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Biomedical subjects

A Hansson

Publications and source records attributed to A Hansson.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacodynamics of rituximab in kidney allotransplantation.

The anti-CD20 antibody rituximab has recently gained interest as a B-cell depleting agent in renal transplantation. However, little is known about the pharmacodynamics of rituximab in renal transplant recipients. We have therefore studied the effect of single-dose rituximab in combination with conventional triple immunosuppressive therapy on the B-cell population in peripheral blood as well as in tissues. A total of 49 renal transplant recipients received single-dose rituximab, as induction therapy (n = 36) or as anti-rejection therapy (n = 13). We counted B cells in peripheral blood and performed immunohistochemical staining on lymph nodes and kidney transplant tissue samples to assess the prevalence of B cells. In all but 6 patients (88%) complete depletion of B cells in peripheral blood was achieved. In adults, 15 months after treatment the CD19+ and CD20+ cell counts were still below 5 cells/muL in the majority of patients (78%). The immunohistochemical staining showed a complete elimination of B cells in kidney tissue and a reduction of B cells in lymph nodes. In conclusion, single-dose rituximab in kidney transplant recipients evokes a long-term elimination of B cells in peripheral blood as well as within the kidney transplant. The effect seems to extend beyond the expected 3-12 months observed in lymphoma patients.

Adult↗
PubMed2006

Measurement of the electronic transition dipole moment by Autler-Townes splitting: Comparison of three- and four-level excitation schemes for the Na2 A 1Sigma(u)+ - X 1Sigma(g)+ system.

We present a fundamentally new approach for measuring the transition dipole moment of molecular transitions, which combines the benefits of quantum interference effects, such as the Autler-Townes splitting, with the familiar R-centroid approximation. This method is superior to other experimental methods for determining the absolute value of the R-dependent electronic transition dipole moment function mu(e)(R), since it requires only an accurate measurement of the coupling laser electric field amplitude and the determination of the Rabi frequency from an Autler-Townes split fluorescence spectral line. We illustrate this method by measuring the transition dipole moment matrix element for the Na2 A 1Sigma(u)+ (v' = 25, J' = 20e)-X 1Sigma(g)+ (v" = 38, J" = 21e) rovibronic transition and compare our experimental results with our ab initio calculations. We have compared the three-level (cascade) and four-level (extended Lambda) excitation schemes and found that the latter is preferable in this case for two reasons. First, this excitation scheme takes advantage of the fact that the coupling field lower level is outside the thermal population range. As a result vibrational levels with larger wave function amplitudes at the outer turning point of vibration lead to larger transition dipole moment matrix elements and Rabi frequencies than those accessible from the equilibrium internuclear distance of the thermal population distribution. Second, the coupling laser can be "tuned" to different rovibronic transitions in order to determine the internuclear distance dependence of the electronic transition dipole moment function in the region of the R-centroid of each coupling laser transition. Thus the internuclear distance dependence of the transition moment function mu(e)(R) can be determined at several very different values of the R centroid. The measured transition dipole moment matrix element for the Na2 A 1Sigma(u)+ (v' = 25, J' = 20e)-X 1Sigma(g)+ (v" = 38, J" = 21e) transition is 5.5+/-0.2 D compared to our ab initio value of 5.9 D. By using the R-centroid approximation for this transition the corresponding experimental electronic transition dipole moment is 9.72 D at Rc = 4.81 A, in good agreement with our ab initio value of 10.55 D.

Journal Article↗
PubMed2004

Alcohol dehydrogenase 3 transcription associates with proliferation of human oral keratinocytes.

Gene expression underlying cellular growth and differentiation is only partly understood. This study analyzed transcript levels of the formaldehyde-metabolizing enzyme alcohol dehydrogenase 3 (ADH3) and various growth and differentiation-related genes in human oral keratinocytes. Culture of confluent cells both with and without fetal bovine serum inhibited colony-forming efficiency and induced a squamous morphology. Confluency alone decreased the transcript levels of ADH3, the proliferation markers cell division cycle 2 (CDC2) and proliferating cell nuclear antigen (PCNA), and the basal cell marker cytokeratin 5 (K5), but increased transcripts for the suprabasal differentiation markers involucrin (INV) and small proline-rich protein 1B (SPR1). These changes were variably influenced by serum, i.e., loss of CDC2 and PCNA was inhibited, loss of K5 promoted, increase of SPR1 transcripts inhibited, and increase of INV promoted. The extent and onset of the effects implied that ADH3 transcription serves as a proliferation marker and that confluency with or without serum exposure can serve to selectively analyze proliferative and differentiated cellular states.

