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The standard approach to finding optimal experimental designs employs conventional measures of design efficacy, such as the $A$, $E$, and $D$-criterion, that assume equal interest in all estimable functions of model parameters. This paper develops a general theory for weighted optimality, allowing precise design selection according to expressed relative interest in different functions in the estimation space. The approach employs a very general class of matrix-specified weighting schemes that produce easily interpretable weighted optimality criteria. In particular, for any set of estimable functions, and any selected corresponding weights, analogs of standard optimality criteria are found that guide design selection according to the weighted variances of estimators of those particular functions. The results are applied to solve the $A$-optimal design problem for baseline factorial effects in unblocked experiments.

Computer generation of experimental designs, for reasons including flexibility, speed, and ease of access, is the first line of approach for many experimentalists. The algorithms generating designs in many popular software packages employ optimality functions to measure design effectiveness. These optimality functions make implicit assumptions about the goals of the experiment that are not always considered and which may be inappropriate as the basis for design selection. General weighted optimality criteria address this problem by tailoring design selection to a practitioner's research questions. Implementation of weighted criteria in some popular design software is easily accomplished. The technique is demonstrated for factorial designs and for designing experiments with a control treatment. WIREs Comput Stat 2017, 9:e1393. doi: 10.1002/wics.1393 For further resources related to this article, please visit the WIREs website.

Consider a linear model with targeted parameters . We derive a necessary and sufficient condition on the matrix M for the average variance of functions to be proportional to the A value for comparing designs. This establishes the full range of interpretations of the A criterion.

In this paper, we consider the problem of monitoring a linear functional relationship between a response variable and one or more explanatory variables (a linear profile).

Maximizing data information requires careful selection, termed design, of the points at which data are observed. Experimental design is reviewed here for broad classes of data collection and analysis problems, including: fractioning techniques based on orthogonal arrays, Latin hypercube designs and their variants for computer experimentation, efficient design for data mining and machine learning applications, and sequential design for active learning. © 2012 Wiley Periodicals, Inc. © 2012 Wiley Periodicals, Inc.

Optimal blocking is explored for experiments, such as those incorporating one or more controls, where not all treatment comparisons are of equal interest. Weighted optimality functions are employed in gaining both analytic and enumerative results; a catalogue of smaller optimal designs is provided. It is shown how design selection based on functions of variances, and on functions of efficiency factors, are both subsumed by the weighted approach. Copyright 2011, Oxford University Press.

E-optimality for test treatments versus control (TvC) experiments is studied from a weighted perspective. A definitive interpretation for the E criterion is established in the TvC setup, and a wide class of E-optimal block designs is determined. Secondary criteria are easily brought to bear, producing designs that are firstly optimal for test/control comparisons, and secondarily optimal for test/test comparisons.

We evaluate and compare the performance of Phase II simple linear regression profile approaches when only two observations are used to establish each profile. We propose an EWMA control chart based on average squared deviations from the in-control line, to be used in conjunction with two EWMA control charts based on the slope and Y-intercept estimators, to monitor changes in the three regression model parameters, i.e., the slope, intercept and variance. Simulations establish that the performance of the proposed technique is generally better than that of other approaches in detecting parameter shifts.

Summary Objectives: To evaluate distinctive features of pelvis and hip joint development of English Bulldogs throughout the first year of life. Methods: The pelves of 20 English Bulldogs were radiographed at three different ages ( Results: Although none of the dogs were considered lame at the end of the study, none of the hips showed normal development; 77.5% were moderately to severely deformed at 12–14 months of age. At this age, 75% of the hemipelves had moderate to severe torsional deformity (>5.2° of external rotation), with retroversion of the acetabulum confirmed by the presence of the crossover sign. An external rotation of the hemipelvis on its long axis >5° was likely associated with a moderate to severely altered hip joint conformation. Clinical Significance: Abnormal hip conformation was common in this series of English Bulldogs. Torsional deformity of the pelves with acetabular retroversion was a common and distinctive feature, which has not yet been thoroughly studied in dogs. These findings need further evaluation in English Bulldogs as well as in other breeds.

There is a long standing discrepancy between the Standard Model prediction for the muon and the value measured by the Brookhaven E821 Experiment. At present the discrepancy stands at about three standard deviations, with a comparable accuracy between experiment and theory. Two new proposals – at Fermilab and J-PARC – plan to improve the experimental uncertainty by a factor of 4, and it is expected that there will be a significant reduction in the uncertainty of the Standard Model prediction. I will review the status of the planned experiment at Fermilab, E989, which will analyse 21 times more muons than the BNL experiment and discuss how the systematic uncertainty will be reduced by a factor of 3 such that a precision of 0.14 ppm can be achieved.

The clinical and radiological incidence of lumbosacral (LS) disease was studied on 57 German Shepherd dogs (GSDs) used in active service. The study included a clinical history, a neurological examination, and plain radiographs of the caudal lumbar vertebrae. The neurological examinations revealed lower back pain and/or neural deficits in 21 dogs, of which 14 had a history of pain or pelvic gait abnormalities. Radiographic findings were spondylosis at L7-S1, degeneration of L7-S1 disc, LS malalignment, transitional LS vertebrae and/or primary spinal canal stenosis in 15 dogs with neurological abnormalities and/or back pain and in 18 dogs with no clinical signs. No correlation between the neurological and the radiographic findings were found. This study demonstrates that even prominent radiographic LS abnormalities are of minimal value in the evaluation of LS disease in the GSD.

