New directions in dentistry: an exclusive interview with Dr. Gordon Christensen. Interview by Phillip Bonner.
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Humans↗
Biomedical subjects
G Christensen
Publications and source records attributed to G Christensen.
Thyroid hormone control of contraction and the Ca(2+)-ATPase/phospholamban complex in adult rat ventricular myocytes.
Thyroid hormones may have important long-term effects on cellular Ca2+ handling in the heart. We investigated isolated adult rat cardiomyocytes in a primary culture exposed (T3-cells) or not exposed to (control cells) 10(-8) M triiodothyronine (T3) for 48 h. Northern blot analysis revealed reciprocal alterations in the expression of SERCA2 and phospholamban. The ratio of the SERCA2/phospholamban signal was approximately 10 times higher in the T3-cells as compared with the control cells (P < 0.05). Phospholamban protein content was significantly reduced by 33% but SR-Ca(2+)-ATPase protein content was not significantly altered in T3-cells. These results were associated with functional alterations measured by an inverted microscope equipped to monitor fluorescence at two excitation wavelengths as well as cell shortening by a video edge detection unit. The peak calcium transients as measured by fura-2 acetoxymethyl ester (AM) were increased significantly during stimulation at 0.25 and 0.5 Hz in T3-cells compared with control cells (P < 0.05). The monoexponential decline of the fura-2 transient was significantly faster at all frequencies in the T3-cells as compared with control cells (P < 0.05). Interestingly, we observed blunted responses to both isoproterenol stimulation and post rest potentiation in the T3-cells. The intracellular level of sodium as represented by SBFI-AM was significantly lower in the T3-cells compared with the control cells (P < 0.05). The increased SR-Ca(2+)-ATPase/phospholamban ratio and decrease in phospholamban protein content in T3-treated cells was reflected in a parallel increase of contraction and calcium transients and more rapid Ca2+ reuptake, but the post-rest potentiation and response to isoproterenol were reduced.
Animals↗
Treatment of a Class III malocclusion with maxillary constriction and an anterior functional shift.
This case was chosen by the CDABO student case selection committee for publication in the AJO/DO.
Adolescent↗
Dentistry at the turn of the century: an interview with Dr. Gordon Christensen. Interview by Phillip Bonner.
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Air Abrasion, Dental↗
Associations between behavioural indicators of "stress" in weaner pigs and respiratory lesions at slaughter.
The aim of the study was to investigate associations on the individual-pig level between eight behavioural indicators of 'stress' (defined in a very general sense), in seven to eight-week old piglets four weeks after weaning and the occurrence of atrophic rhinitis (AR) and chronic pleuritis (CP) at slaughter. The study was designed as a cohort study, including 512 pigs from two commercial farms. With one exception Actinobacillus pleuropneumoniae serotype 2 (App2) infection was not associated with any of the behaviour patterns observed. Using random-effects logistic regression, weak statistical associations, positive as well as negative, were found between the performance of several behaviour patterns and the two pathological lesions. This suggests the existence of biological associations between oral behaviour patterns in young pigs and the health status later in life. However, the results were not consistent between specific oral behaviour patterns or between the two herds indicating that the associations found are either due to chance or reflect the existence of herd-specific confounders. Therefore, results based on studies within only one herd should not be generalized to other herds without care. Behavioural observations on seven- to eight-week-old piglets on the basis of the present investigation cannot be recommended for use as early predictors of AR or CP at slaughter. Further studies are needed in order to elucidate causal relations between behaviour and health.
Abattoirs↗
Reduced myocardial Na+, K(+)-pump capacity in congestive heart failure following myocardial infarction in rats.