Aldehyde Oxidoreductases↗
PubMed2002

Three semidominant barley mutants with single amino acid substitutions in the smallest magnesium chelatase subunit form defective AAA+ hexamers.

Many enzymes of the bacteriochlorophyll and chlorophyll biosynthesis pathways have been conserved throughout evolution, but the molecular mechanisms of the key steps remain unclear. The magnesium chelatase reaction is one of these steps, and it requires the proteins BchI, BchD, and BchH to catalyze the insertion of Mg(2+) into protoporphyrin IX upon ATP hydrolysis. Structural analyses have shown that BchI forms hexamers and belongs to the ATPases associated with various cellular activities (AAA(+)) family of proteins. AAA(+) proteins are Mg(2+)-dependent ATPases that normally form oligomeric ring structures in the presence of ATP. By using ATPase-deficient BchI subunits, we demonstrate that binding of ATP is sufficient to form BchI oligomers. Further, ATPase-deficient BchI proteins can form mixed oligomers with WT BchI. The formation of BchI oligomers is not sufficient for magnesium chelatase activity when combined with BchD and BchH. Combining WT BchI with ATPase-deficient BchI in an assay disrupts the chelatase reaction, but the presence of deficient BchI does not inhibit ATPase activity of the WT BchI. Thus, the ATPase of every WT segment of the hexamer is autonomous, but all segments of the hexamer must be capable of ATP hydrolysis for magnesium chelatase activity. We suggest that ATP hydrolysis of each BchI within the hexamer causes a conformational change of the hexamer as a whole. However, hexamers containing ATPase-deficient BchI are unable to perform this ATP-dependent conformational change, and the magnesium chelatase reaction is stalled in an early stage.

Adenosine Triphosphate↗
PubMed2001

Group I mGluR antagonist AIDA protects nigral DA cells from MPTP-induced injury.

The effects of i.c.v. injection of AIDA, a group I mGluR antagonist, were studied on the nigral DA cells after MPTP-induced injury in the black mouse, using TH immunocytochemistry and unbiased stereology. MPTP reduced the total number of TH-IR neurons by 55.2% and non-TH-IR neurons by 27.5%. A 15 min AIDA pre-treatment (10 nmol) selectively counteracted the loss of TH-IR cells caused by MPTP as evaluated 10 days after the insult without changing the total number of non-neuronal cell nuclei. The results suggest that group I mGluR antagonists may have a neuroprotective role against MPTP-induced degeneration of DA neurons and thus probably also against neurodegenerative processes occurring in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase.

In chlorophyll biosynthesis, insertion of Mg(2+) into protoporphyrin IX is catalysed in an ATP-dependent reaction by a three-subunit (BchI, BchD and BchH) enzyme magnesium chelatase. In this work we present the three-dimensional structure of the ATP-binding subunit BchI. The structure has been solved by the multiple wavelength anomalous dispersion method and refined at 2.1 A resolution to the crystallographic R-factor of 22.2 % (R(free)=24.5 %). It belongs to the chaperone-like "ATPase associated with a variety of cellular activities" (AAA) family of ATPases, with a novel arrangement of domains: the C-terminal helical domain is located behind the nucleotide-binding site, while in other known AAA module structures it is located on the top. Examination by electron microscopy of BchI solutions in the presence of ATP demonstrated that BchI, like other AAA proteins, forms oligomeric ring structures. Analysis of the amino acid sequence of subunit BchD revealed an AAA module at the N-terminal portion of the sequence and an integrin I domain at the C terminus. An acidic, proline-rich region linking these two domains is suggested to contribute to the association of BchI and BchD by binding to a positively charged cleft at the surface of the nucleotide-binding domain of BchI. Analysis of the amino acid sequences of BchI and BchH revealed integrin I domain-binding sequence motifs. These are proposed to bind the integrin I domain of BchD during the functional cycle of magnesium chelatase, linking porphyrin metallation by BchH to ATP hydrolysis by BchI. An integrin I domain and an acidic and proline-rich region have been identified in subunit CobT of cobalt chelatase, clearly demonstrating its homology to BchD. These findings, for the first time, provide an insight into the subunit organisation of magnesium chelatase and the homologous colbalt chelatase.