Background/aims: Effector T cell activation is particularly important in the initiation of autoimmune uveitis. This pilot study seeks to demonstrate activation of human peripheral effector T cells in response to the uveitis candidate autoantigen, retinal S antigen (SAg), using cytokine flow cytometry (CFC). Methods: Peripheral blood mononuclear cell (PBMC) suspensions from uveitis patients and controls were stimulated with bovine SAg. Activation responses were detected by CFC. Results: Electronic gating enabled analysis of CD69+, IFN-γ+ CD4+ lymphocytes. An SAg specific response was detectable in four of 13 patients and four of eight controls. Conclusion: SAg specific, peripheral, effector T cell activation can be detected by CFC. Similar levels of responsiveness were seen in patient and control groups. More detailed cytokine profiling may demonstrate functional differences between the groups.

During ischemia, large amounts of catecholamine are released to the myocardium from the sympathetic nerve endings in the heart. It has not been clearly shown whether the released catecholamine has detrimental or beneficial effects on postischemic myocardial contractile function. The aim of the present study was to investigate the effect of endogenous catecholamine released during ischemia on myocardial contractile function, using ferret papillary muscles in a stimulated ischemia model. Papillary muscles were excised and mounted in organ baths containing oxygenated physiological salt solution at 37 degrees C. In order to eliminate the effect of endogenous catecholamine, a subset of animals was reserpinized for 2 days prior to the experiments. Muscles were stabilized for 1 h, and stretched to the length at which maximal isometric tension developed. Ischemia was simulated by changing the solution to liquid fluorocarbon bubbled with 95% N2 and 5% CO2. After 20 min of ischemia, the bathing medium was replaced with oxygenated physiological salt solution and developed tension was measured for 60 min. Pharmacologic agents with specific effects on myocardial autonomic pathways were used to investigate the cellular mechanisms of the observed effects. Tension recovery of reserpinized muscles was significantly better than control muscles (65.5 +/- 2.8% vs. 54.9 +/- 5.0%, P < 0.01). Exogenously administered beta-adrenergic antagonists did not attenuate stunning in control muscles; whereas forskolin and carbachol exacerbated stunning. These results indicate that catecholamine released during ischemia exacerbates myocardial stunning and overrides the effect of clinically relevant concentrations of beta-adrenergic antagonists, which may limit their ability to protect myocardium from acute ischemic insult. The effect of endogenous catecholamine was simulated by forskolin, but not attenuated by carbachol, which suggests that changes in the contractile apparatus activated by excess cyclic AMP were relevant to the mechanical dysfunction that developed.

We tested the hypothesis that changes in phosphorylation of the sarcoplasmic reticulum (SR) protein, phospholamban (PIB) and myofibrillar proteins troponin I (TnI) and C protein are responsible for the decreased relaxant response to isoproterenol in cardiac hypertrophy and failure induced by ascending aortic banding in rats. In isolated perfused heart preparations under maximal isoproterenol stimulation, the capacity for in vitro cAMP-dependent phosphorylation of PIB was significantly increased at the compensatory stage of hypertrophy (126-130%, P0.001), but decreased with failure (70-76%, P0.001). Phosphorylation of TnI also decreased in the failing hearts, however to a lesser extent (80-83%, P0.05). No significant hypertrophy-related difference was evident in isoproterenol-induced phosphorylation of C protein. The relative tissue level of PIB was increased (150-168%, P0.001) in hypertrophied and decreased (71-83.8%, P0.05) in failing hearts compared with the respective age-matched sham-operated controls (100%). As a percentage above baseline, the maximal isoproterenol-induced increase in the EC50 of the SR Ca2+ pump in response to phosphorylation of PIB was 38.5+/-1.1% for sham-operated rats, and 26.0+/-3.8% and 15.4+/-4.2% for hypertrophied and failing hearts respectively. As a consequence, linear correlation was observed between the maximal increase in EC50 and the maximal rate of relaxation [(-dP/dt)/DevP] upon isoproterenol stimulation, declining with progressive hypertrophy to failure. These data suggest that hypertrophy-induced alterations in PIB phosphorylation and protein level contribute to the diminished relaxant response of the hypertrophied and failing heart to adrenergic agonists.

Transitional lumbosacral vertebral anomalies have for some time been suggested as a possible cause of cauda equina syndrome (especially in the German shepherd dog [GSD]), a condition recently thought to be inherited. The frequency of this condition within a large clinical population and the radiographic features used in its detection are reported. In a group of 143 patients, the sexes were similarly represented and the GSD was greatly overrepresented. The anomaly is characterised by separation of the first sacral segment that was identified on the lateral view by the presence of a radiolucent disc space between what are normally the first and second sacral segments. On the ventrodorsal view, the anomaly was characterised by separation of the spinous processes between what are normally the first and second sacral segments. In the presence of the transitional segment, the nature of the sacroiliac joint at the level of the anomalous segment varies from a strong ilial attachment, with the presence of a wing-like lateral process, to a weakened ilial attachment because of the presence of a lateral process, shaped as that seen on a lumbar segment. These patterns were present unilaterally or bilaterally and result in symmetrical or asymmetrical patterns. The effect of the weakening of the sacroiliac attachment was thought to result in premature disc degeneration, which, together with spinal canal stenosis, resulted in potential compression of the overlying spinal nerves and creation of a cauda equina syndrome. The condition is thought to have clinical significance and should be selected against in breeding, especially in the GSD.

