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Biomedical subjects

A Nilsson

Publications and source records attributed to A Nilsson.

At least 127 records · Page 7Linked to original sources
PubMed1999

Cell cycle-dependent regulation of the DNA-dependent protein kinase.

Human DNA-dependent protein kinase (DNA-PK) is a nuclear-localized serine/threonine protein kinase. The holoenzyme consists of a catalytic subunit with a molecular mass of 465 kDa and a DNA-binding heterodimer Ku86/70. The kinase has been implicated in a variety of nuclear processes including V(D)J recombination, double-strand break repair, and transcription. Cells with defective DNA-PK activity show increased radiosensitivity and lack of V(D)J recombination. To study DNA-PK activity during the cell cycle, HeLa cells were separated by elutriation centrifugation into different cell cycle compartments based on cellular size. DNA-PK activity was found to vary during the cell cycle. The kinase activity was lowest during G1 phase and increased dramatically as the cells entered S phase and remained high during the G2-phase. The subcellular distribution of DNA-PKcs is relocalized from the cytoplasm during M and G1 phases to the nucleus during G1-S phase transition and S phase. Expression of both the catalytic subunit and the Ku86/70 heterodimer was found to be constant throughout the cell cycle. This study demonstrates that DNA-PK activity as well as its subcellular localization fluctuates during the cell cycle. In addition, the distribution of DNA-PK during M phase corresponds with low DNA-PK activity.

Blotting, Western↗
PubMed1999

Bruton's tyrosine-kinase-deficient murine B lymphocytes fail to enter S phase when stimulated with anti-immunoglobulin plus interleukin-4.

One of the earliest recognized defects of B cells carrying the xid mutation in the gene encoding for Bruton's tyrosine kinase (Btk) was their inability to proliferate in response to anti-immunoglobulin plus interleukin (IL)-4 stimulation. Previous attempts to define the stage at which this proliferative block occurred using xid B cells provided dissimilar results. We decided to reinvestigate this question using B cells from C57BL/6-Btk-protein-deficient (BtkM) mice. Upon stimulation with anti-IgM and IL-4, BtkM cells increase in size and up-regulate early activation markers such as CD69 and B7-2, however, they do not progress into the cell cycle further than a very early G1 stage. They down-regulate the cyclin-dependent kinase (cdk) inhibitor p27 to some extent but fail to up-regulate the G1-phase cyclins D2 and E and the retinoblastoma protein (pRb) remains hypo-phosphorylated. While approximately 25% of the wild-type cells enter S phase after 36 h stimulation, only 1% of the BtkM cells do so. The proliferative responsiveness of the BtkM cells is restored when the phorbol ester phorbol 12,13-di-butyrate (PDBu) is added to the anti-IgM plus IL-4 cultures. Collectively, our data demonstrate that a dramatically reduced frequency of responsive cells underlies the low proliferation of anti-IgM plus IL-4-stimulated Btk-deficient B cells and point towards an early block in the G1 phase due to inadequate activation of a pathway that regulates PKC activation.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Ursodeoxycholic acid increases the activities of alkaline sphingomyelinase and caspase-3 in the rat colon.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been found to inhibit the development of colon carcinoma induced by chemical carcinogens with unidentified mechanisms. Sphingomyelin metabolism has emerged as a novel signal transduction pathway closely related to cell proliferation and apoptosis. We recently found that alkaline sphingomyelinase (SMase) activity was decreased in human colon cancer. The present study is to investigate whether UDCA has effect on the levels of SMase and whether the activity of caspase-3, a key regulatory protease in apoptosis that can be activated by sphingomyelin breakdown products, is also influenced by UDCA. METHODS: Rats were fed UDCA in amounts ranging from 37.5 to 300 mg/kg/day for 10 days by gavage. The colonic mucosa was scraped, homogenized, and sonicated. The activities of acid, neutral and alkaline SMases, and caspase-3 were determined. RESULTS: UDCA dose-dependently increased alkaline SMase activity in colonic mucosa and faeces, slightly increased acid SMase activity in the mucosa, and had no effect on neutral SMase. UDCA also dose-dependently increased caspase-3 activity in the colonic mucosa, and the increase correlated significantly with the changes in alkaline but not that in acid or neutral SMase activity. CONCLUSIONS: UDCA increases alkaline sphingomyelinase and caspase-3 activities, which might be a mechanism involved in its anticarcinogenic effect on colon cancer development.

Acid Phosphatase↗
PubMed1999

Distribution and elimination of the solute and water components of urological irrigating fluids.

