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Biomedical subjects

A Lindblom

Publications and source records attributed to A Lindblom.

At least 109 records · Page 6Linked to original sources
PubMed1993

Four separate regions on chromosome 17 show loss of heterozygosity in familial breast carcinomas.

Two genes predisposing females to autosomal dominant breast cancer are located on chromosome 17. Mutations in the p53-gene on the short arm have been shown to predispose females to early onset breast cancer in families with the rare Li-Fraumeni syndrome. Another locus on 17q (BRCA1), was found to be linked to the disease in a subset of families with breast cancer. In order to determine the involvement of tumour suppressor genes at these loci in tumour development, we studied allele losses for markers on chromosome 17 in 78 familial breast carcinomas. The analysis used six polymorphic DNA markers, three on each arm. We found support for at least four separate regions displaying allele losses on chromosome 17: the p53-region, the distal part of 17p, the BRCA1 region and the distal part of 17q. The frequency of allele losses on distal 17p (16%) is low in these familial tumours compared with the previously reported incidence in sporadic tumours (> 50%), whereas the frequency of losses at the p53 locus and on 17q was similar to sporadic tumours (5%-40%). These data suggest that several regions on chromosomal 17 can harbour tumour suppressor genes involved in tumour development of familial breast cancer.

Alleles↗
PubMed1993

Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer.

Hereditary colon cancer is caused by mutations in several different loci. The APC gene on chromosome 5 causing adenomatous polyposis coli represents a minority of the inherited colon cancer cases, while hereditary-non polyposis colon cancer (HNPCC) may cause five percent of all human colon cancer. One gene causing HNPCC was recently mapped to chromosome 2 but the same study also showed that at least one additional locus may cause HNPCC. We now present tight linkage between a polymorphic marker on the short arm of chromosome 3 and the disease locus, and find that these families also manifest signs of a general DNA replication disorder.

Chromosome Mapping↗
PubMed1993

Linkage analysis with markers on 17q in 29 Swedish breast cancer families.

Recently, a putative breast cancer gene was localized to the long arm of chromosome 17. A collaboration study was undertaken to confirm linkage, to further map the gene, and to determine to what extent breast cancer families are linked to this locus. The Swedish material consisted of 29 breast cancer families in which 68 affected members were studied. Linkage analysis of breast cancer susceptibility was performed with a number of markers on 17q. In this material a weakly positive LOD score in favor of linkage was observed in a subgroup of families with early onset, while no such linkage was observed in a subgroup of families with late onset.

Adult↗
PubMed1992

Hereditary breast cancer in Sweden: a predominance of maternally inherited cases.

The family history of breast cancer was studied in 1975 breast cancer patients of all ages. All the patients were found in an ongoing care program for breast cancer patients in the Stockholm area. One hundred and thirty-three families (6.7%) with hereditary breast cancer, 87 (4.4%) families with hereditary breast- and other cancers, and 14 (0.7%) families with the SBLA syndrome were found. There was no association between familiarity and bilateral disease, but familial cases tended to be younger at the time of diagnosis. Determination of the parental origin of the disease gene among the index cases revealed twice as many cases where the disease was maternally transmitted. This might be due to a better prognosis when the predisposing gene is maternally transmitted, and could be explained by parental imprinting or environmental factors influencing the expression of the gene.

Age Factors↗
PubMed1992

A randomized, double-blind, placebo-controlled study to evaluate topical anaesthesia of the pharynx in upper gastrointestinal endoscopy.

Reduction of discomfort during diagnostic upper endoscopy may not be desired by patients if the medication has long-lasting and severe after-effects. The present study was designed to examine whether topical anaesthesia of the pharynx without concomitant sedation is of overall benefit to patients undergoing diagnostic upper endoscopy. Two hundred out-patients were randomized to receive in the form of a pharyngeal spray either 80-120 mg lidocaine or placebo. Patients assessed discomfort on a 100 mm visual analogue scale the day after examination. Patients undergoing endoscopy who received lidocaine spray experienced significantly less discomfort from the intubation (p = 0.0001), and discomfort induced by the rest of the examination was also reduced (p = 0.003). The outcome of the endoscopists' assessment was also in favour of lidocaine spray for intubation (p = 0.157) and ease of examination (p = 0.0014). The assessment of throat discomfort suffered by patients after endoscopy did not differ between the groups. A majority of patients, the same proportion in each group, stated they would prefer their next endoscopy to be performed with topical anaesthesia.