We evaluated the cardiac effects of the principle pyrolysis product of crack cocaine smoking, methylecgonidine (MEG), in comparison with cocaine. Peak cell shortening and intracellular Ca2+, as detected by the Ca2+ indicator indo 1, were recorded in enzymatically isolated ferret myocytes. Both cocaine and MEG decreased peak cell shortening and peak intracellular Ca2+ concentration ([Ca2+]i) in a dose-dependent manner (10(-8)-10(-4) M). MEG shifted the peak [Ca2+]i-to-peak shortening relationship downward and was more potent than cocaine. Atropine (10(-6) M) upwardly shifted the dose-response curves of MEG, cocaine, and carbachol but not of procaine. The negative inotropic effects of MEG were inhibited by methoctramine, a selective M2 receptor blocker but not by M1 (pirenzepine) or M3 (4-diphenylacetoxy-N-methylpiperidine methiodide) blocking agents. In contrast to cocaine, the effects of large doses of MEG were irreversible over the time course of our experiments, raising the possibility of structural damage. We conclude that MEG acts primarily on M2 cholinergic receptors in the heart to produce acute cardiac intoxication and, in contrast to cocaine, may decrease the myofilament Ca2+ responseness and cause structural damage to myocytes by a direct toxic effect.

We tested the hypothesis that the negative inotropic effect (NIE) of cocaine is mediated, at least in part, by cholinergic stimulation and can be correlated with the degree of adenosine 3',5'-cyclic monophosphate (cAMP) dependency of the inotropic state. Cardiac myocytes were isolated from left ventricles of ferrets and loaded with the fluorescent Ca2+ indicator indo 1. Cells were placed in physiological solution containing 2.0 mM Ca2+ and stimulated at 0.5 Hz and 30 degrees C. Cocaine decreased peak cell shortening and peak intracellular Ca2+ in a concentration-dependent manner (10(-8)-10(-4) M). The concentration-response curve of cocaine was shifted significantly downward compared with those of lidocaine and procaine in the same range of concentrations. Atropine (10(-6) M) shifted the concentration-response curve of cocaine, but not those of lidocaine and procaine, rightward, with a pA2 value (7.66) similar to that obtained with carbachol (7.99). With prior addition of isoproterenol (ISO, 10(-8) M) or increased Ca2+ (4.0 mM) to increase cell shortening to the same degree (approximately 60%), cocaine and carbachol decreased contractility to a significantly greater extent in ISO-stimulated myocytes. To clarify whether these treatments changed responsiveness of the contractile elements to Ca2+, the effect of 2,3-butanedione monoxime, an agent that interferes with the interaction of myosin and actin, was tested with previous addition of ISO or increased Ca2+, and no differential effect occurred. Therefore, we postulate that 1) the NIE of cocaine on myocytes is caused by decreased Ca2+ availability; 2) this effect is due to specific stimulation of cholinergic receptors in addition to other direct myocardial (probably local anesthetic) effects; and 3) the NIE correlates with the level of cAMP dependence of the inotropic state.

Metabolic changes have been shown to precede mechanical abnormalities in the early stages of adriamycin cardiotoxicity. This study examines the early changes in calcium homeostasis and their mechanical implications in a model of adriamycin cardiomyopathy. Hearts isolated from control and adriamycin-treated rats were coronary-perfused and isovolumic left ventricular (LV) pressure, coronary perfusion pressure and calcium transients from aequorin-loaded cardiomyocytes were recorded. Treated rats received three injections of adriamycin (6 mg/kg) for a period of 1 week. They were sacrificed for experiments 1-2 or 4-5 weeks after the final injection. The LV systolic and end-diastolic pressures were similar in both groups at varied external calcium concentrations (0.5-2.0 mM). However, systolic levels of myoplasmic calcium were substantially higher in the adriamycin-treated hearts, the difference being less at higher external calcium concentrations. Similar responses in both groups to paired pulse stimulation, increased stimulation frequency and caffeine (0.5-2.0 mM) were observed. However, adriamycin-treated hearts exhibited a smaller rise in LV developed pressure, as well as in systolic and diastolic calcium levels, in response to elevated coronary perfusion pressure. The elevated intracellular systolic calcium level is suggestive of an early but persistent effect of adriamycin on the calcium release channels of the sarcoplasmic reticulum. That the elevated systolic myoplasmic calcium levels are not accompanied by an increase in inotropy suggests a decrease in myofibrillar calcium sensitivity in this model of the early stage of adriamycin cardiomyopathy.