OBJECTIVE: Irrigating fluids are used to dilate mucosal spaces and to remove blood and cut tissue from the operating field during endoscopic procedures. We have studied their disposition, since irrigating solutions are sometimes absorbed and may therefore be regarded as intravenous drugs. MATERIAL AND METHODS: The distribution and the rate of elimination of four irrigating fluids containing glycine, mannitol and sorbitol were studied after infusing 0.75 ml/kg/min of them over a period of 20 min in 10 male volunteers. Kinetic calculations were based on 12 blood samples collected over 120 min using traditional pharmacokinetics for the solutes and volume kinetics for the water component. RESULTS: The solutes had distribution half-lives of between 3 and 7 min; the elimination half-lives were 39 min (glycine), 97 min (mannitol) and 33 min (sorbitol). The volume of distribution during steady state was between 20 and 36 litres, while the volume of the body fluid space expanded by the water component of the irrigating fluids varied between 6 and 9 litres. Although the solutes became distributed over a much larger space than the infused fluid volume, the intersubject variation was smaller for the solute concentrations than for the dilution of the plasma fraction of the blood. CONCLUSIONS: The kinetics of the solute and water components of urological irrigating fluids can be analysed and compared using computer-based mathematical models.

Adult↗
PubMed1999

Direct transcriptional control of the chloroplast genes psbA and psaAB adjusts photosynthesis to light energy distribution in plants.

Two photosystems, I and II, absorb and convert light energy in photosynthesis in chloroplasts of green plants. The genes psbA and psaAB of the cytoplasmic chloroplast genome encode core components of photosystem II and photosystem I, respectively. Here we show that the absolute amounts of photosystem I and photosystem II respond, in a complementary manner, to changes in light quality that preferentially excite each photosystem in mustard seedlings. We also show that the initial response to altered energy distribution is a change in the rates of transcription of psbA and psaAB. Changes in chlorophyll fluorescence emission in vivo suggest that the signal initiating this change is the oxidation-reduction state of plastoquinone, a component of the photosynthetic electron transport chain that connects photosystem I and photosystem II. The results are consistent with transcriptional effects observed previously with chloroplasts isolated in vitro and demonstrate that redox control of chloroplast transcription initiates long-term adjustments that compensate for imbalance in energy distribution and adapt the whole plant to altered light environments.

Chloroplasts↗
PubMed1999

Postnatal time frame for renal vulnerability to enalapril in rats.

Angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade in neonatal, but not in weaned, rats induces irreversible renal histologic abnormalities and an impaired urinary concentrating ability. The aim of the present study was to define the postnatal time frame when the rat kidney is vulnerable to an interruption of the renin-angiotensin system. Male Wistar rats received daily injections of enalapril (10 mg/kg, intraperitoneally) during different age intervals within 3 to 24 d,of age. Fluid handling and urinary concentrating ability, renal function under pentobarbital anesthesia, and kidney histology using stereologic techniques were evaluated in adult rats. Enalapril treatment within 3 to 13 d after birth induced abnormalities in renal function and morphology long-term, whereas treatment initiated at 14 d of age did not. The main histologic alterations were papillary atrophy, and a reduction in the volume of tubular epithelial cells in association with an increase in the proportion of interstitium, throughout the cortex and outer medulla. Functionally, the predominant defect was an impairment in urinary concentrating ability, which correlated with the degree of papillary atrophy. In conclusion, the vulnerable age interval for the induction of irreversible renal abnormalities by enalapril was the first 13 d after birth in the rat. This postnatal time span coincides with the completion of nephrogenesis and a period of marked tubular growth and differentiation, suggesting a pivotal role for angiotensin II in these processes.

Age Factors↗
PubMed1999

Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.

The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.

Alleles↗
PubMed1999

Transportation and storage of cryosections in PBS-Dulbecco.

Tissue pieces that cannot be fixed and embedded before immunostaining must be cryosectioned and stained quickly. We describe an easy and reliable technique to keep cryosections with immune complexes and complement stored for several weeks until the final immunostaining. The same technique was used for long distance transportation of cryosections and it was extensively tested for human kidney biopsies with excellent results.

Animals↗
PubMed1999

Power Doppler ultrasonography: alternative to computed tomography in abdominal trauma patients.

