Search PubMed⌕ Search

Biomedical subjects

A Isaksson

Publications and source records attributed to A Isaksson.

At least 19 recordsLinked to original sources
PubMed2006

Constitutional downregulation of SEMA5A expression in autism.

There is strong evidence for the importance of genetic factors in idiopathic autism. The results from independent twin and family studies suggest that the disorder is caused by the action of several genes, possibly acting epistatically. We have used cDNA microarray technology for the identification of constitutional changes in the gene expression profile associated with idiopathic autism. Samples were obtained and analyzed from 6 affected subjects belonging to multiplex autism families and from 6 healthy controls. We assessed the expression levels for approximately 7,700 genes by cDNA microarrays using mRNA derived from Epstein-Barr virus-transformed B lymphocytes. The microarray data were analyzed in order to identify up- or downregulation of specific genes. A common pattern with nine downregulated genes was identified among samples derived from individuals with autism when compared to controls. Four of these nine genes encode proteins involved in biological processes associated with brain function or the immune system, and are consequently considered as candidates for genes associated with autism. Quantitative real-time PCR confirms the downregulation of the gene encoding SEMA5A, a protein involved in axonal guidance. Epstein-Barr virus should be considered as a possible source for altered expression, but our consistent results make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism.

Adolescent↗
PubMed2006

Characterization of an imatinib-sensitive subset of high-grade human glioma cultures.

High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.

Antineoplastic Agents↗
PubMed2005

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles.

Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug-gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.

Antineoplastic Agents↗
PubMed2005

Increased bone density and decreased bone turnover, but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus.

Bone density, bone turnover and fracture susceptibility were evaluated in 1,132 randomly recruited women, all 75 years old. Seventy-four of the women had diabetes, while 1,058 women did not. Areal bone mineral density (aBMD) of the hip and lumbar spine was investigated by dual energy X-ray absorptiometry (DXA), and bone mass of the calcaneus was measured by ultrasound. Urinary deoxypyridinoline/creatinine (U-DPD/Crea) and serum C-terminal cross-linked telopeptide of type 1 collagen (S-CTX) were assessed as markers of bone resorption. Serum bone-specific alkaline phosphatase (S-bone ALP) and serum osteocalcin (S-OC) were assessed as markers of bone formation. Also, serum 25(OH) vitamin D and serum parathyroid hormone (S-PTH) were assessed. Fracture susceptibility was evaluated retrospectively and prospectively for up to 6.5 years. In diabetic women, the aBMD of the femoral neck was 11% higher (p<0.001), and BMD of the lumbar spine was 8% higher (p=0.002) than in non-diabetic women. There was no difference in bone mass by ultrasound of the calcaneus. Women with diabetes had higher BMD of the femoral neck (p<0.001) and lumbar spine (p=0.03) also after correction for differences in body weight. In diabetic women, U-DPD/Crea, S-CTX, and S-OC were decreased when compared with non-diabetic women (p=0.001 or less). After correction for covariance of body weight and plasma creatinine, S-CTX (p<0.001) and S-OC (p<0.001) were still lower in the diabetic women. Diabetic patients had hypovitaminosis D (p=0.008), a difference explained by differences in time spent outdoors and body weight. S-PTH did not differ between the groups. Women with diabetes had no more lifetime fractures (52%) than women without diabetic disease (57%), (p=0.31). This study shows that elderly women with diabetes and without severe renal insufficiency have high bone mass and low bone turnover. The high bone mass and low bone turnover is not likely to have a strong influence on fracture susceptibility.

Absorptiometry, Photon↗
PubMed2005

Plasma homocysteine and markers of bone metabolism in psychogeriatric patients.

