[Ambulatory blood pressure measurement--guidelines for registration and data processing].
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Ambulatory Care↗
Biomedical subjects
L Lindholm
Publications and source records attributed to L Lindholm.
[Antihypertensive treatment reduces the risk of stroke even in elderly hypertensive patients].
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Age Factors↗
Tumor-cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small-cell lung carcinoma.
Monoclonal antibodies (MAbs) reactive with the ganglioside fucosyl GM1 (Fuc-GM1), an antigen associated with small-cell carcinoma of the lung (SCLC), were tested for their ability to mediate tumor-cell killing in vitro in conjunction with humoral and cellular effectors and to inhibit tumor engraftment in nude mice in vivo. MAbs F12 and F15, both IgG3k, induced human complement-mediated cytolysis of 3 Fuc-GM1-expressing tumor cell lines: one rat hepatoma cell line, H4-II-E, and 2 human SCLC cell lines, NC1 H69 and NC1 H128. F12 and F15 also induced ADCC of these cell lines in the presence of either murine or human effector cells. Addition of sub-cytolytic amounts of fresh human serum as complement source resulted in enhanced ADCC induced by MAb F12 (IgG3). Also a Fuc-GM1-reactive MAb of IgM isotype, F9, was able to induce such complement-aided ADCC (CADCC). F12 and F15 both proved to effectively inhibit engraftment of H4-II-E tumors in nude mice. A single dose of a modest amount (40 micrograms) of MAb conferred 65 to 100% protection against development of tumors. Our results demonstrate that Fuc-GM1 can act as a target antigen on tumor cells for specific immunotherapy in vitro and in a mouse model in vivo. Complement and murine and human mononuclear effector cells were effective mediators of tumor cytolysis in vitro in the presence of murine Fuc-GM1-reactive MAbs. Our results also suggest that humoral and cellular effectors may co-operate in specific tumoricidal reactions and that these may be induced by antibodies of both IgG and IgM isotypes.
Animals↗
Purification and characterization of a membrane-bound and a secreted mucin-type glycoprotein carrying the carcinoma-associated sialyl-Lea epitope on distinct core proteins.
Two mucin-type glycoproteins detected by the monoclonal antibody C50, which reacts with the carcinoma-associated sialyl-Lewis a and sialyl-lactotetraose epitopes, were found in secreted and solubilized materials from the colon carcinoma cell line COLO 205. The larger glycoprotein (H-CanAg; heavy cancer antigen) was predominantly found in extracts of cells grown in vitro or as nude mice xenografts whereas the smaller species (L-CanAg; light cancer antigen) was the major component in spent culture medium and serum from grafted mice. Using detergent in the extraction buffer doubled the yield of H-CanAg, suggesting that this glycoprotein is membrane bound whereas the yield of L-CanAg was relatively unaffected. The two glycoproteins were purified from xenograft extracts and spent culture medium using perchloric acid precipitation, monoclonal antibody affinity purification, ion exchange chromatography, and gel filtration. Both glycoproteins were unaffected by reduction and alkylation in guanidine HCl. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, relative molecular masses were estimated to be 600-800 kDa for H-CanAg and 150-300 kDa for L-CanAg. Carbohydrate analysis revealed that the CanAg glycoproteins were highly glycosylated (81-89% carbohydrate by weight), carrying carbohydrate chains with average lengths of 13-18 sugars which were rich in fucose and sialic acid (2-3 residues/chain for each sugar). L-CanAg isolated from spent medium was glycosylated to a higher degree than its counterpart from xenograft extract. Immunochemical studies of the intact glycoproteins showed that both H-CanAg and L-CanAg expressed the monoclonal antibody-defined, sialic acid-containing carbohydrate epitopes CA203 and CA242 as well as the Lewis a blood group antigen whereas only H-CanAg appeared to carry the sialyl-Lewis x epitope. The amino acid compositions were typical of mucins, containing high amounts of serine, threonine (more than 25% together), and proline (11-18%). Significant differences in amino acid composition between H-CanAg and L-CanAg were found. A rabbit antiserum against the cytoplasmic C-terminal part of the MUC1 gene product, core protein of the carcinoma-associated polymorphic epithelial mucin (PEM) and DU-PAN-2, reacted with H-CanAg. After deglycosylation with trifluoromethanesulfonic acid, H-CanAg but not L-CanAg was recognized by the monoclonal antibodies SM-3 and HMFG-2, directed to the tandem repeat of the PEM apoprotein. However, these antibodies which react with PEM from mammary carcinomas without prior deglycosylation were unable to recognize intact H-CanAg, probably as a consequence of a more extensive glycosylation of this glycoprotein.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acids↗
Comparison of serological expression of different epitopes on the CA50-carrying antigen CanAg.