Adenosine Triphosphatases↗
PubMed2001

Expression of keratins in normal, immortalized and malignant oral epithelia in organotypic culture.

Keratins have been extensively studied in tissues and cultured keratinocytes but limited information is available on epithelia reconstructed in vitro. The aim of this study was to examine keratin expression in organotypic epithelia with normal (NOK), immortalized (SVpgC2a) and malignant (SqCC/Y1) human buccal cells. Organotypic epithelia were derived from 10 days of culture at the air-liquid interface of collagen gels containing human oral fibroblasts using a standardized serum-free medium. Sections were stained immunohistochemically with selected mono-specific antibodies to a range of keratins. Organotypic epithelia showed sharp differences in keratin expression and distribution. K4/K13, K1/K10, K6/K16 were variably expressed in NOK and SqCC/Y1 but were not detected in SVpgC2a. K5 was expressed in all organotypic epithelia but K14 was absent in SVpgC2a. K7 and K8 showed variable expression while K18 was expressed uniformly in all epithelia. K19 was expressed consistently in NOK and K20 was distributed heterogeneously in SVpgC2a. Overall, organotypic cultures of normal keratinocytes express many of the same keratins as buccal mucosa. Further, the loss of keratins in SVpgC2a and their retention in SqCC/Y1 have several features in common with the respective keratin profile of oral epithelial dysplasia and well-differentiated oral squamous cell carcinoma. Although qualitative and quantitative differences exist compared to keratin expression in vivo, these cell lines in organotypic culture may serve in studies of the multi-step progression of oral cancer.

Carcinoma, Squamous Cell↗
PubMed2001

Pharmacokinetics of nicotine in healthy elderly people.

BACKGROUND: Mortality hazards of smoking extend well into later life; this suggests that smoking cessation will continue to improve life expectancy in older people. The pharmacology and pharmacokinetics of nicotine have not been studied in elderly subjects. Drug disposition and pharmacodynamic responsiveness to nicotine may change with age, and conclusions founded on data from studies of younger populations may not apply to elderly populations. Our aim was to assess the pharmacokinetics of nicotine in healthy elderly subjects compared with healthy adults. METHODS: Twenty healthy elderly subjects (age, 65-76 years) and 20 healthy adult subjects (age, 22-43 years) were given an intravenous infusion of 0.028 mg/kg of nicotine over 10 minutes. Nicotine and cotinine concentrations were measured in plasma and urine. Heart rate and blood pressure were monitored. RESULTS: For most adult and elderly subjects nicotine distributed according to a two-compartment system. Even though there was a large interindividual variation within and overlap between groups, nicotine total clearance (-23%), nonrenal clearance (-21%), renal clearance (-49%), volume of central compartment (-37%), volume of distribution at steady state (-17%), and cotinine renal clearance (-18%) were statistically significantly decreased in elderly subjects compared with adults. Maximal heart rate response to nicotine was decreased in the elderly subjects (-29%). CONCLUSION: Even though statistically significant differences were observed, the disposition of nicotine does not seem to be changed to a clinically important extent in elderly subjects compared with younger adults.

Adult↗
PubMed2001

A serial study of heart function during pregnancy, lactation and the dry period in dairy goats using echocardiography.

Echocardiography and Doppler measurements were performed to investigate changes in heart dimensions and function during pregnancy, lactation and the non-pregnant, non-lactating (dry) period in dairy goats. Eight Swedish domestic goats (Capra hircus) were studied with two-dimensional (2DE), M-mode and continuous wave Doppler measurements. Cardiac dimensions did not differ between periods. The mean cardiac outputs were 35 and 28% greater during pregnancy and lactation, respectively, vs. the dry period. Arterial blood pressure (measured by telemetry) did not differ between reproductive periods before echocardiographic measurements, but became elevated during the measurements, with the smallest rise during lactation. Heart rate was elevated during pregnancy and increased further during echocardiographic measurements, but was not elevated during the other periods. The cranial location of the heart influenced the selection of examination window and caused some difficulties in positioning the ultrasound transducer. This may have led to underestimation of the velocity trace integral and therefore to underestimation of cardiac output. However, our values were within the range of these obtained with dye- and thermodilution methods. The goats tolerated the investigations well during lactation and the dry period, but showed increased blood pressure and heart rate during pregnancy. Therefore, the non-invasive and safe echocardiographic-Doppler method appears to be a good alternative for studies of heart dimensions and function during lactation and the dry period in the dairy goat.