In clinical and experimental heart failure, the inotropic response to beta-adrenergic receptor stimulation is depressed. Therefore, non-beta-adrenergic mechanisms may assume increasing importance for summoning inotropic reserve in the failing heart. To test the integrity of the inotropic pathway mediated by alpha 1-adrenergic receptor stimulation in a model of chronic ischemic heart failure, we administered phenylephrine to noninfarcted left ventricular papillary muscles isolated from sham-operated rats (n = 10) and rats with large (> 40% left ventricular circumference) anterior myocardial infarctions (n = 9). Isometric force was monitored, and intracellular Ca2+ (Cai2+) transients were recorded with the bioluminescent protein aequorin. Compared with muscles from sham-operated rats, contractility of muscles from rats with postinfarction heart failure was depressed at extracellular Ca2+ concentrations between 0.5 and 3.0 mM. Phenylephrine produced comparable dose-dependent increases in developed tension (126 +/- 4 vs. 125 +/- 7% of baseline) and peak rate of tension rise (125 +/- 4 vs. 140 +/- 9% of baseline) in muscles from sham and infarcted rats, respectively. There was no significant change in the time course of the isometric twitch or in the time course or amplitude of the Cai2+ transient after phenylephrine administration in muscles from either group. No evidence of Cai2+ overload, as defined by spontaneous Ca2+ release, was observed during phenylephrine administration in muscles from normal or failing hearts. The density of alpha 1-adrenoceptors measured with [3H]prazosin binding in crude membranes isolated from noninfarcted left ventricular tissue was not different in control and infarcted hearts (48 +/- 5 vs. 53 +/- 4 fmol/mg protein). These data indicate that the positive inotropic effect of alpha-agonists may be preserved in chronic ischemic heart failure. In both normal and failing myocardium, the inotropic effects of alpha 1-adrenergic stimulation occurred with little or no increase in Cai2+ availability and no apparent adverse effects on myocardial relaxation. Therefore, agents that act by similar mechanisms may have certain therapeutic advantages over traditional inotropic agents in patients with heart failure.

Objective: The aim was to test the hypothesis that reperfusion induced arrhythmias are associated with major alterations in intracellular calcium ([Ca2+]i) regulation. Methods: Intracellular calcium, epicardial electrical potentials, and isovolumetric left ventricular pressure were simultaneously recorded in isolated perfused intact rat hearts during ischaemia (10 min) and reperfusion. [Ca2+]i was measured using the bioluminescent calcium indicator aequorin. Results: Neither ventricular tachycardia nor ventricular fibrillation occurred during ischaemia. However, during the first minute of reperfusion ventricular tachycardia or fibrillation were frequently observed. Cellular calcium was altered by varying the perfusate calcium ([Ca2+]o; 0.5, 1.0, and 3.0 mmol·litre−1). 0% (0/6), 50% (5/10), 91% (10/11), respectively, of hearts showed ventricular tachycardia, ventricular fibrillation, or both upon reperfusion (P < 0.001, 0.5 v 3.0 mmol·litre−1). At all [Ca2+]o values examined, early ischaemia was associated with a rapid decrease in developed pressure and transient increase in the peak calcium transient followed by a gradual decline and subsequent increase in diastolic calcium during late ischaemia. The initiation of ventricular tachycardia/fibrillation upon reperfusion was immediately preceded by large increases in the amplitude of the calcium transient. These increases in systolic calcium were not seen in hearts in which ventricular arrhythmias did not occur. Conclusions: The association between reperfusion induced abrupt increases in peak calcium and the occurrence of ventricular tachycardia or fibrillation suggests that intracellular calcium transients may have a significant role in initiating these ventricular arrhythmias.

A six-month-old, female German shepherd dog was presented because of depression, anorexia, vomiting, polyuria, and polydipsia of approximately 10 days' duration. The puppy was depressed, and pain could be elicited on palpation of both shoulders and hips. The most significant results of serum chemistries and hematology were hypercalcemia; increased blood urea nitrogen, creatinine, and alkaline phosphatase; and leukocytosis with neutrophilia. Thoracic radiographs revealed a large thymic mass, diagnosed on histological examination as a thymic lymphoma. Radiographs of the shoulders revealed destructive bone lesions involving the proximal metaphyses of the humeri, causing slipped epiphyses. Bone lesions were found at necropsy on the proximal and distal aspects of both humeri and femurs. Bone resorption was due to local neoplastic infiltration and presumed humoral factors secreted locally and systemically by neoplastic thymic lymphocytes.

We studied functional and intracellular calcium responses to treppe and extracellular calcium in spontaneously hypertensive rat (SHR) hearts during the transition from compensated pressure overload to failure. Intracellular calcium was measured using aequorin, a bioluminescent Ca2+ indicator. Experiments were performed with intact, isovolumically contracting, buffer-perfused hearts from three rat groups: (1) aging SHR with evidence of heart failure (SHR-F), (2) age-matched SHR with no evidence of heart failure (SHR-NF), and (3) age-matched normotensive Wistar-Kyoto (WKY) rats. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Hearts were studied at 30 degrees C and paced at a rate of 1.6 Hz while being perfused with oxygenated Krebs-Henseleit solution (95% O2/5% CO2) at 100 mm Hg. At the baseline state, peak systolic pressure was greatest in the SHR-NF group and lowest in the SHR-F group. Peak and resting [Ca2+]i were not significantly different among groups; however, the calcium transient was prolonged in the SHR-NF and SHR-F groups. With increasing perfusate [Ca2+]o from 0.5 to 3.0 mmol/L, the relative increases in peak [Ca2+]i and peak systolic pressure were similar among groups. When stimulation rate was increased from 1.6 to 2.0, 2.4, 2.8, and 3.2 Hz, peak [Ca2+]i, peak systolic pressure, and +/- dP/dt fell in SHR-F hearts. Peak systolic pressure decreased in the SHR-NF group at rates above 2.4 Hz but did not decline in the WKY group. Peak [Ca2+]i increased in the WKY and SHR-NF groups with increasing heart rates. Peak systolic pressure did not fall significantly in the WKY group at any heart rate. Elevation of diastolic [Ca2+]i and/or calcium transient and pressure alternans were present in 8 of 13 SHR-F hearts at the highest stimulation rate, findings that were absent in both the WKY and SHR-NF hearts. We conclude the following: (1) Under baseline conditions, depressed contractile function of failing myocardium cannot be explained by decreased peak [Ca2+]i, (2) relative increases in [Ca2+]i and inotropy with increasing [Ca2+]o are proportional among groups; and (3) although peak systolic [Ca2+]i and inotropy are maintained with increasing stimulation rate in the WKY and SHR-NF groups, peak systolic [Ca2+]i and pressure decrease in parallel in the SHR-F heart with increasing stimulation rate, suggesting that impaired calcium cycling may contribute to compromised pump function in the SHR-F heart.