Adult↗
PubMed1991

Domain structure of endothelial heparan sulphate.

The domain structure of heparan sulphate chains from an endothelial low-density proteoglycan was examined using specific degradations of the chains while attached to the intact proteoglycan. 'Inner' chain fragments, remaining on the protein core, were separated from 'outer' fragments by gel chromatography, and were subsequently released from the protein core by alkaline cleavage. The structure of 'inner' and 'outer' chain fragments was then examined and compared. Using deaminative cleavage we obtained evidence that the first N-sulphated glucosamine residue is variably positioned some 10-17 disaccharides from the xylose-serine linkage of the proteoglycan. Digestion with heparinase yielded 'inner' and 'outer' fragments covering a broad range of different sizes, indicating a scarce and variable distribution of sulphated iduronic acid in the native chains. N-sulphated glucosamine occurred more frequently in the 'outer' fragments. We also studied the affinity of the endothelial heparan sulphate chains towards two presumptive biological ligands, namely antithrombin III and lipoprotein lipase. A major part of the endothelial heparan sulphate chains showed a weak affinity for antithrombin III and the affinity was essentially lost on heparinase digestion. On lipoprotein lipase-agarose the endothelial heparan sulphate chains were eluted at the same salt concentration as heparin, and the binding persisted, although with decreased strength, after digestion with heparinase.

Chromatography, Affinity↗
PubMed1991

Oral sedation for diagnostic upper endoscopy.

Heavy i.v. sedation is often used in upper GI endoscopy. Sedation, however, creates the need for recovery facilities and precludes patients from returning to their normal daily activities. This is undesirable, since endoscopy is routinely performed as an out-patient procedure. Also the cost for medication and recovery facilities militate against the indiscriminate use of i.v. sedative premedication. The present study was undertaken in an attempt to establish what proportion of patients can benefit from oral premedication, and whether such an administration route can eliminate some of the disadvantages associated with i.v. sedation. Four hundred out-patients were randomized to receive orally either triazolam, 0.125 mg, or placebo. Of the patients, 359 were evaluable; 177 received placebo and 182 triazolam. All major aspects of the procedure were covered using visual analogue scale questionnaires for the endoscopist and patient. There were no differences in endoscopic experience, or sex and age distribution between the groups. Triazolam reduced patient discomfort, 38.6 +/- 25.6 vs 44.8 +/- 30.1 (p = 0.0379). Recollection of post-endoscopy information was the same in both groups. One patient complained of drowsiness following the procedure. No patient needed to stay in hospital to complete recovery. Endoscopy quality was identical in the two groups. Oral premedication has the potential to be of significant value, may optimize the use of endoscopy resources, and does not impair patient activities post-endoscopy.

Adult↗
PubMed1991

Anticholinergic medication in diagnostic endoscopy of the upper gastrointestinal tract.

The effects of two different forms of anticholinergic medication on endoscopic quality and patient discomfort were studied in 235 consecutively observed out-patients. Patients were randomized to receive either scopolamine i.v. and placebo transdermally, saline i.v. and saline transdermally, or placebo i.v. and scopolamine transdermally. No differences could be observed between the groups with respect to gastric motor function or endoscopic quality (as judged by the endoscopist), or discomfort during endoscopy (as judged by the patient). Transdermally applied scopolamin resulted in a significant increase (2p = 0.002) in post-endoscopy discomfort due to dryness of the mouth. The findings speak against the use of i.v. scopolamine (20 mg) or transdermally applied scopolamine (0.5 mg) in endoscopy of the upper gastrointestinal tract.

Administration, Cutaneous↗
PubMed1991

Patient attitudes to sedation for diagnostic upper endoscopy.