Animals↗
PubMed2000

Rapid Ca2+ influx and diacylglycerol synthesis in growth hormone-mediated islet beta -cell mitogenesis.

Growth hormone (GH) is an important mitogenic stimulus for the insulin-producing beta-cell. We investigated the effects of GH on Ca(2+) handling and diacylglycerol (DAG) and cAMP formation in the beta-cell. GH elicited a rapid increase in the cytoplasmic free [Ca(2+)], which required extracellular Ca(2+) and was also blocked by pertussis toxin or protein kinase C (PKC) inhibition. GH also elevated islet DAG content, which should lead to PKC activation. Pertussis toxin and PKC inhibitors obliterated the mitogenicity of GH, suggesting involvement of GTP-binding proteins. PKC activation stimulated beta-cell proliferation, and it also activated phospholipase D. Islet cAMP content was not elevated by GH. Addition of a specific protein kinase A antagonist failed to influence the mitogenicity of GH, whereas a stimulatory cAMP agonist stimulated beta-cell replication. We conclude that GH rapidly increases the beta-cell cytoplasmic free [Ca(2+)] and also evokes a similar increase in DAG content via a phosphatidylcholine-specific phospholipase C, but does not affect mitogen-activated protein kinases, phospholipase D, or the cAMP signaling pathway. This rise in DAG may be of importance in translation of the stimulatory signal of GH into a proliferative response by the beta-cell, which seems to occur through GTP-binding proteins and PKC-dependent mechanisms.

Animals↗
PubMed2000

Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy.

We recently described a mouse model that reproduces important pathophysiological features of mitochondrial DNA (mtDNA) mutation diseases. The gene for mouse mitochondrial transcription factor A, Tfam (also called mtTFA), a nucleus-encoded key regulator of mtDNA expression, was targeted with loxP sites (Tfam(loxP)) and disrupted in vivo by transgenic expression of cre-recombinase from the muscle creatinine kinase (Ckmm) promoter. This promoter is active from embryonic day 13, and the knockouts had normal respiratory chain function in the heart at birth and developed mitochondrial cardiomyopathy postnatally. In this paper, we describe a heart-knockout strain obtained by mating Tfam(loxP) mice to animals expressing cre-recombinase from the alpha-myosin heavy chain (Myhca) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction can thus be controlled by temporal regulation of cre-recombinase expression. Further characterization demonstrated that approximately 75% of the knockouts died in the neonatal period, whereas, surprisingly, approximately 25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying gene(s) affect the life span of the knockouts, because approximately 95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts we describe here not only reproduce important pathophysiological features of mitochondrial cardiomyopathy but also provide a powerful system by which to identify modifying genes of potential therapeutic value.

Animals↗
PubMed2000

Structural and mechanistic basis of porphyrin metallation by ferrochelatase.

Ferrochelatase, the enzyme catalyzing metallation of protoporphyrin IX at the terminal step of heme biosynthesis, was co-crystallized with an isomer mixture of the potent inhibitor N-methylmesoporphyrin (N-MeMP). The X-ray structure revealed the active site of the enzyme, to which only one of the isomers was bound, and for the first time allowed characterization of the mode of porphyrin macrocycle distortion by ferrochelatase. Crystallization of ferrochelatase and N-MeMP in the presence of Cu(2+) leads to metallation and demethylation of N-MeMP. A mechanism of porphyrin distortion is proposed, which assumes that the enzyme holds pyrrole rings B, C and D in a vice-like grip and forces a 36 degrees tilt on ring A.

Amino Acid Sequence↗
PubMed2000

A vesicle capture sensor chip for kinetic analysis of interactions with membrane-bound receptors.