Experiments were performed in aequorin-loaded left ventricular myocytes isolated from hypertrophied hearts and age-matched controls. Five to six months after postvalvular aortic banding, left ventricular hypertrophy was present, as indicated by a 97% (P < 0.001) increase in the left ventricular weight-to-body weight ratio and a 24% (P < 0.001) increase in cell width. In comparison with controls, the hypertrophied myocytes demonstrated that 1) contraction duration was prolonged by 37% (P < 0.001) and was associated with a 44% (P < 0.001) prolongation of the intracellular Ca2+ transient; 2) peak systolic shortening was decreased by 31% (P < 0.001) and was associated with a 21% (P < 0.001) decrease in peak systolic intracellular Ca2+ concentration; 3) both the peak systolic intracellular Ca2+ concentration-to-peak shortening relationship and the intracellular Ca2+ concentration-to-cell shortening relationship at the time of the peak twitch were shifted downward, suggesting a decrease in myofilament Ca2+ responsiveness; and 4) isoproterenol (5 x 10(-8) M) produced equal increases in the peak systolic intracellular Ca2+ of control and hypertrophied myocytes (88 vs. 90%; P > 0.05) in contrast to much smaller increases in the peak cell shortening (170 vs. 73%; P < 0.02) of the hypertrophied myocytes, suggesting a decrease in myofilament Ca2+ responsiveness. These data demonstrate that the hypertrophy-related abnormalities in intracellular Ca2+ handling and mechanical function, previously reported in aequorin-loaded multicellular muscle preparations, are present in isolated myocytes, arguing against changes in the interstitium as essential causative factors.

To examine the mechanisms by which thyroid hormone modulates the inotropic state of rat myocardium, we studied the effects of thyroid state on isolated rat left ventricular papillary muscle function and intracellular calcium transients in the baseline state and in response to calcium and isoproterenol. Marked differences in contractile state of papillary muscles from hypothyroid and thyroid hormone-treated rats seen under baseline conditions (1.0 mM bath calcium, 30 degrees C, stimulation rate 12/min) do not appear to be due to differences in intracellular calcium concentration ([Ca2+]i) or to changes in myofilament calcium sensitivity but correlate with shifts in myosin isozyme distribution. In response to superimposed inotropic interventions (calcium, 0.625-5.0 mM, or isoproterenol, 10(-8)-10(-6) M), myocardial thyroid state modulates peak [Ca2+]i and inotropy, both of which are increased in thyroid hormone-treated relative to hypothyroid myocardium. The change in inotropy appears to be proportional to peak [Ca2+]i, whether mediated directly by calcium or as a result of beta-adrenergic stimulation. Thus, whereas baseline differences between hypothyroid and thyroid hormone-treated myocardium appear to be due to differences in myosin isozymes and presumed changes in adenosinetriphosphatase activity and cross-bridge cycling, superimposed inotropic responses appear to be mediated by changes in [Ca2+]i.

An on‐sun, CPV test site has been built at the University of Ottawa consisting of two ring‐mounted, dual‐axis trackers fitted with 38 m2 of highly concentrating, light guiding optics and panels. The site has been designed to monitor photovoltaic performance on the system and panel scale and to record I‐V measurements of individual optics under realistic operating conditions. Measurements of the light‐guiding optic's optical transmission function, lab‐based EQE measurements and time‐synchronized DNI and spectral irradiance data have been used to develop a relative photovoltaic performance model that accurately predicts real‐world results. The in situ I‐V curve tracing system also allows us to estimate the absolute temperature of individual solar cells within a CPV panel. Results indicate a peak temperature of approximately 40 °C under DNI of 1009 W/m2 at an ambient temperature of 2 °C. Finally, optical alignment and acceptance angle measurements have been used to estimate short circuit current values of in...

Objective: The aim was to compare the effects of simulated ischaemia-reperfusion with those of hypoxia-reoxygenation in isolated muscle preparations from the ferret right ventricle. Methods: Ischaemia was simulated using fluorocarbon immersion plus hypoxia. Intracellular calcium transients were determined from aequorin luminescence during isometric contractions. Results: Hypoxia in fluorocarbon and physiological saline solution resulted in a similar reversible depression of the peak of the calcium transient. Peak active tension, however, was more depressed in fluorocarbon than in physiological salt solution. The dissociation between peak light and peak active tension was most pronounced on reoxygenation, with near complete recovery of peak light, while there was little recovery of tension in fluorocarbon. When fluorocarbon was then replaced by physiological salt solution, peak active tension recovered promptly. A prolongation of the decay of the calcium transient was seen in both fluorocarbon and physiological salt solution during hypoxia, which shortened promptly on reoxygenation. The time to the peak of the calcium transient was most prolonged during hypoxia in fluorocarbon and there was gradual recovery on reoxygenation. Conclusions: While some changes in the calcium transient during simulated ischaemia are rapidly reversible with reoxygenation (in fluorocarbon), suggesting an effect of hypoxia, others are incompletely reversed or only reversed with physiological salt solution, suggesting an effect of metabolite accumulation. The pronounced dissociation between peak light and peak active tension during reoxygenation in fluorocarbon is promptly reversed by changing to physiological salt solution, suggesting that metabolite retention in the postischaemic period may contribute to depressed myocardial function after reperfusion. Cardiovascular Research 1993; 27 :1863-1868