C203 and C242 are mouse monoclonal antibodies (MAbs) generated using a human colon carcinoma cell line. They recognize novel tumour-associated epitopes present in elevated levels in sera from patients with colon and pancreatic cancer. These epitopes were found to be co-expressed with sialylated Lewisa on the CanAg molecule. To study the association and distribution of the epitopes of CanAg in sera, these new antibodies, together with C50, were used in different combinations in time-resolved fluoroimmunoassays. Relative serum concentrations were examined in patients with various types of carcinoma and in patients with ulcerative colitis and benign pancreatic, and hepatobiliary diseases. A double-determinant assay using C50 and C242 was shown to distinguish carcinoma from benign biliary and hepatocellular diseases better than a single-determinant assay based on C50 as both catching and tracing antibody. The number of sera with elevated CanAg levels from patients with benign obstructive biliary disease was 17 out of 29 using the single-determinant CA50 assay. This was reduced to 4 out of 29 in the double-determinant assay. When sera from patients with liver cirrhosis were analyzed, 16 of 23 patients showed elevated CanAg levels with the C50-C50 combination, but only 4 of 23 patients had elevated antigen values using the C50-C242 assay. The increased specificity was obtained without loss of sensitivity. MAb C203 was evaluated both in a double-determinant combination with C50 and in an homologous assay, but did not contribute either increased sensitivity or specificity as compared with C50-C50.
Animals↗
Tumour-growth suppression in nude mice by a murine monoclonal antibody: factors hampering successful therapy.
The murine MAb C215 has been shown to mediate ADMMC in vitro and to have a tumour-growth-suppressive effect on xenografted COLO 205 human colocarcinoma cells in nude mice. To overcome the limitations of MAb therapy, it is necessary to understand the underlying mechanisms of tumour-growth suppression. In the present work, we have used C215 to define the importance of different parameters involved in tumour therapy with murine IgG2a antibodies. The results show that there exists a period of roughly 2 days after inoculation into animals during which the tumour cells are sensitive to an inhibitory antibody-mediated effect. After this initial period, the in-vivo sensitivity of tumour cells to antibody-mediated inhibition is much reduced. Tumour cells can remain "dormant" and, despite ongoing antibody treatment, develop into tumours with a reduced growth rate, which is not caused by outgrowth of antigen-deficient tumour cells. Finally, a pronounced dependence of antibody-mediated tumour suppression on antibody dose was observed.
Animals↗
Key learnings from the STOP-Hypertension study: an update on the progress of the ongoing Swedish study of antihypertensive treatment in the elderly.
The Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) is an ongoing multicenter, randomized, double-blind study of antihypertensive treatment (beta-blockers or diuretics) compared to placebo in hypertensive men and women aged 70-84 years. The main trial, which is now in progress, is being carried out at approximately 120 primary health care centers in Sweden, the aim being to recruit 2000 patients, who will be studied for an average period of 3 years. The main study was preceded by a 1-year pilot study in 31 centers. Almost 5000 patients were screened in the pilot study, 55% of whom were labelled hypertensive, i.e., their recumbent blood pressure was greater than or equal to 180/105 mmHg or they were already receiving antihypertensive therapy. After 1 year, 89 patients (1.9%) had been randomized to double-blind treatment and 66 patients (1.4%) were in the run-in/washout period, whereas the remainder had not been included in the trial. The most common reason for not being included as a failure to reach the inclusion blood pressure criteria (greater than or equal to 180 mmHg systolic and/or greater than or equal to 105 mmHg diastolic) following withdrawal of previous antihypertensive medication. In the main trial, recruitment of new centers and new patients has improved gradually and by April 1989 approximately 900 patients had been randomized to double-blind treatment. In an analysis of 961 elderly patients (mean age 70.1 years), the relation between systolic and diastolic blood pressure and mortality was not significant.