A novel sensor chip for use in surface plasmon resonance (SPR) biosensors has been developed to capture vesicles which may contain membrane-bound receptors. Sulforhodamine-containing vesicles were shown by fluorescence microscopy to be immobilized intact on the sensor chip. Binding of cholera toxin to captured vesicles containing ganglioside GM(1) was demonstrated using SPR, and the derived kinetic and affinity constants were similar to literature values. Biotinylated vesicles captured on the sensor chip were used to bind streptavidin and then biotinylated ss-DNA. The hybridization of complementary ss-DNA to the immobilized ss-DNA was then analyzed using SPR. The values obtained were similar to those obtained for an identical interaction analyzed using a commercially available streptavidin-containing sensor chip. Binding of vancomycin-group antibiotics to captured vesicles containing a bacterial cell wall mucopeptide analogue was demonstrated. No binding of the bacterial endotoxin Cry1A(c) to captured vesicles containing its cell surface receptor could be demonstrated.

Animals↗
PubMed2000

Detection of inter-atrial conduction defects with unfiltered signal-averaged P-wave ECG in patients with lone atrial fibrillation.

AIMS: To demonstrate a possible inter-atrial conduction delay in patients with lone paroxysmal atrial fibrillation (PAF) using 'unfiltered' signal-averaged P-wave ECG (PSAECG) and compare these results with those obtained with conventional filter settings. METHODS AND RESULTS: Twenty one patients with lone PAF and 20 healthy volunteers (control group) were enrolled in the study. An orthogonal lead surface ECG was high-pass filtered at 0.8 Hz, averaged with template matching, and combined into a spatial magnitude ('unfiltered' technique). Results were compared with conventionally filtered (40-300 Hz) PSAECG. The filtered technique revealed no differences in P-wave duration between the two groups (121 +/- 12 vs 128 +/- 15 ms, control and PAF groups respectively, ns). Double-peaked P-wave spatial magnitudes (interpeak distance >30 ms) were revealed in 11 of 21 PAF patients but only in two of 18 controls (P<0.01). The nadir in the spatial magnitude was located significantly later in the PAF group (114 +/- 13 vs 103 +/- 9 ms, P<0.01). CONCLUSION: 'Unfiltered' PSAECG revealed significant differences in orthogonal P-wave morphology in patients with lone PAF, indicating the possibility of an inter-atrial conduction delay, while conventional P-wave duration analysis failed to discriminate between the two groups.

Adult↗
PubMed2000

Pharmacokinetics of nicotine in kidney failure.

BACKGROUND: Smoking is an important risk factor for cardiovascular and cerebrovascular complications in patients with chronic kidney failure. Very high plasma nicotine concentrations have been reported in patients with severe kidney failure, indicating that the disposition of nicotine in these patients may be different. The purpose of this study was to assess the pharmacokinetics of intravenously administered nicotine in healthy subjects and in patients with kidney failure. METHODS: Nine healthy subjects (glomerular filtration rate [GFR], 84 to 143 mL/min/1.73 m2), four patients with mild kidney failure (GFR, 63 to 73 mL/min/1.73 m2), five patients with moderate kidney failure (GFR, 18 to 36 mL/min/1.73 m2), and six patients with severe kidney failure (GFR, 1 to 10 mL/min/1.73 m2) were recruited. Three patients were treated with continuous ambulatory peritoneal dialysis. An intravenous infusion of nicotine (0.028 mg/kg) was given for 10 minutes. Nicotine and cotinine concentrations were measured in plasma, urine, and peritoneal dialysate from 0 to 24 hours after start of infusion RESULTS: There were significant correlations between GFR and total clearance, nonrenal and renal clearance of nicotine, area under the plasma concentration-time curve extrapolated to infinity, terminal elimination half-life, and mean residence time. Nonrenal clearance was 1303 mL/min and 661 mL/min in healthy subjects and patients with severe kidney failure, respectively. Only 1% to 2% of the nicotine dose was excreted unchanged in a 24-hour collection of peritoneal dialysate. The elimination of cotinine was also decreased in patients with kidney failure. CONCLUSION: Progressive kidney failure is associated with a gradual decrease of renal and nonrenal elimination of nicotine.

Adult↗