We examined changes in expression and function of the cardiac Na+, K(+)-pump in a post-infarction rat model of hypertrophy and congestive heart failure (CHF). Myocardial infarction was induced by ligation of the left coronary artery in Wistar rats and hearts were obtained from animals with CHF and from sham operated rats after 6 weeks. In the CHF group the ratio of heart weight to body weight was 70% greater compared to sham (*P < 0.05) and all left-ventricular end-diastolic pressures (LVEDP) were above 15 mmHg. The expression of the alpha 1- and beta 1-subunits (mRNA and protein) of the Na+, K(+)-pump was not significantly different in CHF and sham. As compared to sham the alpha 2 isoform, mRNA and protein levels were lower in CHF hearts by 25 and 55%, respectively, whereas the alpha 3 isoform mRNA was greater by 120% in CHF. The alpha 3 protein was not detectable in sham but a prominent band was seen in CHF. Cell volume of isolated cardiomyocytes was 30% larger in CHF. Cardiomyocytes containing the Na+ sensitive fluorescent dye SBFI were loaded to an intracellular Na+ concentration ([Na+]i] of about 140 mM in a K(+)- and Mg(2+)-free medium (140 mM Na+, free Ca2+ of 10(-8) M). To avoid back leak of Na+ and to ensure no voltage effects on the Na+, K(+)-pump extracellular Na+ was subsequently removed, and 6 mM Mg2+ was added to the superfusate, The Na+, K(+)-pump was then reactivated by 10 mM Rb+. SBFI fluorescence ratio decreased mono-exponentially with a time constant (tau) of 191 +/- 15 s in sham (n = 8) and 320 +/- 38 s in CHF (n = 9) rats (P < 0.01). These changes in fluorescence indicate that the maximum rate of decline of [Na+]i from 100 to 35 mM was 39% (P < 0.005) slower in CHF compared to sham, whereas maximum pump rate per cell was not significantly altered (9.0 +/- 0.7 fmol/s in sham and 7.1 +/- 0.7 fmol/s in CHF cells). The [Na+]i which caused 50% pump activation (k0.5) was also not altered in CHF (40 mM in both groups). We conclude that the number of Na+, K(+)-pumps per cell was maintained in CHF but an isoform switch of the alpha 3-replacing the alpha 2-isoform occurred. However, maximum Na+, K(+)-pump rate in terms of rate of change of [Na+]i was significantly attenuated in CHF, most likely as a result of increased cell size.
Animals↗
Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats.
Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is scarce. In rats with congestive heart failure (CHF), we examined cardiomyocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventricular pressure was reduced and diastolic pressure was markedly increased in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts had increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.01 for all). Peak L-type calcium currents were not significantly changed, but peak calcium transients measured with fura-2 were reduced by 19% (P<0.01). Moreover, the decline of the calcium transients as measured by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the Ca2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytosolic Ca2+ during relaxation by superfusing cells with 1 microM thapsigargin that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-cells was significantly less prolonged when this drug was used (P<0.01). This suggests that other mechanisms, probably the Na+-Ca2+ exchanger, contribute significantly to the relaxation rate in CHF. Simultaneous measurements of fura-2 transients and mechanical shortening did not reveal any alteration in the calcium-myofilament sensitivity in CHF. Our study clearly shows reduced shortening and prolonged relaxation in cardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardiomyocyte dysfunction to changes in specific steps in the excitation-contraction coupling.
Actin Cytoskeleton↗
Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide.
OBJECTIVES: Recent reports indicate that endothelin (ET) plays an important pathophysiological role in congestive heart failure (CHF). However, existing data on local cardiopulmonary ET production are few. No studies have hitherto examined the specific anatomic localization of cardiopulmonary ET synthesis in CHF. Thus, the aims of the present study were to examine whether cardiopulmonary preproET-1 mRNA synthesis is upregulated in CHF and to determine the anatomic localization of preproET-1 mRNA and the mature peptide. METHODS: CHF was induced in rats by occluding the left coronary artery. Only animals with a left ventricular end-diastolic pressure above 15 mmHg after one week were included (n = 28). Sham-operated animals served as controls (n = 24). Hearts and lungs were examined by mRNA slot blot analyses, in situ hybridization (ISH) and immunohistochemistry (IHC). RESULTS: In CHF-rats, slot blot analyses revealed a 3.5 +/- 1.1-fold and a 6.4 +/- 0.8-fold upregulation of preproET-1 mRNA in the noninfarcted and the infarcted area of the left ventricles, respectively (p < 0.05 for both). ISH revealed that the preproET-1 mRNA was localized predominantly over the granulation tissue in the infarcted region. The ET peptide was predominantly localized to inflammatory cells and remaining cardiomyocytes in the infarcted region as determined by IHC. Lungs from CHF-rats showed a 1.5 +/- 0.1-fold upregulation of preproET-1 mRNA (p = 0.01). The most abundant preproET-1 mRNA and ET-1-like-immunoreactivity (ET-1-ir) was seen over inflammatory cells and over airway epithelial cells. Some ET-1-ir was also located to bronchial and vascular smooth muscle cells. CONCLUSION: Increased cardiopulmonary ET synthesis strongly suggest a pathophysiological role for ET in CHF.
Animals↗
Increased synthesis and release of endothelin-1 during the initial phase of airway inflammation.