Aged↗
Extracted atrial natriuretic peptide not elevated in treated hypertensives.
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Atrial Natriuretic Factor↗
How good are standardized blood pressure recordings for diagnosing hypertension? A comparison between office and ambulatory blood pressure.
Ambulatory blood pressure monitoring was compared with office blood pressure in 48 normotensive, 81 borderline hypertensives and 35 untreated hypertensives. The studied groups were chosen from a geographically defined population of middle-aged men in southern Sweden. The mean 24-h ambulatory blood pressure values for the normotensives, borderline hypertensives and untreated hypertensives were 120/76, 127/82 and 140/92 mmHg, respectively. The diurnal mean ambulatory blood pressure in the three groups was 126/80, 134/86 and 146/96 mmHg, respectively. The percentage of 24-h diastolic blood pressure peaks greater than or equal to 95 mmHg in the groups were 7%, 22% and 53%, respectively. The corresponding values greater than or equal to 90 mmHg were 16%, 38% and 69%, respectively. In the untreated hypertensive group, there was a more pronounced (P less than 0.05) systolic blood pressure increase during the morning hours (0600-1000 h) than in the normotensive and borderline hypertensive groups. Fourteen per cent of the hypertensives showed normal blood pressure values during 24-h blood pressure monitoring. Fifteen per cent of the borderline hypertensives were normotensive during ambulatory blood pressure monitoring despite repeated office diastolic blood pressure greater than or equal to 90 mmHg. The opposite (increased blood pressure during ambulatory blood pressure monitoring and at screening but normal office blood pressure) was seen in 14% of the borderline hypertensives. Normotensives were characterized by lower mean blood pressure values, fewer blood pressure peaks and a lower systolic blood pressure increase during the morning hours than hypertensives in this study of middle-aged men. The established way of diagnosing hypertension, borderline hypertension and normotension correlated well with the results of ambulatory blood pressure monitoring.
Blood Pressure↗
Immunohistochemical detection of two small cell lung carcinoma-associated antigens defined by MAbs F12 and 123C3 in bronchoscopy biopsy tissues.
We have studied MAbs* for their ability to detect SCLC and differentiate this tumor type from the other lung tumor histotypes in cryostat sections of biopsy specimens taken at bronchoscopy from patients with suspected primary lung tumor disease. MAb F12, specific for the ganglioside fucosyl-GM1, reacted with 58% of the cases with SCLC (n = 19) and with less than 3% of those with non-SCLC (n = 38). MAb 123C3, specifically reactive with NCAM, reacted with 78% of the SCLC cases (n = 23). With this MAb no positive staining was seen in the non-SCLC cases (n = 41). None of the two MAbs reacted with tissue sections without tumor. In combined analysis with MAbs F12 and 123C3, all SCLC cases (n = 15) were positive with either and 47% with both of the MAbs. Our results show that both MAbs F12 and 123C3 are highly specific for SCLC in bronchoscopic biopsy tissue specimens, whereas the sensitivity for this histotype tends to be higher with MAb 123C3 than with F12 (P = 0.14). When used in combination, all SCLC cases could be identified. These MAbs may therefore be valuable as complements to current histopathologic characterization and differentiation of lung cancer.
Adenocarcinoma, Bronchiolo-Alveolar↗
Clinical evaluation of tumour marker combinations in the differential diagnosis of benign and malignant liver disease.
CEA, CA19-9 and CA50 are tumour associated antigens defined by monoclonal antibodies which have been raised against adenocarcinoma cell lines. The aim of this study was to determine whether their combined use could improve diagnostic accuracy in patients with primary and secondary liver tumours. An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system for CA50. Serum was collected from 65 normal subjects, 40 with hepatobiliary carcinoma (26 primary, 14 secondary) and 17 with benign hepatobiliary disease. The cut-off levels were calculated as the mean of the control group plus 2 standard deviations. All three antibodies contributed to improving the correct classification of secondary liver tumours (multivariant discriminant analysis p less than 0.05), but only CA19-9 and CA50 contributed to the diagnosis of primary liver tumours (multivariant analysis p less than 0.05). The diagnostic accuracy versus benign disease was 81% for primary carcinoma and 91% for secondary carcinoma. Combined use of CEA, CA19-9 and CA50 helps to differentiate benign from malignant hepatobiliary disease.