OBJECTIVE: In recent studies high plasma total homocysteine (tHcy) levels were reported to be associated with increased risk of osteoporotic fractures. In elderly psychogeriatric patients there is a high frequency of elevated plasma tHcy concentration. The present study therefore investigates the association between plasma tHcy concentration and markers of bone metabolism in psychogeriatric patients. MATERIAL AND METHODS: A total of 152 psychogeriatric patients were investigated and plasma tHcy and its major determinants (serum folate, serum cobalamin and renal function) were measured. Osteocalcin and crosslaps were chosen as markers of bone metabolism. RESULTS: Bone markers (crosslaps and osteocalcin) were increased in elderly patients with dementia compared to patients without dementia. Stepwise multiple regression analysis showed that plasma tHcy concentration made only a small contribution to the prediction of crosslaps in serum, whereas plasma tHcy concentration was not an independent predictor of serum osteocalcin. CONCLUSIONS: The present study does not provide support for the hypothesis that a moderately increased plasma tHcy concentration is a risk factor for impaired bone metabolism.

Aged↗
PubMed2004

Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992-2001.

OBJECTIVE: To evaluate the longitudinal development of the tricuspid gradient (TG) for screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc). METHODS: Doppler echocardiography was performed 506 times in order to estimate TG in 227 consecutive patients with SSc. The value of biochemical markers for predicting TG levels and development was assessed through analyses of pro-brain natriuretic peptide (proBNP), calcitonin-gene related peptide, thrombomodulin and von Willebrand factor in 76 patients with a borderline increase in TG, defined as TG 24-38 mmHg, and for the purpose of comparison also in 10 patients with a normal TG (< 23 mmHg) and in 10 patients with increased TG (TG > 38 mmHg). RESULTS: TG > 23 mmHg was found in 102 patients (44.9%) at the first assessment point and in 139 patients (61.2%) respectively, cumulatively at follow-up. TG values > 33 mmHg were measured in 24 patients (10.6%) initially and in 38 patients (16.7%) cumulatively in a subsequent assessment. Age and the presence of interstitial lung disease (ILD) were associated with more frequent occurrence of TG > 23 and > 33 mmHg initially and at follow-up, but were not associated with progression rate. The change in TG (mean +/- S.D.) was 1.34 +/- 4.55 mmHg/yr. ProBNP correlated to TG. CONCLUSION: An increased TG, indicating possible PAH, is common and progressive in SSc. Age and ILD increase the risk of increased TG. Patients with or without ILD have similar progression of TG. ProBNP has potential as an adjunct to TG in selecting patients eligible for invasive treatment.

Age Factors↗
PubMed2001

Interaction of metals and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol.

In the present study, we have investigated the effects of extracellular redox status and metal/thiol interactions on glutathione distribution in HeLa cell cultures. No effects were seen on glutathione distribution after the addition of different thiols, whereas the pro-oxidant copper ions affected glutathione distribution in several ways. The addition of dithiothreitol (DTT) but not the other thiols potentiated the effects of mercury ions on glutathione distribution and cell toxicity. In the presence of DTT, increased intra- and extracellular glutathione concentrations were noted already at 0.05 micromol/l, which was below the previously reported toxicity threshold for mercury ions in blood. Likewise DTT potentiated the effects of copper ions on glutathione distribution and cell toxicity, whereas the addition of DTT to cell cultures with a non-metal thiol reactive agent (hydroquinone) or an oxidative agent (hydrogen peroxide) did not affect glutathione distribution or cell toxicity. Thus, it seems as the synergistic effects between DTT and thiol reactive agents only apply to metal ions.

Acetylcysteine↗
PubMed2001

Markers for the functional availability of cobalamin/folate and their association with neuropsychiatric symptoms in the elderly.

Cobalamin/folate deficiency is common in elderly subjects and may lead to psychiatric symptoms, but even more often it increases the severity of other organic and non-organic mental diseases. This paper reviews the literature relevant for markers of cobalamin/folate status and their relation to neuropsychiatric symptoms in the elderly. Plasma homocysteine, a marker of cobalamin/folate status, is frequently increased in psychogeriatric patients. Among markers of cobalamin/folate status, plasma homocysteine shows the best association with neuropsychiatric dysfunction.

Aged↗
PubMed2001

More keys to padlock probes: mechanisms for high-throughput nucleic acid analysis.

