-, 8.4- and 10.3-fold higher in the CD34+ compartment of mobilized blood than that of marrow, resulting in significantly higher yields of clonogenic HPCs in LPs when compared to BM grafts. We conclude that G-CSF preferentially mobilizes clonogenic progenitors capable of short- and, in particular, longterm reconstitution, and that the engraftment potential of single LPs is superior to that of BM allografts. Hence, the use of PBPCs may be favorable for protocols that include graft manipulations with expected cell loss (eg T cell depletion, CD34+ selection). PBPCs may also be advantageous for gene therapy trials due to their high numbers of potential target cells (eg CAFCs).

Adolescent↗
PubMed1999

The graft versus leukemia effect after bone marrow transplantation: a case study using structural nested failure time models.

Over the last decade, J. M. Robins has developed a set of tools for assessing, from observational data, the causal effects of a time-dependent treatment or exposure in the presence of time-dependent covariates that may be simultaneously confounders and intermediate variables. This report concerns a case study of the application of one these techniques, G-estimation using structural nested failure time models, to the problem of assessing the effect of graft versus host disease on leukemia relapse after bone marrow transplantation.

Biometry↗
PubMed1999

A comparative study of CD34+ cells, CD34+ subsets, colony forming cells and cobblestone area forming cells in cord blood and bone marrow allografts.

Cord blood (CB) has become an alternative source of hematopoietic progenitor cells (HPCs) for allogeneic transplantation. We have developed a new efficient protocol for CB collection. Using this method an average of 17.7 x 10(8) [range (6.8-29.6) x 10(8), n = 13] total nucleated cells (TNCs) were harvested. Based on recent Eurocord data, which have shown safe engraftment using a threshold dose of 0.37 x 10(8) CB TNCs/kg body weight (BW), we calculated that six out of thirteen CB grafts collected by this method were sufficient to engraft adults. The CB derived CD34+ population contained two-fold higher numbers of committed HPCs (CFU-GM, BFU-E) and six-fold higher numbers of pluripotent HPCs [CD34+/CD38- cells, wk 5 and wk 8 cobblestone area forming cells (CAFCs)] than the CD34+ population of BM. Extrapolation revealed that BM grafts providing the threshold dose for allogeneic transplantation of 2 x 10(8) TNCs/kg BW contained nearly 3 times more pluripotent HPCs than CB grafts providing the Eurocord threshold dose. The assessment of CD34+/CD38(-) cell numbers in CB grafts was highly reproducible and correlated well with the in vitro performance of pluripotent HPCs, i.e. numbers of CAFCs. We conclude that CB grafts providing high numbers of TNCs have the potential to engraft adults and that the enumeration of pluripotent HPCs by flow cytometry may be a useful tool to define the ultimate threshold dose for CB transplantation.

ADP-ribosyl Cyclase↗
PubMed1999

Dental workplace exposure and effect on fertility.

OBJECTIVES: This study assessed occupational exposure in dental surgeries on the basis of the reported use of dental materials and techniques and applied waiting-time-to-pregnancy methodology to study fertility in relation to the occupational exposure. METHODS: Data were collected retrospectively using a self-administered postal questionnaire addressing the occupational and reproductive history of the participants. The study groups consisted of 558 female dental surgeons and 450 high school teachers that had given birth in Norway to at least 1 living child. The present study comprised data from a total of 1408 pregnancies. The effects of practicing dentistry and of the given workplace exposure on fertility were analyzed with the discrete proportional hazard regression method. RESULTS: Most of the female dental surgeons were using amalgam for fillings during the period they tried to conceive, and 1/3 placed more than 50 fillings a week. Tooth-colored fillings were in limited use. Prior to 75% of the pregnancies, the dental surgeons reported handling chloroform-based root canal sealers. Forty percent of the dental surgeons were daily exposed to disinfectants containing ethanol and benzene. No difference was found in fertility between the dental surgeons and the high school teachers. Exposure to mercury, chloroform, and benzene was not associated with decreased fertility, except for a possible effect of mercury in the last pregnancy of multiparous dental surgeons. CONCLUSIONS: Occupational exposures had no clear adverse effects on fertility among the female dental surgeons studied.

Dental Amalgam↗