The presumed need for sedation in upper gastrointestinal endoscopy differs widely between countries and between endoscopists. Very little is known about patient attitudes and the factors that influence patient discomfort. We investigated all ambulatory patients scheduled for diagnostic upper GI endoscopy during a 4-month period (n = 1169) for their attitudes to sedation. One week before the examination they were asked whether they wanted sedation in addition to topical throat anesthesia. A brief description of the endoscopic procedure was given together with an explanation of presumed advantages and disadvantages of sedation. Only 399 patients (34.1%) wanted sedation. The two groups of patients were comparable as to age, gender, and previous experience of endoscopy. Of the 399 patients wanting sedative medication 54.2% were afraid of the diagnosis and 45.8% of the procedure. Male sex and young age were associated with a lower rate of preferring sedation. Patient discomfort during endoscopy was negatively correlated with age (r = -0.309; p = 0.000). Patients who had had more than one previous endoscopy had less discomfort than those without endoscopy experience (p = 0.0069). Men had less discomfort than women (p = 0.0014). The vast majority of our patients preferred 'a normal afternoon to endoscopy sedation'. Young women not previously endoscoped potentially benefit most from sedation.

Adult↗
PubMed1990

[Families with hereditary cancer--a target group for prevention].

Although a large proportion of the population contract cancer, the risk is not uniform. In a small group (an estimated five per cent) with hereditary predisposition, the risk of cancer is high (often as high as 50 per cent) in every child of an affected parent. Another, considerably larger group consists of individuals at high risk (though how high is unknown), where a combination of hereditary and environmental factors is probably involved. In all likelihood, it is this group which would benefit most from general recommendations as to preventive measures. The study of such individuals will enhance our knowledge of the source of their vulnerability, thus facilitating the understanding of tumorigenic mechanisms in general, and on the basis of such knowledge improve the prospect of general and specific screening programmes, prevention and treatment.

Adolescent↗
PubMed1990

Endothelial heparan sulphate: compositional analysis and comparison of chains from different proteoglycan populations.

From cultures of human umbilical vein endothelial cells incubated with 3H-glucosamine or 35S-sulphate, we have purified three heparan sulphate proteoglycans: 1) a low density (1.31 g/ml) proteoglycan from the cell extract, 2) a low density proteoglycan from the medium, and 3) a high density (greater than 1.4 g/ml) proteoglycan from the medium. The disaccharide composition of heparan sulphate chains from the low density proteoglycan of the medium was examined, using specific chemical and enzymic degradations followed by gel chromatography and strong anion exchange HPLC. Chains released from each of the different proteoglycan populations were then compared by gel chromatography and gradient polyacrylamide gel electrophoresis before and after various specific degradations. The results indicate that heparan sulphate from human endothelial cells are large polymers (MW greater than 50,000) of low overall sulphation (32-35% N-sulphated glucosamine and an N/O-linked sulphate ratio of 2.0) with rare and solitary heparin-like disaccharides. Heparan sulphate from the different proteoglycan populations appeared to have similar structure except that chains from the high density fraction were larger polymers.

Carbohydrate Sequence↗
PubMed1989

Identification of the core proteins in proteoglycans synthesized by vascular endothelial cells.

Proteoglycans, metabolically labelled with [3H]leucine and 35SO4(2-), were isolated from the spent media and from guanidinium chloride extracts of cultured human umbilical-vein endothelial cells by using isopycnic density-gradient centrifugation, gel filtration and ion-exchange h.p.l.c. The major proteoglycan species were subjected to SDS/polyacrylamide-gel electrophoresis before and after enzymic degradation of the polysaccharide chains. The cell extract contained mainly a heparan sulphate proteoglycan that has a buoyant density of 1.31 g/ml and a protein core with apparent molecular mass 300 kDa. The latter was heterogeneous and migrated as one major and one minor band. After reduction, the apparent molecular mass of the major band increased to approx. 350 kDa, indicating the presence of intrachain disulphide bonds. The proteoglycan binds to octyl-Sepharose and its polysaccharide chains are extensively degraded by heparan sulphate lyase. The proteoglycans of the medium contained 90% of all the incorporated 35SO4(2-). Here the predominant heparan sulphate proteoglycan was similar to that of the cell extract, but was more heterogeneous and contained an additional core protein with apparent molecular mass 210 kDa. Furthermore, two different chondroitin sulphate proteoglycans were found: one 200 kDa species with a high buoyant density (approx. 1.45 g/ml) and one 100 kDa species with low buoyant density (approx. 1.3 g/ml). Both these proteoglycans have a core protein of molecular mass approx. 47 kDa.

