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Biomedical subjects

E Holmberg

Publications and source records attributed to E Holmberg.

At least 73 records · Page 4Linked to original sources
PubMed1994

Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group.

This study describes the occurrence of renal failure among 1353 newly diagnosed cases of multiple myeloma. Renal function was evaluated by serum creatinine concentration in 1353 cases, 31% of whom had renal failure at the time of diagnosis. In 1206 cases an estimation of creatinine clearance was made. When renal failure was defined by using creatinine clearance estimation, 49% had renal failure at the time of diagnosis. Renal failure was present in 24% of patients with an M component of IgG-, 31% of IgA- and 100% of IgD-type. 52% of patients with light chain disease had renal failure. The frequency of renal failure was similar in lambda- and kappa-light chain disease. Patients with a high excretion of Bence Jones protein in the urine (> 10 g/24 h) had renal failure significantly more often than patients with lower excretion. Renal failure was related to advanced disease; 41% of patients with stage III (Durie-Salmon) disease had renal failure. Renal failure was found in 45% of patients with hypercalcaemia. When estimated creatinine clearance was used as a predictor of renal function, the same trends were found as mentioned above. In addition, the proportion of patients with renal failure was found to increase with advancing age.

Adult↗
PubMed1993

Site-directed mutagenesis of tyrosine residues at nicotinamide nucleotide binding sites of Escherichia coli transhydrogenase.

Nicotinamide nucleotide transhydrogenase (E.C.1.6.1.1) from Escherichia coli was investigated with respect to the role of specific conserved tyrosine residues of putative substrate-binding regions. The enzyme from E. coli is made up of two subunits, alpha (510 residues) and beta (462 residues). The corresponding enzyme from bovine mitochondria is a single polypeptide (1043 residues) whose N-terminal region corresponds to the alpha subunit and whose C-terminal region corresponds to the beta subunit. Tyrosines 245 and 1006 of the mitochondrial enzyme have been shown to react selectively with 5'-(p-fluorosulfonylbenzoyl)adenosine with inactivation of the enzyme. In E. coli these residues correspond to tyrosine 226 of the alpha subunit and tyrosine 431 of the beta subunit. In addition, tyrosine 315 of the beta subunit is of interest since mutation of an adjacent residue (glycine 314) leads to inactivation [Ahmad, S., Glavas, N. A., & Bragg, P. D. (1992) Eur. J. Biochem. 207, 733-739]. In order to assess the role of the aforementioned conserved tyrosine residues in the mechanism and structure of transhydrogenases, these were replaced by site-specific mutagenesis, using the cloned and overexpressed E. coli transhydrogenase genes [Clarke, D. M., & Bragg, P. D. (1985) J. Bacteriol. 162, 367-373]. Phenylalanine mutants of all three tyrosine residues showed approximately 50% activity or more with regard to catalytic activity assayed as reduction of 3-acetylpyridine-NAD+ by NADPH. These mutants were also active in proton pumping assayed as quenching of 9-methoxy-6-chloro-2-aminoacridine or quinacrine fluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden.

From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty-five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M-protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well-informed and well-controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.

Adult↗
PubMed1993

HLA DR and DQ RFLP analysis in Crohn's disease.

A study of 109 Swedish patients and 85 healthy Swedish controls with Crohn's disease (CD) by HLA class II RFLP genotyping was carried out. There was no significant association for any single DR or DQ specificity or phenotypic combination of DR and/or DQ specificities among our study group of Caucasian extraction.

Base Sequence↗
PubMed1993

HLA-DQ primarily confers protection and HLA-DR susceptibility in type I (insulin-dependent) diabetes studied in population-based affected families and controls.

The association between HLA-DR and -DQ and insulin-dependent diabetes mellitus (IDDM) in a defined high-incidence area was analyzed in a total of 58 population-based patients, representing 77% of IDDM patients with age at onset below 16 years, and in 92 unrelated parents in control families without IDDM. HLA haplotypes were confirmed by analyzing first-degree relatives in both groups. Seven different methods were used to analyze risk: (1) odds ratio, (2) absolute risk, (3) haplotype relative risk, (4) transcomplementation relative risk, (5) relative predisposing effects, (6) stratification analysis, and (7) test of predisposing allele on haplotype. DQB1*0302 indicated somewhat higher risk than did DR4, while DR3 had a higher risk than DQB1*0201; however, the 95% confidence intervals of the risk estimates overlapped. The positive association between IDDM and the DQB1*0201-DQA1*0501-DR3 haplotype seems to be due to DR3 or to an unknown linked gene. More important, DQA1*0301 was present among 93% of the patients, and this allele in various transcomplementation combinations with DQB1 alleles showed closer association to IDDM than did any other alleles. The strong negative association of the DQB1*0602 allele also in the presence of either DR4 or DQB1*0302 or both suggests that, in a high-risk population for IDDM, HLA-DQ primarily confers protection, perhaps by induction of tolerance. Consistent with known functions, HLA-DR may primarily confer susceptibility, perhaps by induction of autoreactive T lymphocytes.