Recently, we have shown a substantial increase in the endothelin-1 (ET-1) concentration in bronchoalveolar fluid (BALF) during an experimental eosinophilic airway inflammation. Moreover, we observed a significant inhibition of the inflammatory response after treatment with an endothelin receptor antagonist. This indicates that ET-1 may have proinflammatory properties and play a key role in eosinophilic inflammations, such as bronchial asthma. Accordingly, we hypothesized that the synthesis and release of ET-1 precedes the inflammatory response, and that the bronchial epithelium is the site of ET-1 synthesis in the lungs. An eosinophilic airway inflammation was induced by intratracheal Sephadex instillation in rats, and the animals were evaluated after 15 min, 30 min, 1, 2, 3, 6, 12, and 48 h. The ET-1 mRNA synthesis, assessed by Northern and slot blot analyses, was significantly increased 15 min after Sephadex challenge, peaking at 30 min with a 4.7-fold increase, before any signs of inflammation in the BALF could be observed. The increased synthesis was mainly located to the bronchial epithelium and macrophages at sites of inflammation as determined by in situ hybridization. A significant increase in tissue ET-1 was observed 3 h after provocation, and the recruitment of eosinophils followed a substantial release of ET-1 peptide in BALF peaking at 24 h with a 13-fold increase. Therefore, the rapid ET-1 mRNA synthesis and the considerable increase in the level of ET-1 indicate that this peptide plays an important role in the initiation of an eosinophilic airway inflammation.
Animals↗
Benzalkonium chloride. A potential disinfecting irrigation solution for orthopaedic wounds.
The efficacy of benzalkonium chloride was evaluated as an irrigating solution for the eradication of Staphylococcus aureus from a contaminated orthopaedic wound. Thirty Sprague Dawley rats were randomized into two groups. A stainless steel wire was placed in a lumbar spinous process, and the wound was inoculated with 10(7) or 10(6) colony forming units of Staphylococcus aureus. The wound was irrigated with 1 L of normal saline or 0.1% benzalkonium chloride solution. The animals were sacrificed, and cultures were obtained. Rats inoculated with 10(7) colony forming units of Staphylococcus aureus and irrigated with benzalkonium chloride had a significant decrease in the total number of positive cultures, deep wound cultures, and stainless steel wire cultures. Rats inoculated with 10(6) colony forming units of Staphylococcus aureus and irrigated with benzalkonium chloride also had a significant decrease in the total number of positive cultures, deep wound cultures, and stainless steel wire cultures. In a parallel noninoculation study, histologic evaluation of tissues did not show toxicity in the rats irrigated with benzalkonium chloride. This study shows that benzalkonium chloride is more effective than normal saline as an irrigating agent for eradicating Staphylococcus aureus from a contaminated orthopaedic wound.
Animals↗
[Relationship between profession and salary].
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Clinical Competence↗
Electrical stimulation of adult rat cardiomyocytes in culture improves contractile properties and is associated with altered calcium handling.
A major limitation in long-term studies of quiescent adult cadiomyocytes in culture has been the decline in contractile properties of the cells over time. Regular contracting cardiomyocyte cultures may represent a more physiological model. The aim of the present study was to investigate the mechanical properties and calcium handling of myocytes after 24 hours of electrical stimulation at 1 Hz. In a random and blind design, stimulated (S) and unstimulated (U) myocytes were examined using an inverted microscope which allows continuous length recordings and measurements of intracellular Ca2+. Fractional shortening examined at 0.25 Hz was 14.67 +/- 0.51% in S cells and was not significantly different from U cells. However, at higher frequencies we found a significant difference in mechanical properties between the two groups. At 2 Hz fractional shortening was 12.03 +/- 0.67% in S cells, but only 8.07 +/- 0.94% U cells (P < 0.05). We were able to abolish the difference between the two groups by stimulating with the beta-adrenergic agonist isoproterenol. Measurements of Ca2+ transients were made at 1 Hz after loading with fura 2-AM. Peak fura 2 ratio was 25.4% greater in S cell compared to U cells. Resting fura ratios were not significantly different. Caffeine-induced transients were greater in S than in U cells. [3H]-ryanodine-binding and Ca(2+)-ATPase contents were not significantly different. In conclusion, we have found that regular electrical stimulation of adult ventricular myocytes in culture, so that they contract rhythmically, enhances both mechanical properties and calcium transients when compared to quiescent myocytes. These results suggest that regular electrical stimulation is important when studying the function of adult ventricular myocytes in culture.
Adenosine Triphosphate↗
Increased cardiac expression of endothelin-1 mRNA in ischemic heart failure in rats.