Objective: Calcium transients in muscles from patients with end stage heart failure consist of two components (L1 and L2) at physiological extracellular calcium concentrations ([Ca2+]); the second component (L2) can appear in normal human myocardium at high [Ca2+]. In muscles from end stage heart failure patients L2 is associated with significant hypertrophy. To expand these observations a group of muscles from control patients with mild hypertrophy but without overt heart disease was studied (n=8), in which a second calcium transient component was present during high [Ca2+]. Methods: Using the ratio of the two components of the calcium transient (L2/L1) seen in trabeculae from heart failure patients as a marker of intracellular calcium mobilisation, the hypothesis was tested that the extent of abnormality in transsarcolemmal calcium flux, and/or sarcoplasmic reticular calcium release and reuptake, correlates with the degree of hypertrophy present. Results: In contrast to non-hypertrophied myocardium, hypertrophied myocardium from patients without heart failure often showed an increase in the L2/L1 ratio at higher [Ca2+]. Hypertrophied myocardium from patients with failure showed a progressive increase in the L2/L1 ratio, reflecting further impairment of calcium mobilisation. There was a positive correlation between the degree of hypertrophy and calcium mobilisation alterations that was enhanced by raised [Ca2+]. Altered [Ca2+]i mobilisation may develop early in the course of hypertrophy, before the onset of clinical signs of cardiac dysfunction. Cardiovascular Research 1993; 27 :199-203

To examine the cellular mechanisms of contractile dysfunction in postinfarction heart failure, we studied the effects of beta-adrenergic receptor stimulation on contractile function and Ca2+i handling of noninfarcted papillary muscles from sham-operated (n = 17) and infarcted (n = 17) rats. Ca2+i transients measured with the bioluminescent protein aequorin and parameters of isometric contraction were recorded during graded isoproterenol stimulation. Developed tension and peak rate of tension rise were depressed (p less than 0.05) in muscles from infarcted rats at physiological and maximally stimulating [Ca2+]oS. The time to peak tension was prolonged in the muscles from the infarcted rats, corresponding with prolongation of the time to peak Ca2+i. In muscles from sham-operated rats, isoproterenol increased both the amplitude of the Ca2+i transient and the peak rate of tension rise. In contrast, the inotropic response to isoproterenol was severely blunted in the muscles from infarcted rats despite a large increase in the amplitude of the Ca2+i transient. Isoproterenol abbreviated the time course of the isometric twitch and the Ca2+i transient in both groups. These findings suggest that postinfarction heart failure may be related in part to decreased force-generating capacity of the myofilaments. Treatment with captopril for 5 weeks, beginning 1 week after infarction (n = 14), resulted in reduction of left ventricular filling pressures and partial normalization of myocardial contractility and Ca2+i handling. In addition, compared with muscles from untreated infarcted rats, muscles from the captopril-treated rats exhibited improved contractile responses to increasing [Ca2+]o or isoproterenol. The inotropic response to isoproterenol in muscles from all three groups of rats had a significant negative correlation (r = -0.64, p less than 0.0001) with left ventricular end-diastolic pressure measured in vivo. Thus, the defect in excitation-contraction coupling in rats with postinfarction heart failure may be partially normalized by chronic load reduction with an angiotensin converting enzyme inhibitor.

Endothelin may play an important role in modulating myocardial contractility under certain pathophysiological conditions. To determine whether endothelin beneficially modulates myocardial contractility in the common clinical condition of acidosis, we compared the effects of endothelin-1 on intracellular Ca2+ transients and isometric contractions under normal (extracellular pH [pH(o)] 7.4) and acidotic (pH(o) 6.4) conditions in ferret papillary muscles (n = 33) loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. A pH(o) of 6.4 was induced by replacing 92% of HCO3- with Cl- in the bathing medium. The effects of endothelin at pH(o) 6.4 differed from the effects at pH(o) 7.4 in that 1) the minimally effective concentration of endothelin was 30-fold lower (1 x 10(-10) M at pH(o) 6.4; 3 x 10(-9) M at pH(o) 7.4) and the concentration-response curve of endothelin was significantly shifted to the left with a decrease in log EC50 from -7.83 +/- 0.13 to -8.92 +/- 0.10 (p less than 0.001), indicating an increased sensitivity of myocardium to endothelin; 2) endothelin produced an increase of approximately 375% in tension development at pH(o) 6.4 (approximately 62% at pH(o) 7.4) (p less than 0.001) without increasing peak [Ca2+]i (approximately 13% increase at pH(o) 7.4, p less than 0.001), indicating an increase in myofilament Ca2+ responsiveness; and 3) endothelin significantly abbreviated (approximately -19%, p less than 0.001) the prolonged intracellular Ca2+ transient induced by acidosis (pH(o) 6.4). In addition, pretreatment with 10 microM of the Na(+)-H+ exchange inhibitor 5-(N-methyl-N-isobutyl)-amiloride significantly attenuated endothelin-induced effects on the intracellular Ca2+ transient and contraction during acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3-Butanedione monoxime (BDM) exerts a marked negative inotropic effect and has been shown to have protective actions on human myocardial force production that may be of clinical use. To determine the underlying mechanisms, we studied the effects of BDM on chemically skinned and aequorin-loaded myopathic human myocardium from transplant recipients. Eighteen muscles were chemically skinned with saponin (250 micrograms/ml) and then subjected to activation-relaxation cycles, with and without 5 mM BDM. Contracture force vs. Ca2+ data were fitted to a modified Hill equation, and values for 50% maximal activation (pCa50) and maximal Ca(2+)-activated force (Fmax) were obtained. pCa50 was decreased by 0.2 pCa units, indicating myofilament Ca2+ desensitization, and Fmax was reduced by 48% in 5 mM BDM. A second group of intact muscles (n = 8) was loaded with aequorin to monitor intracellular calcium (Cai2+) transients (peak light) and twitch force in the presence of BDM (1-30 mM). Over a range of 1-20 mM, BDM depressed peak light by 3-49% while force was depressed by 10-82%. This was accompanied by an abbreviation of the duration of the twitch but not of the Cai2+ transient. At a concentration of 30 mM, BDM completely inhibited force generation, but an Cai2+ transient was still present. We conclude that in human myocardium, 5 mM BDM predominantly affects cross-bridge force production and Ca2+ sensitivity and has a less pronounced effect on Cai2+.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