Adolescent↗
PubMed1992

Energy-linked transhydrogenase. Characterization of a nucleotide-binding sequence in nicotinamide nucleotide transhydrogenase from beef heart.

Purified nicotinamide nucleotide transhydrogenase from beef heart was investigated with respect to labeling and subsequent sequence analysis of a nicotinamide nucleotide-binding site. A photo-activated azide derivative, 8-azidoadenosine 5'-monophosphate, was used as an active-site-directed photoaffinity label, which was shown to be specific for the NAD(H)-binding site in the dark. Light-activated incorporation of the label in transhydrogenase was accompanied by an inactivation, which approached 100% at the incorporation of about 1 mol label/mol transhydrogenase monomer. As expected from the assumed site-specificity of the label. NADH prevented both labeling and inactivation to some extent. However, NADPH also prevented labeling and inactivation marginally. The oxidized substrates NAD+ and NADP+ were inhibitory by themselves under these conditions, and the substrate analogs 5'-AMP and 2'-AMP were also poor protectors. The NAD(H)-site specificity of the azido compound was thus largely lost upon illumination and covalent modification. Radioactive labeling of transhydrogenase with 8-azido-[2-3H]-adenosine 5'-monophosphate followed by protease digestion, isolation of labeled peptides and amino-acid sequence analysis showed that Tyr 1006 in the sequence 1001-1027 close to the C-terminus was labeled. This sequence shows homologies with nucleotide-binding sequences in, e.g., F1-ATPase. On the basis of sequence homologies with other NAD(P)-dependent enzymes it is proposed that transhydrogenase contains 4 nucleotide-binding sites, of which 2 constitute the adenine nucleotide-binding domains of the catalytic sites for NAD(H) and NADP(H) close to the N- and C-terminals, respectively. Each of these domains has an additional vicinal nucleotide-binding sequence which may constitute a non-catalytic nucleotide-binding site or the nicotinamide nucleotide-binding domain of the catalytic site. The present results indicate that 8-azidoadenosine 5'-monophosphate is kinetically specific for the catalytic NAD(H)-binding site, but reacts covalently with Tyr 1006 of the putative non-catalytic site or nicotinamide nucleotide-binding domain formed by the 1001-1027 amino acid sequence of the catalytic NADP(H)-binding site. Interactions between the catalytic NAD(H) and NADP(H) binding sites, and the assumed non-catalytic sites, may be facilitated by a ligand-triggered formation of a narrow pocket, which normally allows an efficient hydride ion transfer between the natural substrates.

Affinity Labels↗
PubMed1992

Impact of active and passive exclusions on the results of a clinical trial in multiple myeloma. The Myeloma Group of Western Sweden.

During the 3 years 1984-86, 314 cases of multiple myeloma were diagnosed in the Health Care Region of Western Sweden. 180 of these cases were included in a clinical trial; 71 were notified to the trial but excluded; 49 cases were not reported to the trial; 14 were diagnosed post mortem. The crude incidence rate of myeloma was 6.3 cases per 100,000 inhabitants per year, corresponding to an age-adjusted (world standard population) incidence rate of 2.9 cases per 100,000 inhabitants per year. The excluded and the non-reported patients had a significantly shorter survival than those included in the clinical trial (median survival 22, 13 and 33 months, respectively). This was partly due to differences in age and proportion of actively treated patients between the groups, but the same tendency remained also after correction for these factors. Considering the included patients separately, the effect of tentative application of presumptive exclusion criteria corresponding to major prognostic factors was studied. Prolonged survival was seen when the upper age limit was lowered and when patients with renal failure or low performance status were excluded. The results illustrate the fact that for multiple myeloma the survival in a trial population is markedly influenced by active and passive exclusion of patient groups with unfavourable prognostic characteristics. When reporting results of clinical trials, discussion of the representativeness of the trial population for the total patient population is recommended in order to facilitate application of the trial results to medical practice and comparisons between trials.

Adult↗
PubMed1992

Association of ploidy and cell proliferation, Dukes' classification, and histopathological differentiation in adenocarcinomas of colon and rectum.