OBJECTIVES: Plasma endothelin (ET) concentrations are increased in heart failure. The aims of the present study were to investigate to what extent cardiac ET mRNA expression is induced in ischemic heart failure and whether there may be compensatory downregulation of myocardial mRNA levels for the ETA and ETB receptor subtypes. METHODS: In rats with ischemic heart failure (left ventricular end-diastolic pressure > 15 mmHg) due to left coronary artery ligation. Northern blot analyses were performed on mRNA isolated from cardiac tissues. RESULTS: A substantial upregulation was revealed in all chambers of the failing hearts. Up to 27-fold upregulation (mean 10.6 +/- 4.0, P = 0.002) of left ventricular ET-1 mRNA levels was measured 1 week after myocardial infarction, whereas only a modest upregulation was detected after 6 weeks (mean 2.7 +/- 0.5, P < 0.05). Ribonuclease protection assay revealed 2.8 +/- 0.4-fold higher levels of ET-1 mRNA in the left ventricular area subjected to myocardial infarction compared to the non-infarcted tissue after 1 week. Left ventricular ET-1 mRNA correlated significantly with left ventricular end-diastolic pressure after 1 week (r2 = 0.86, P = 0.007). The ETA and ETB receptor mRNA levels tended to increase 1 week after myocardial infarction although these changes were not statistically significant. CONCLUSIONS: Cardiac ET-1 mRNA levels are increased in ischemic heart failure and correlate significantly with left ventricular end-diastolic pressure 1 week after myocardial infarction. The increase in cardiac ET-1 mRNA is not accompanied by a decrease in ET receptor mRNA.
Animals↗
Atrial systolic pressure, as well as stretch, is a principal stimulus for release of ANF.
The mechanism for increased secretion of atrial natriuretic factor (ANF) during tachycardia and atrial fibrillation has remained unsettled. In seven open-chest pigs, the plasma concentration of ANF increased from 49.8 +/- 12.4 to 131.8 +/- 15.7 pg/ml when heart rate was increased from 133 +/- 13 to 212 +/- 4 beats/min by atrial pacing. Right atrial maximal diameter, recorded by ultrasonic technique at the maximal atrial filling, did not increase. During pacing tachycardia, the atrial contraction (a wave) occurs during atrial filling, and the a wave becomes superimposed on the v wave. In the present study the systolic atrial pressure (a wave) increased from 5.8 +/- 0.8 to 9.6 +/- 0.5 mmHg. The significance of this pressure rise was subsequently examined. After complete atrioventricular (AV) block, the AV delay was progressively increased, without altering heart rate, until the a wave was similar to the the a wave during the preceding tachycardia. Plasma ANF increased to 113.8 +/- 14.7 pg/ml, which showed that the increase in atrial pressure during atrial systole is a stimulus for ANF release. In the second part of the study, atrial fibrillation was induced in six open-chest pigs by rapid atrial pacing after complete AV block. Plasma ANF increased from 83.5 +/- 7.2 to 269.0 +/- 45.4 pg/ml during atrial fibrillation. No increase in atrial dimensions occurred during atrial fibrillation, but atrial pressure was substantially elevated. Thus, although passive atrial stretch stimulates ANF release during blood volume expansion, the present study shows that the increase in atrial pressure during atrial contraction is a stimulus for release of ANF during tachycardia and atrial fibrillation.
Animals↗
Physiological assessment of complex cardiac phenotypes in genetically engineered mice.
The recent development of techniques for surgical manipulation and for the assessment of cardiac physiology in genetically engineered mice has allowed scientists to address some of the most fundamental questions related to congenital and acquired forms of human heart disease. This review discusses recent advances in the techniques for studying cardiac disease using the mouse as a model system. Because cardiac overload is one of the most important stimuli for development of hypertrophy and heart failure in humans, various models of cardiac pressure and volume overload, as well as myocardial ischemia, have been developed and characterized. Moreover, it is possible to reliably examine murine cardiac physiology in vivo with microtransducers, echocardiography, and other miniaturized techniques. Sophisticated methods have also been developed to enable an examination of single-cell phenotypes of isolated cardiomyocytes derived from genetically engineered mice. These physiological assessments, coupled with conventional histology and molecular markers, have allowed the characterization of several gene-targeted and transgenic mouse models of hypertrophy and dilated cardiomyopathy, as well as mouse models of cardiac developmental defects. Such mouse models of heart disease will ultimately allow the molecular dissection of the interplay between the various factors leading to heart disease, and they may serve as a guide to appropriate therapeutic strategies for human heart disease.