With the impending availability of total information about nucleic acid sequences in humans and other organisms, tools to investigate these sequences on a large scale assume increasing importance. Methods currently in use, however, cannot offer the required combination of high-throughput, sensitivity and specificity of detection. Padlock probes, circularizing oligonucleotides, may provide a means to detect, distinguish, quantitate and also locate very large numbers of DNA or RNA sequences. Recent developments in areas such as the biochemistry of ligation and characterization of ligases, methods to replicate circularized probes and the development of assays based on these principles augment the potential of padlock probes.

Biotechnology↗
PubMed2001

Evaluation of surgery for acromegaly: role of intraoperative growth hormone measurement?

OBJECTIVE: Intraoperative growth hormone (GH ) measurement has earlier been tried to improve surgery for acromegaly. We calculated GH half-life after adenomectomy and evaluated the possible role of this variable in predicting the final outcome of pituitary surgery in 28 consecutive patients with acromegaly. The sensitivity, specificity and predictive values were determined in relation to the results from GH suppression during an oral glucose load and IGF-1 3 months postoperatively. The GH half-life data were also compared to the corresponding results obtained from GH measurements between 60 min and 180 min after adenomectomy, and early, within 1 week, postoperatively. RESULTS: GH half-life < or =31 min was recorded in 8/13 cured patients but also in 2/15 unsuccessful cases. A mean GH concentration < or =4.4 mU/L between 60 min and 120 min after adenomectomy was found in 11/13 cured subjects but also in 3/15 not cured patients. A mean GH < or =4.0 mU/L between 90 min and 180 min was found in 11/13 cured and in 4/15 not cured patients. A mean early postoperative GH concentration < or =2.6 mU/L was noted in all 13 cured patients, but also in 2/13 unsuccessful cases. The specificity of early postoperative GH < or = 2.6 mU/L was 100% compared to 62% for a GH half-life < or =31 min (p<0.05) and 85% for the GH mean values between 60 min and 120 min and 90 min and 180 min, respectively. The sensitivity for persistent disease of values above the four cut-off limits used was between 73% and 87%. The positive predictive value for a mean early postoperative GH value >2.6 mU/L was 100%, and 72% for a GH half-life >31 min (n.s.). CONCLUSION: Although intraoperative GH half-life might be useful in some cases, it was not a reliable tool for predicting outcome of pituitary surgery in acromegaly. In cases with a 51% decrease of a basal GH concentration >5.5 mU/L, mean GH values < or =4 to < or =4.4 mU/L late intraoperatively were more informative but not as good as those obtained from the mean of a series of GH values drawn on one occasion within 1 week postoperatively, offering a 100% specificity for cure if < or =2.6 mU/L. Intraoperative GH half-life measurements should therefore be used with caution. The predictive values of the cut-off limits used in this study should be further evaluated before general application.

Acromegaly↗
PubMed2001

Peripheral effects of PTH are not altered after thyroid surgery in euthyroid patients.

BACKGROUND: We have previously found decreased serum levels of both ionized calcium and 1,25(OH)2D and an increase in serum phosphate levels at 1 year after hemithyroidectomy. However, basal and stimulated parathyroid hormone (PTH) secretions were not altered. To investigate whether the observed biochemical changes after unilateral thyroid surgery may be due to a relative end-organ resistance to PTH, we studied the peripheral effects of infused hPTH-(1-34) in 6 patients preoperatively and 3 months after hemithyroidectomy. METHODS: Serum levels of TSH, FT4 and FT3 were measured pre- and postoperatively. hPTH-(1-34) was infused at 0.9 IU/kg/h during 6 h. Blood samples for analysis of ionized calcium, intact PTH, phosphate, 25(OH)D, 1,25(OH)2D and urinary samples for calcium, phosphate and nephrogenous(n)-cAMP analysis were taken at baseline, when the infusion was discontinued after 6 h and at 24 h. RESULTS: Three months after hemithyroidectomy, serum levels of FT3 were decreased and TSH levels increased. Pre- and postoperative hPTH-(1-34) infusions induced increased serum levels of ionized calcium, 1,25(OH)2D, increased urinary excretion of phosphate and elevated n-cAMP levels. The changes in the studied biochemical variables during the hPTH-(1-34) infusions did not differ between the two study occasions. CONCLUSION: By using a 6-hour hPTH-(1-34) infusion protocol, we have shown that the peripheral PTH effect is not altered by a slight reduction in thyroid hormone levels at 3 months after hemithyroidectomy.