Antigens, Tumor-Associated, Carbohydrate↗
Novel epitopes on the CA50-carrying antigen: chemical and immunochemical studies.
Novel tumour-associated epitopes showing elevated levels in sera from patients with colon carcinoma were studied by means of monoclonal antibodies with respect to co-expression with the tumour-associated epitope CA50 on the cancer antigen (CanAg) glyco-conjugate complex. Co-expression of the different epitopes and CA50 was found on CanAg both from COLO 205 spent medium and sera from patients with colorectal cancer. In a few sera from patients with non-mucinous ovarian tumours, the CanAg complex was also found to express the CA125 epitope. The chemical characterisation showed that all of the novel epitopes on CanAg were of carbohydrate nature, and the results may suggest a structural relationship between several of them.
Adenocarcinoma↗
Comparison of seven iodine-labelled monoclonal antibodies in nude mice with human colon carcinoma xenografts.
The biokinetics of seven 131I-labelled monoclonal antibodies (MAbs), directed against human colon carcinoma and one 125I-labelled unspecific MAb have been examined. The study in nude mice, carrying human colon carcinoma, was intended to be a step in the selection of the most suitable antibody for clinical scintigraphy. The biological half-life in blood was found to be between 1.3 and 7.4 days for the different MAbs. Chromatography of plasma samples showed that the radioiodine was mainly bound to IgG-sized molecules. The (normal tissue)/blood ratios were similar for all the MAbs. The tumour/blood ratio was 0.41 for the unspecific MAb and 0.49-1.1 for the specific MAbs, and the tumour/muscle ratio was between 3.2 and 6.8 for the specific MAbs 6 days after injection. For one MAb tumour/blood and tumour/muscle ratios were 3.9 and 9.8 respectively 9 days after injection. Localization indices were at their highest 2.6 6 days after injection. For at least two of the monoclonal antibodies the tumour/blood and tumour/muscle ratios found are high enough to justify clinical trials regarding their usefulness for scintigraphy of colon cancer in man.
Adenocarcinoma↗
Precipitation of angioedema by antihypertensive drugs.
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Adrenergic beta-Antagonists↗
Clinical evaluation of combined use of CEA, CA19-9 and CA50 in the serum of patients with pancreatic carcinoma.
CEA, CA19-9 and CA50 are tumour-associated antigens defined by monoclonal antibodies that have been raised against adenocarcinoma cell lines, but no single antibody is specific for the detection of pancreatic malignancy. The aim of this study was to determine whether the combined use of CEA, CA19-9 and CA50 would improve diagnostic accuracy. An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system for CA50. Serum was collected from 65 normal subjects, 16 with pancreatitis and 28 with pancreatic carcinoma. Of the 28 cancer patients, 24 (85%) had a CA19-9 level above 46 mu/ml, 26 (92%) had a CA50 level above 21 mu/ml and 10 (37%) had a CEA level above 7 ng/ml. Multivariant discriminant analysis on the combined antibodies showed that 96% of the malignant group, 13% of the pancreatitis group and 11% of the normal group were positive, with an overall correct classification of 91% into the three groups (multivariant discriminant analysis P less than 0.05). Thus the combined use of CEA, CA19-9 and CA50 improves diagnostic accuracy in differentiating benign from malignant disease of the pancreas.
Adult↗
Effects of antihypertensive therapy on glucose tolerance: focus on calcium antagonists.