Animals↗
Transient Ca2+ overload alters Ca2+ handling in rat cardiomyocytes: effects on shortening and relaxation.
Transient Ca2+ overload in cardiomyocytes occurs during pathophysiological conditions. The aim of the present study was to investigate the effects of transient Ca2+ overload on shortening and relaxation in isolated rat cardiomyocytes electrically stimulated at 0.5 Hz and to examine whether transient Ca2+ overload induces alterations in Ca2+ handling and myofilament sensitivity. Fractional shortening and shortening velocity fell to 79 +/- 5% (P < 0.05) and 78 +/- 4% (P < 0.01) 2 min after exposure to high Ca2+. A transient decrease in resting length, a reduction in relaxation velocity to 86 +/- 7% (P < 0.05), and a prolonged time of relaxation with 8.3 +/- 4.3% (P < 0.05) were also observed. Systolic fluorescence ratio using fura 2 as the Ca2+ indicator fell by 11.0%, and the decline of the fluorescence ratio was prolonged by 29.8%. By applying caffeine, we observed a significant reduction in sarcoplasmic reticulum Ca2+ content after transient Ca2+ overload. A significant reduction in myofilament sensitivity was also observed. In conclusion, the systolic dysfunction observed after transient Ca2+ overload is the result of both decreased systolic Ca2+ and reduced myofilament sensitivity. The relaxation abnormalities are most likely caused by altered Ca2+ handling, since we observed a reduction in the sarcoplasmic reticulum Ca2+ content and a prolongation of the decline of the fura 2 transient.
Adenosine Triphosphate↗
Transient, isopeptide-specific induction of myocardial endothelin-1 mRNA in congestive heart failure in rats.
Increased myocardial expression of preproendothelin-1 (ppET-1) mRNA has been associated with congestive heart failure (CHF) in rats. However, the time course and isoform pattern of ppET mRNA induction and the cellular localization of ET in failing hearts are unknown. Thus our aim was to investigate myocardial ppET mRNA expression in CHF rats during the first 6 wk after induction of myocardial infarction. Furthermore, performing immunohistochemical analysis, we also investigated the origin and localization of immunoreactive endothelin (ET) in different regions of the failing heart. Ribonuclease protection assays revealed a marked increase in ppET-1 mRNA levels in rat myocardial tissues during CHF. The induction of ppET-1 mRNA was isopeptide specific and transient. The most substantial upregulation was observed in the infarcted area, where maximal expression of ppET-1 mRNA was observed after 7 days (25-fold increase, P < 0.05). However, a marked and statistically significant induction of ppET-1 mRNA was also observed in the nonischemic myocardium. Immunohistochemical analysis revealed ET-1-like immunoreactivity in cardiomyocytes, vascular endothelial cells, macrophages, and proliferating fibroblasts. Thus immunohistochemistry revealed the structural basis for the dramatic upregulation of the myocardial ET system in the infarcted region, suggesting a role for ET in the healing process after myocardial infarction. However, the global upregulation of ppET-1 mRNA in the heart also suggests an autocrine/paracrine regulatory mechanism in the nonischemic myocardium during CHF.
Animals↗
Endothelin production and effects of endothelin antagonism during experimental airway inflammation.
Endothelin (ET) has strong bronchoconstrictor properties, stimulate mucus secretion and mucosal edema, and may also exert proinflammatory effects. Therefore, ET may play a pathogenic role in inflammatory airway diseases such as bronchial asthma. The production and localization of ET and the effect of blocking ET receptors was investigated in rats during airway inflammation induced by intratracheal instillation of dextran (Sephadex). We observed a considerable increase in the concentration of ET in bronchoalveolar lavage fluid (BALF) during the early phase of inflammation, with an increase from 2.2 +/- 0.6 pg/ml in controls to 40.0 +/- 6.7 pg/ml at Day 1, declining to 5.3 +/- 1.1 pg/ml at Day 14. Correlated with the ET response in BALF was a considerable increase in total cell count (r = 0.61), eosinophils (r = 0.83), and neutrophils (r = 0.81). Plasma ET was not elevated. Immunohistochemical analyses revealed ET-like staining in the bronchial epithelium. Treatment with the ET receptor antagonist bosentan inhibited the increase in eosinophils in BALF and reduced the inflammatory reaction in the lung tissue. In summary, a considerable increase in the ET concentration in BALF was demonstrated during the acute phase of an experimental eosinophilic airway inflammation, coinciding with an increased ET-like immunostaining in the bronchial epithelium. Treatment with an ET receptor antagonist inhibited the inflammatory response in BALF and in the tissue.
Animals↗