The use of phenylpropanolamine (PPA) as an anorectic has provoked commentary and disagreement. Its use in the last decade has been associated with a series of adverse clinical events. As in all case reports, these associations may be noncausal, particularly in light of PPAs extensive use. We have reviewed prospective clinical trials in which the administration of PPA was planned to assess impact on blood pressure. Many of these employ sedentary, healthy volunteers but also included are studies of overweight, moderately hypertensive, and ambulatory subjects. An analysis of such studies leads us to believe that PPA is an appropriately marketed over-the-counter drug, with an acceptable margin of safety. Further, we have reanalyzed our own earlier published data, which indicate that the margin of safety may actually be increased in subjects with elevated basal sympathetic tone; eg, those who are overweight and those with slight elevations of arterial blood pressure.

The purpose of this study was to test the hypothesis that systolic and diastolic dysfunction in left ventricular pressure-overload hypertrophy is caused by abnormal intracellular calcium handling. Experiments were performed with intact, buffer-perfused, isovolumic ferret hearts (n = 9 hypertrophied, n = 9 control) that were loaded with the bioluminescent indicator aequorin to monitor changes in cytoplasmic calcium. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Compared with their age-matched controls, significant hypertrophy of the left ventricle developed 4 weeks after postvalvular aortic banding; at the time the animals were killed, the left ventricular weight/body weight ratio was increased in the banded animals (5.3 x 10(-3) versus 3.6 x 10(-3), p less than 0.001). As indicated by the diastolic pressure-volume relation, left ventricular distensibility was significantly diminished in the hypertrophied hearts. In comparison to the controls, the hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 278 +/- 5.4 versus 247 +/- 10.2 msec, p less than 0.05), but a marked decrease in peak systolic midwall stress (22.4 +/- 5.0 versus 38.6 +/- 5.7 g/cm2, p less than 0.05). The increased duration of isovolumic contraction correlated with a similar prolongation of the calcium transient (time to 90% decline from peak: 245 +/- 19.5 versus 127 +/- 13.2 msec, p less than 0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the hypothesis that mechanical alternans of the heart is due to alternations in intracellular calcium (Cai2+) levels. Eight papillary muscles were isolated from the right ventricles of male ferrets and were chemically loaded with aequorin to record cytoplasmic Cai2+. To produce a steady-state mechanical alternans, the preparations were perfused with a physiological salt solution containing a low calcium concentration (0.25 mM), at 22 degrees C, and stimulated at 0.5-1.0 Hz in the presence of carbachol and propranolol. The aequorin signal (Cai2+) and isometric contraction were simultaneously recorded. In each muscle, the strong beats (beats with higher peak tension) were associated with larger Ca2+ transients than the weak beats. The relationships between peak Cai2+ and peak tension, both during strong and weak beats, were similarly modified by short-term frequency responses. On the other hand, the time courses of the isometric contractions and Ca2+ transients during strong beats and weak beats were superimposable. These data indicate that mechanical alternans is caused by an alternate change of Cai2+ available for activation of the myofilaments. Prolongation of the time for recycling Ca2+ by the sarcoplasmic reticulum, i.e., a depressed uptake function of the Ca2+ pump with concomitant slow transportation of Ca2+ from the uptake compartment to the release compartment in the sarcoplasmic reticulum, is suggested as a cause of the abnormal Cai2+ handling during mechanical alternans.

In fatigued muscles the T-system is swollen; thus the action potential may fail to travel along the T-system or the T-tubule terminal cisternae signal may fail to bring about TC Ca2+ release. This would lead to a decrease in the number of myofibrils activated and in force development, but if fatigue is the result of a generalized process, all the myofibrils would be affected equally leading to a lower activation of all of them. We have investigated this possibility in isolated twitch muscle fibres by giving them repetitive tetanic stimulations until fatigue developed. The behaviour of myofibrils was followed with cinemicrophotography. Before fatigue, no lack of shortening of myofibrils could be found. During fatigue groups of myofibrils became wavy. When exposed to caffeine, the wavy myofibrils disappeared and tension similar to the control developed. The tension-caffeine concentration relationship was shifted to the left after development of fatigue. In low Na+ solution fatigue developed faster and after reintroducing normal Ringer, tension recovered substantially. K-contractures were smaller during fatigue. These results indicate that in this type of fatigue, a step in the EC coupling chain of events is involved in its development.