Adult↗
PubMed2000

[Homocysteine and methylmalonic acid as markers of cobalamin/folate status. The association to neuropsychiatric symptoms in the elderly is explored].

Cobalamin/folate deficiency in elderly subjects may lead to psychiatric symptoms. Most studies concerning the relation between mental disorders in the elderly and deficiencies of cobalamin and folate have used methods that determine the blood concentrations of these vitamins, which might not reflect vitamin status in the tissues. Two new markers, plasma homocysteine and serum methylmalonic acid, have attracted growing interest since they are considered to reflect the functional status of cobalamins and folates in the tissues. This review summarizes present findings concerning the different markers for cobalamin/folate deficiency as well as their association with functional parameters of the central nervous system such as cognitive and behavioral performance. Plasma homocysteine seems to be much more closely associated with neuropsychiatric dysfunction than is plasma methylmalonic acid.

Aged↗
PubMed2000

[Laboratory diagnosis of gastrinoma. Nordic collaboration can improve the quality].

Measurement of gastrin in serum or plasma in patients with gastrinoma may be complicated by the presence of circulating biosynthetic intermediates which may not be detected by commonly available immunoassays. In contrast, the "processing-independent analysis" of gastrins developed by professor Jens Rehfeld et al in Copenhagen detects gastrin forms irrespective of their size. The authors review gastrinoma pathophysiology, the biochemistry of gastrin and other biomarkers of gastrinoma, the differential diagnosis of hypergastrinemia as well as other methods currently employed in the workup of gastrinoma patients, and illustrate with a clinical case.

Biomarkers, Tumor↗
PubMed2000

PCR-generated padlock probes detect single nucleotide variation in genomic DNA.

Circularizing oligonucleotide probes, so-called padlock probes, have properties that should prove valuable in a wide range of genetic investigations, including in situ analyses, genotyping and measurement of gene expression. However, padlock probes can be difficult to obtain by standard oligonucleotide synthesis because they are relatively long and require intact 5'- and 3'-end sequences to function. We describe a PCR-based protocol for flexible small-scale enzymatic synthesis of such probes. The protocol also offers the advantage over chemical synthesis that longer probes can be made that are densely labeled with detectable functions, resulting in an increased detection signal. The utility of probes synthesized according to this protocol is demonstrated for the analysis of single nucleotide variations in human genomic DNA both in situ and in solution.

Adenosine Triphosphatases↗
PubMed2000

Hypomethylation as a cause of homocysteine-induced cell damage in human cell lines.

Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. In the present study we have investigated the possible role of hypomethylation as a cause of homocysteine-induced cell damage in two human cell lines. A significant growth retardation was observed in HeLa cell cultures in the combined presence of homocysteine and adenosine, but first at concentrations of 250 micromol/l of each. A significant decrease of intracellular glutathione concentration was noted both in the presence of homocysteine (250 micromol/l) alone and in the presence of the combination of homocysteine and adenosine (250 micromol/l). Intracellular concentration of homocysteine was increased to a similar extent both in the presence of homocysteine alone and in the presence of a combination of homocysteine and adenosine. Similar findings to those described for HeLa cell cultures were observed in endothelial cell cultures. Furthermore, in the presence of copper ions together with 100 micromol/l of adenosine and homocysteine a significantly retarded cell growth was observed in HeLa cell cultures. This finding shows that a combination of two potentially cell-damaging mechanisms (formation of oxygen radicals and hypomethylation) aggravated the retardation of cell growth compared to only one of these mechanisms being present. Thus, it is likely that several mechanisms of homocysteine-induced cell damage contribute to the increased rate of the atherogenic process observed in hyperhomocysteinemia.

Adenosine↗