OBJECTIVES: To find out if there is an association between DNA indexes and DNA synthesis (S) phase measurements and Dukes' classification and histopathological differentiation in colorectal cancers, and to investigate the interrelationship between DNA indexes and S phase measurements. DESIGN: Prospective open study. MATERIAL: 182 colorectal carcinomas in 181 consecutive patients. INTERVENTION: Tumours biopsied immediately after resection or at rectoscopy or colonoscopy. RESULTS: One or more aneuploid cell populations were found in 113 of 182 carcinomas (62%). There was no correlation between Dukes' stage and either degree of differentiation or S phase measurements, but there were significant correlations between S phase measurements and histological grading (p less than 0.05), and between the percentage of cells in the S phase and the DNA index when values for both diploid and aneuploid tumours were included (p less than 0.001). CONCLUSION: The degree of aneuploidy indicates how far tumour cells have progressed in their cellular disarrangement, and information about a tumour's proliferative capacity is given by the S phase measurements.

Adenocarcinoma↗
PubMed1992

Energy and macronutrient intake in relation to cancer incidence among Swedish women.

Two dietary reporting methods were used to examine associations between macronutrient intake and subsequent cancer incidence in a cohort of Swedish women born between 1908 and 1930. 1361 subjects gave 23-h dietary recalls at their baseline examinations in 1968-1969, and 412 of them also provided detailed dietary histories. The cohort was followed up 19 years later by means of linkages with the National Cancer and Death Registries. Both dietary methods indicated that subjects who were ranked in the highest tertile of energy intake, relative to the lowest, were at significantly greater risk of developing cancer (all-site). Relative risks across energy intake tertiles were 1, 1.15 and 2.04, respectively, using the dietary history method and 1, 1.02 and 1.55 using the 24-h recall data. Examination of specific macronutrient energy sources indicated that dietary fat and carbohydrate are likely to have made the largest contribution to this association. However, after adjustment for total energy, none of the individual macronutrients was significantly associated with all-site cancer, by either dietary reporting method. When expressed as a percentage of total energy, low protein density of the diet was associated with increased cancer risk, by both dietary methods. However, this appeared to be a function of high energy intake rather than low protein intake. Simultaneous statistical adjustment for seven potential confounders of the association between energy intake and cancer was performed using both the 24-h recall and the dietary history data.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Association of the Robin sequence with the fragile X syndrome.

We report on 4 individuals with the fragile X [fra(X)] syndrome and the Robin sequence (or elements of that sequence). To our knowledge, this association has been described in only one other boy. However, males with the fra(X) syndrome have been reported to have an increased incidence of cleft palate. We recommend that children with a cleft palate or the Robin sequence be assessed for developmental delays and a family history of mental retardation. The fra(X) syndrome may be one of the genetic causes of the Robin sequence and, when indicated, children with the sequence should be tested for fra(X).

Cleft Palate↗
PubMed1991

Gadolinium-labeled liposomes containing various amphiphilic Gd-DTPA derivatives: targeted MRI contrast enhancement agents for the liver.

Unique paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. A series of amphipathic gadolinium complexes, which mimic phospholipids, was incorporated into the lamella of small unilamellar liposomes such that they become an integral part of its surface. The amphipathic complexing agents consisted of DTPA reagents in which two stearyl chains are attached via amide, ester, and thioester linkages. The in vitro stability and the in vivo lifetimes of the new amphipathic agents were dependent on the method used to attach the long-chain alkyl groups.

Animals↗
PubMed1991

Gadolinium-labeled liposomes containing amphiphilic Gd-DTPA derivatives of varying chain length: targeted MRI contrast enhancement agents for the liver.

Paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. Amphiphilic gadolinium complexes, which mimic phospholipids, were incorporated into the lamella of small unilamellar liposomes (SUV) such that they become an integral part of its surface. The amphiphilic complexing agents consisted of DTPA reagents in which a pair of alkyl chains of varying lengths are attached via amide linkages. The in vivo lifetimes of the amphiphilic agents were found to be dependent on the chain length of the alkyl groups.

Animals↗
PubMed1990

Characterization of in vivo immunoliposome targeting to pulmonary endothelium.