The aim of this study was to determine if power Doppler ultrasonography, contrast enhanced when necessary, can be used as an alternative to computed tomography in the diagnosis of trauma-related organ rupture or hematoma. Fifteen patients who had sustained abdominal trauma but who had normal results on B-mode scans were included in the study. Twenty organs (13 livers and 7 spleens) were examined with both contrast-enhanced computed tomography and power Doppler ultrasonography in a blinded fashion. Ultrasonographic contrast was used in five patients. Lack of contrast enhancement (computed tomography) or lack of color in power color Doppler ultrasonography in all or part of the organ was taken as a sign of rupture or hematoma. Five ruptures were detected with both modalities (two hepatic and three splenic). Thus, ultrasonography showed no false-positive or false-negative studies when compared to the computed tomographic results. No significant difference was found in the estimated size of the damaged area between the two types of investigation. The study indicates that power color Doppler ultrasonography may be considered an alternative when a computed tomographic scan of a trauma patient is impossible.

Abdomen↗
PubMed1999

Lithium therapy and suicide risk.

BACKGROUND: Studies from the early 90s have suggested that patients selected for and compliant with treatment at specialized lithium clinics have lower-than-expected suicide rates. The present study examines whether such findings can be replicated under less select treatment conditions. METHOD: All 362 patients in Göteborg, Sweden, with DSM-III-R mood or schizoaffective disorders, hospitalized at least once during an 8-year period and treated with lithium for a minimum of 1 year, were followed. The study included 3911 patient-years on lithium and, because of permanent or temporary discontinuation, 1274 patient-years off lithium. RESULTS: The risk of suicide was significantly increased on (standard mortality ratio [SMR] = 6.1) as well as off lithium (SMR = 29.0), but the relative risk of suicide was 4.8 times higher during periods off lithium (p < .02; 95% confidence limits 1.1 to 12.6). Ongoing lithium treatment was associated with a 77% reduction in the risk of suicide, whereas alcohol or drug abuse was associated with a 284% increased risk. CONCLUSION: The findings suggest that ongoing lithium treatment is associated with a lower suicide risk. Whether this is due to lithium's mood-stabilizing properties, to lower suicide risk per se in the patients who remain in treatment, or to a specific antisuicidal effect of the lithium ion cannot be determined since patients were not randomized to discontinue treatment. This methodological shortcoming is shared with every study in the field. All results regarding the influence of lithium on suicide rates must therefore be interpreted with extreme caution.

Cause of Death↗
PubMed1999

MAOA: association and linkage studies with lithium responsive bipolar disorder.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

Alleles↗
PubMed1998

Fatty acid alpha-oxidation of tetradecylthioacetic acid and tetradecylthiopropionic acid in cucumber (Cucumis sativus).

Fatty acid alpha-oxidation in cucumber (Cucumis sativus) involves enzymatic conversion of long-chain Cn-fatty acids to the C(n-1)-aldehyde and CO2. However, the mechanism of this process is not well understood. In this study, the alpha-oxidation of the fatty acid analogues tetradecylthioacetic acid (TTA) and tetradecylthiopropionic acid (TTP) with a sulphur atom substituting the methylene group in positions 3 and 4, respectively, was investigated and compared to palmitic acid. Both [1-14C]TTA and [1-14C]TTP could be alpha-oxidised in the cucumber subcellular 150000xgmax fraction. [1-14C]TTP was an even better substrate compared to the natural palmitic acid, while [1-14C]TTA was alpha-oxidised to a lower extent. [2-14C]TTA revealed no 14CO2, indicating that only one cycle of alpha-oxidation occurred. TTA was an inhibitor of the palmitic acid alpha-oxidation, and the inhibitory effects were examined.

Animals↗
PubMed1998

Detection of threonine structural changes upon formation of the M-intermediate of bacteriorhodopsin: evidence for assignment to Thr-89.

The behavior of threonine residues in the bacteriorhodopsin (bR) photocycle has been investigated by Fourier transform infrared difference spectroscopy. L-Threonine labeled at the hydroxyl group with 18O (L-[3-(18)O]threonine) was incorporated into bR and the bR-->M FTIR difference spectra measured. Bands are assigned to threonine vibrational modes on the basis of 18O induced isotope frequency shifts and normal mode calculations. In the 3500 cm-1 region, a negative band is assigned to the OH stretch of threonine. In the 1125 cm-1 region, a negative band is assigned to a mixed CH3 rock/CO stretch mode. The frequency of both these bands indicates the presence of at least one hydrogen bonded threonine hydroxyl group in light adapted bR which undergoes a change in structure by formation of the M intermediate. Spectral changes induced by the substitution Thr-89-->Asn but not Thr-46-->Asn or Asp-96-->Asn are consistent with the assignment of these bands to Thr-89. These results along with another related study on the mutant Thr-89-->Asn indicate that the active site of bR includes Thr-89 and that its interaction with the retinylidene Schiff base and Asp-85 may play an important role in regulating the color of bacteriorhodopsin and the transfer of a proton to the Schiff base.