Aggrecans↗
PubMed1989

Interferon treatment in patients with malignant carcinoids.

Thirteen patients with ileal carcinoids complicated by liver metastases were treated with human leukocyte interferon (IFN) subcutaneously (s.c.) at doses of 3-6 x 10(6) IU/day 5 days weekly during 12 months. Objective tumour response was obtained in 2 patients, based on reduction in tumour size in one patient and on reduction in tumour markers in the other. Stable disease was noted during the 12-month treatment period in 10 patients. Progressive disease was seen in one patient. This patient exhibited tumour growth, new metastases and increases in tumour markers. Among patients with daily flushing prior to treatment, 50% were free of flush after 12 months of IFN. Adverse effects, including a mild influenza-like syndrome, joint and muscle pains, tiredness and reduction of blood cells were observed but did not necessitate long-term dose reductions. Thus, IFN therapy to midgut carcinoid patients resulted in tumour response or stable disease in 12 out of 13 patients without causing severe side effects.

Aged↗
PubMedDate not supplied

BRCA2 germline mutations in Swedish breast cancer families.

Mutations in the breast cancer susceptibility gene (BRCA2) are believed to be responsible for a significant fraction of hereditary breast cancer. To determine the BRCA2 mutation spectrum in a subset of Swedish breast cancer families, 162 families were screened for germline mutations in this gene. A combination of RT-PCR, PTT and direct DNA sequencing was used. Two mutations and one previously reported polymorphic variant resulting in a truncated protein were identified. Our data suggest that only a small proportion of Swedish breast cancer families is attributable to BRCA2 germline mutations. This result, in combination with the low frequency of BRCA1 germline mutations identified in our previous study, suggests additional high penetrant as well as low penetrant breast cancer susceptibility genes are involved in familial breast cancer.

BRCA2 Protein↗
PubMedDate not supplied

Histological changes pertinent to local tumor progression in hereditary nonpolyposis colorectal cancer (HNPCC). A preliminary report.

While the genetic profiles of hereditary colorectal tumors are being unravelled, the mechanisms implicated in their local progression remain to be deciphered. In this work histological features occurring at the invading tumor front were investigated in ten hereditary non-polyposis colorectal cancers (HNPCC). Of eight moderately-differentiated (i.e. gland-forming) adenocarcinomas, six had dilated glands with a thin layer of tumor cells and all eight had dilated glands in which a group of cells was lacking, i.e. with a glandular pore. It was apparent that the thin glandular epithelium was a stage preceding pore formation. In glands with pores, the contents of the neoplastic glands--rich in proteolytic enzymes--were extruded directly into the extracellular matrix (ECM), leading to the local destruction of the juxtaposed matrix. It was assumed that to restore the continuity of the glands new cancer cells would grow from the tip of the free borders of the pore into the damaged ECM, thus guaranteeing a stepwise, but everlasting, tumor progression in untreated patients.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Treatment of malignant midgut carcinoid with a highly purified human leukocyte alpha-interferon.

Fourteen patients with liver metastases due to midgut carcinoid tumours were treated with a highly purified human leukocyte alpha-interferon (Interferon Alfanative) at a dose of 2-6 x 10(6) IU subcutaneously 5 days a week. In all patients, the primary tumour was removed before alpha-interferon was given. We found that after one year of treatment with alpha-interferon, 4 patients (= 29%) showed objective response (= reduction by more than 50% of urinary excretion of 5-HIAA and/or by more than 50% of tumour area as determined by computed tomography). Four patients (= 29%) showed stable disease. After 2 years of treatment with alpha-interferon, 4 patients (= 29%) showed objective response. During the second year of treatment, 3 patients died due to tumour progression and in 4 patients the treatment was stopped due to adverse effects. Specific adverse effects to alpha-interferon were reported by 11 of the patients (= 79%). We conclude that the one year objective response to alpha-interferon in 14 patients with liver metastases due to midgut carcinoids is 29% and that the frequency of side effects is high.

Aged↗