Two rat monoclonal antibodies, 34A and 201B, which specifically bind to a surface glycoprotein (gp112) of the pulmonary endothelial cell surface, have been coupled to unilamellar liposomes of approximately 0.25 microns in diameter. The 34A- and 201B-liposomes (monoclonal antibodies 273-34A and 411-201B, respectively), but not antibody-free liposomes and liposomes coupled to 14, a nonspecific monoclonal antibody, accumulate efficiently (approximately 30% injected dose) in the lung of mice which have been injected via the tail vein. Immunoliposome targeting to lung is demonstrated both by using a 125I-labeled lipid marker and an entrapped water-soluble marker. Lung accumulation of 34A-liposomes is completely blocked by a preincubation of free antibody 34A, but not antibody 14, indicating that the immunoliposome accumulation at the target site is immunospecific. Time course studies have revealed that 34A-liposomes bind to lung antigens within 1 min after injection, indicating that the target binding takes place during the first few passages of immunoliposomes through the lung capillary bed. Unbound immunoliposomes are taken up by liver and spleen within 3-5 min after injection. The level of lung accumulation increases significantly as the protein:lipid ratio of the immunoliposome increases. Approximately 50% of injected dose is accumulated in lung for 34A-liposomes, with an average of 935 antibody molecules per liposome. Immunoliposomes of larger size accumulate in lung more significantly than those of smaller size. Injection with higher doses also enhances the level of lung accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Initial treatment in multiple myeloma: no advantage of multidrug chemotherapy over melphalan-prednisone. The Myeloma Group of Western Sweden.

From October 1983 until December 1986, 164 patients with multiple myeloma stage II-III were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) with multidrug chemotherapy (MDC). The patients comprised 77% of all newly diagnosed myeloma stage II-III cases reported from 18 hospitals covering the entire Health Care Region of Western Sweden (1.5 million inhabitants). Patients randomized to MP (29 stage II and 55 stage III patients) were given oral melphalan and prednisone every 6 weeks. For patients randomized to MDC, stage II patients (n = 25) were given VMCP every 4 weeks and stage III patients (n = 53) VBAP and VMCP alternately every 4 weeks. For stage II patients, the response rate for MP compared to VMCP was 69 versus 56% and the median survival 46 versus 33 months. For stage III the response rate for MP compared to VBAP/VMCP was 58 versus 57% and the median survival 26 versus 24 months. No statistically significant differences were seen. The time to response and remission duration were also similar in both treatment arms. The dose intensity index (cumulative given/planned dose of myelosuppressive drugs) was greater than or equal to 0.8 in 89% of the MP patients and 81% of the MDC patients. Patients with index values less than 0.8 had the same response rate as patients with index greater than or equal to 0.8. This study has not demonstrated any advantage of MDC over traditional MP in multiple myeloma stage II-III.

Adult↗
PubMed1990

Relationship between kerma and treatment volume in intracavitary radiation therapy.

Data on 200 patients with carcinoma of the uterine cervix irradiated with afterloading brachytherapy using various high dose rate source configurations have been evaluated with respect to the total reference air kerma and the treatment volume as well as other volumes of interest. The experimental results showed good correlation between kerma and volume, and have also been discussed theoretically for the single-source, double-source and triple-source configurations. The possibility of using the demonstrated kerma-volume relationships for simple estimation of volumes enables us to select the appropriate treatment plan for the individual patient and to evaluate the results of the treatment.

Adsorption↗
PubMed1989

Highly efficient immunoliposomes prepared with a method which is compatible with various lipid compositions.

Monoclonal antibody was conjugated to N-glutaryl-phosphatidylethanolamine in the presence of octylglucoside by using N-hydroxysulfosuccinimide as a carboxyl-activation reagent. The conjugated antibody was then incorporated into liposomes by a simple dialysis method. The method is mild and is compatible with various lipid compositions of the liposomes. We have prepared immunoliposomes containing a lung endothelium-specific monoclonal antibody and showed excellent target binding (approximately 75% injected dose) of the immunoliposomes in mouse. Immunoliposomes can be prepared to contain other acidic lipids such as phosphatidylserine and various amounts of cholesterol. The presence of 20% or more cholesterol in liposomes resulted in high level of target binding. We have used in these experiments a new radioactive lipid-phase marker, 111In-DTPA-SA, which was very stable in vivo. The halflife of clearance in mouse exceeded 3 weeks.

Animals↗
PubMed1988

Diagnosis of familial amyloidotic polyneuropathy in Sweden by RFLP analysis.

Genomic DNA from 17 Swedish patients with familial amyloidotic polyneuropathy (FAP), and 50 healthy controls were tested with a cDNA transthyretin probe. In seven of the patients, FAP was not reported in either of their parents. All 50 controls showed restriction fragments of 6.6 kb and 3.2 kb after cleavage with Nsil, while the 17 FAP patients showed RFLP markers of 5.1 and 1.5 kb. These observations indicate the same methionine for valine substitution at position 30 in Swedish patients with FAP as seen in patients with FAP from Japan, Portugal and FAP-patients of Swedish descent from USA. However, the mean onset of FAP symptoms for the 17 Swedish patients was found to be significantly later than for the patients from Japan, Portugal and USA.

Adult↗