The prohormone form of insulin is contained in the secretory granules of the pancreatic beta-cell and released as the mature peptide sequence by exocytosis. One of the factors believed to trigger the movement of the secretory granules to the cell surface and their fusion with the plasma membrane is an increase in the cytosolic Ca2+ concentration [Ca2+]i. Extracellular glucose depolarizes the cells and favours the opening of voltage-dependent Ca2+ channels, which results in a rise in [Ca2+]i and activation of protein kinases. The phosphorylation of proteins associated with the functions of the secretory granules will influence the movement of the granules towards the plasma membrane. Due to their effects on voltage-dependent Ca2+ channels, it is suspected that calcium antagonists influence glucose-stimulated insulin release. Current information on calcium antagonists suggests that they may have different effects on glucose tolerance in non-diabetic and diabetic subjects. In non-diabetic hypertensives, fasting blood glucose is generally not affected by verapamil, diltiazem or nifedipine taken in therapeutic doses, although some reports indicate that high-dose nifedipine or diltiazem may deteriorate glucose homeostasis. Studies of the effect of single doses of calcium antagonists on the response to a glucose challenge have yielded somewhat conflicting results. The general picture, however, is that under these circumstances glucose tolerance in non-diabetic individuals remains largely unaffected, although higher doses of verapamil and nifedipine have impaired glucose tolerance slightly in some studies. In patients with non-insulin-dependent diabetes mellitus (NIDDM), acute administration of calcium antagonists with or without glucose challenge does not generally cause any changes in the blood glucose or insulin profiles. During short-term calcium antagonist therapy, conflicting results have been obtained. Overall, the data suggest that these drugs do not significantly modify glucose homeostasis. However, some reports do suggest that diabetic patients may deteriorate on nifedipine treatment. There are as yet no clear indications of any consistent changes in glucose homeostasis during long-term administration of verapamil, diltiazem or nifedipine. However, isolated case reports have indicated unfavourable changes in glucose homeostasis in patients treated with calcium antagonists of the dihydropyridine type, such as nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Hyperinsulinaemia and other metabolic disturbances in well-controlled hypertensive men and women: an epidemiological study of the Dalby population.
Hypertensive subjects who have received no treatment have been found to be hyperinsulinaemic in previous studies using different populations. The present study was carried out to further examine the metabolic disturbances in carefully treated hypertensive subjects [diastolic blood pressure (DBP) less than 90 mmHg] of both sexes from the Dalby population. Three hundred and ten subjects who had been hypertensive for more than 5 years [DBP 88.1 +/- 0.5 (mean +/- s.e.m.)] were compared with 288 normotensive controls, matched for sex and age and chosen from the same population. After an overnight fast and with no medication for 24 h, an oral glucose tolerance test was carried out. P-insulin and P-C-peptide were analysed and insulin sum (P-insulin at start + after 2 h of oral glucose tolerance test) and C-peptide sum were calculated. Insulin and C-peptide sums were higher (P less than 0.001) in the hypertensive than in the normotensive subjects; 0.69 +/- 0.03, 3.36 +/- 0.08 and 0.41 +/- 0.02, 2.74 +/- 0.06, respectively. The diagnosis of hypertension, not the attained blood pressure level, correlated with insulin and C-peptide sums in multivariate analyses; F-values 20.96 (n = 598; P less than 0.001) and 6.68 (P less than 0.01), respectively. Hypertensive subjects under treatment, using calcium antagonists as monotherapy (n = 21), did not differ in age or body mass index from other hypertensives, but they had lower values for insulin and C-peptide sums; 0.45 +/- 0.05 and 2.63 +/- 0.18. Angiotensin converting enzyme inhibitors were not frequently used for monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Antihypertensive Agents↗
High urinary cAMP in hypertensives despite careful drug treatment--an epidemiological study from the Dalby population.
The correlation between serum calcium (S-Ca), plasma parathyroid hormone (P-PTH) and hypertension was determined in a population-based, cross-sectional study of carefully treated hypertensives (n = 391; diastolic blood pressure 90.2 mmHg; 57 years) compared with normotensive controls (n = 328; diastolic blood pressure 82.1 mmHg; 57 years). Levels of urinary cyclic-adenosinemonophosphate (U-cAMP), but not of plasma cAMP (P-cAMP), were higher (P less than 0.001) in hypertensives than in controls. This was the case regardless of the type of drug treatment and the blood pressure level that was reached. U-cAMP correlated with adrenaline in multivariate analyses. S-Ca levels were higher (P less than 0.001) and S-Mg levels were lower (P less than 0.001) in hypertensives than in controls. This was not explained by thiazide treatment. Thus, despite 'adequate' blood pressure reduction, substantial differences in S-Ca, S-Mg and U-cAMP still exist between hypertensives and normotensive controls.
Antihypertensive Agents↗