Bacteriorhodopsins↗
PubMed1998

Laser-based spectroscopic methods in tissue characterization.

Laser-based spectroscopic techniques were developed for tumor tissue characterization utilizing different tumor-localizing substances. In particular, sensitization with the heme precursor delta-amino levulinic acid (ALA) administered topically, orally or intravenously was used for the induction of protoporphyrin IX (PpIX). The autofluorescence as well as the PpIX-related fluorescence signals were monitored, and tumor demarcation functions were calculated for different human malignant tumors, such as tumors in the urinary bladder and the prostatic gland, in the head and neck region, in the breast and in the gastrointestinal tract. In the gastrointestinal tract, colon tumors were examined as well as tumors and dysplastic lesions in the esophagus, where patients with Barrett's esophagus were examined. Time-integrated laser-induced fluorescence measurements utilizing a point monitoring fluorosensor and a multicolor fluorescence imaging system were performed in vivo in patients in different clinical specialities.

Fluorescence↗
PubMed1998

Higher spontaneous apoptotic index in small cell compared with non-small cell lung carcinoma cell lines; lack of correlation with Bcl-2/Bax.

Spontaneous apoptosis was assessed in ten small-cell (SCLC) and five non-small cell (NSCLC) lung carcinoma cell lines by the TUNEL assay and chromatin cleavage. TUNEL staining showed significantly higher apoptotic index (AI) in SCLC (2-20%) compared with NSCLC lines (0.2-1%) in untreated exponentially growing cells. Six out of ten SCLC and none of the NSCLC showed DNA fragmentation when analysed by agarose gel electrophoresis. Field inversion pulse gel electrophoresis was used in a subset of cell lines and showed the presence of high molecular weight fragments in untreated SCLC lines U-1285 and U-1906 cells, but not in the NSCLC line U-1810. Important molecular determinants of apoptosis were studied by Western blot. Bcl-2 was detected at highest level in SCLC. There was no correlation between the ratio Bcl-2/Bax and AI in all tested cell lines. Neither p53 nor c-Myc protein status correlated to AI. Pro-caspase-3 was expressed in all cell lines without correlation to AI and no difference between the SCLC and NSCLC groups was found. In conclusion, this study shows a high degree of spontaneous apoptosis in SCLC lines compared to NSCLC lines unrelated to Bcl-2/Bax ratio.

Apoptosis↗
PubMed1998

Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis.

Previous studies showed that bile salts had a promoting effect on colon cancer development and this effect was inhibited by ursodeoxycholate (UDC). We recently found that both human colorectal adenomas and carcinomas were associated with a specific decrease in alkaline sphingomyelinase activity. In this work, we compared the effects of ursodeoxycholate and other bile salts on the levels of rat intestinal alkaline sphingomyelinase both in the intestinal loops and after oral administration. Bile salts at different concentrations were injected into intestinal loops and the dissociation of alkaline sphingomyelinase from the mucosa was assayed. We found that bile salts, including taurocholate, taurodeoxycholate, glycocholate, glycochenodeoxycholate, and 3-(3-cholamidopropyl dimethylammonio)-1-propanesulonate (CHAPS), dose dependently dissociated alkaline sphingomyelinase from the intestinal mucosa. UDC alone did not dissociate the enzyme but significantly inhibited the dissociation caused by other bile salts and CHAPS. Feeding rats with 0.3% (w/w) taurocholate for four days decreased peak activity of intestinal alkaline sphingomyelinase by 39% and total activity in the intestine by 20% and increased the output of the enzyme in the feces. In contrast, feeding 0.3% (w/w) UDC for four days increased the peak activity of alkaline sphingomyelinase in the small intestine by 87% and the activity in the colon by 187%. The total activity of alkaline sphingomyelinase was increased by 80% and the output of the enzyme in the feces was only slightly increased by UDC administration. The changes in alkaline phosphatase after feeding taurocholate and UDC were much smaller. Our results indicate that UDC and other bile salts have different effects on the levels of alkaline sphingomyelinase, which may be implicated in their different influences on cancer development reported previously.

Administration, Oral↗
PubMed1998

Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

Adult↗