The influence of endothelin 1 on intracellular Ca2+ transients and isometric contractions was investigated in ferret papillary muscles loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. In concentrations of 3 x 10(-9) to 1 x 10(-7) M, endothelin produced dose-dependent increases in the amplitudes of both aequorin light signals (maximum, 31 +/- 12%) and developed tension (maximum, 64 +/- 13%). The peak aequorin light [( Ca2+]i)-peak tension curve generated by increasing endothelin concentrations was steeper and shifted to the left of the curve generated by varying [Ca2+]o; however, the maximum developed tension produced by endothelin did not exceed that produced by 6 mM [Ca2+]o. The effect of endothelin on the amplitude of the aequorin light signal was less than the effect of [Ca2+]o for similar levels of tension development. Moreover, 1 x 10(-7) M endothelin caused an upward shift in the peak aequorin light-peak tension curve generated by varying [Ca2+]o and increased the maximum twitch force by about 12%. The contractions were prolonged, whereas the time course of the Ca2+ transient was not changed in the presence of endothelin. When the function of the sarcoplasmic reticulum was inhibited by 6 microM ryanodine, 10(-7) M endothelin still increased the force generation without increasing the intracellular peak Ca2+, either during isometric twitches or during tetani.(ABSTRACT TRUNCATED AT 250 WORDS)

To elucidate the role of changes in [Ca2+]i in the induction of ventricular fibrillation (VF), Ca2+i signals, epicardial electrical potentials, and isovolumic left ventricular pressure were simultaneously recorded in isolated intact ferret hearts loaded with aequorin, a bioluminescent protein. When the preparations were perfused with 3 microM acetylstrophanthidin and 8 mM Ca2+, or with a low Na+ solution (18 mM Na+, 100 mM Li+), spontaneous transitions to the VF state were consistently observed within a short period of time. The initiation of spontaneous VF was preceded by development of a Ca2+i overload state, coincidental with the ascending phase of diastolic Ca2+i oscillations, and was followed by further elevation in Ca2+i levels, which were associated with augmented Ca2+i oscillations of a saw-toothed pattern. Pretreatment with 10 microM ryanodine, which blocked Ca2+i oscillations in the preparation, did not eliminate inducibility of VF by means of AC electrical stimulations; however, VF no longer occurred spontaneously, and the threshold for VF induction increased markedly. In the absence of a state of Ca2+i overload, spontaneous defibrillation occurred within a minute after the initiation of VF. We conclude that 1) VF can be induced in the absence of Ca2+i oscillations; however, 2) Ca2+i oscillations play a crucial role as a trigger for VF and therefore are an important determinant of the vulnerability to VF; and 3) the augmented Ca2+i oscillations after the transition to VF state may support the maintenance of this type of arrhythmia.

To investigate the mechanism of impaired myocardial function after long-term pressure overload, we studied cardiac muscle mechanical contraction and intracellular calcium transients using the bioluminescent indicator aequorin. Left ventricular papillary muscle preparations were examined from three groups of rats: 1) aging spontaneously hypertensive rats (SHR) with clinical and pathological evidence suggesting heart failure (SHR-F group), 2) age-matched SHRs with no evidence of heart failure (SHR-NF group), and 3) age-matched normotensive Wistar-Kyoto rats (WKY group). Isometric force development was depressed in both SHR groups relative to the WKY group. Resting [Ca2+]i was lower in the SHR-F group, and the time to peak [Ca2+]i was prolonged in this group. The relative increases in peak [Ca2+]i with the inotropic interventions of increased [Ca2+]o and the addition of isoproterenol were similar among groups. Although inotropy increased in all groups with increased [Ca2+]o, after isoproterenol, inotropy increased only in the WKY group. Thus, in SHR myocardium, [Ca2+]i increased after isoproterenol, but inotropy failed to increase. Myosin isozymes were shifted toward the V3 isoform in both SHR groups; the V3 isoform was virtually 100% in papillary muscles from the SHR-F group. These changes may reflect events directly contributing to the development of heart failure or represent adaptive changes to chronic pressure overload and heart failure.

A total of 24 upper gastrointestinal examinations were performed on four weanling beagle puppies over six weeks, using liquid barium (10 ml/kg bodyweight of 60 per cent w/v barium sulphate suspension] and barium food (8 g/kg of crushed kibble dog food and 7 ml/kg bodyweight of 60 per cent w/v barium sulphate suspension) as contrast media. The radiographic appearance was similar to that noted in adult dogs except for the consistent location of the pylorus on or near the midline. Duodenal pseudoulcers were seen more often with liquid barium and the caecal shadows were identified more often with the longer examination time with barium food. The stomach of the puppies appeared to have discriminatory emptying function; that is, semi-solid food was emptied from the stomach at a slower rate (210 to 450 minutes) than liquid (60 to 90 minutes). Solid meals emptied faster in puppies than in adult dogs. Dosages of 13 to 15 mg/kg bodyweight for the liquid barium examination and 14 g of ground kibble and 16 ml of barium sulphate suspension per m2 of body surface area for the barium food examination are suggested as more appropriate for contrast studies in puppies.

Radiographic interpretation of dental or periodontal disease is dependent in part on an understanding of ageing changes, A progressively ageing colony of healthy beagle dogs (120 to 3759 days) was studied by use of high-detail radiographs made following the death of the dog. Morphological features whose radiographic appearance was found to be especially age-dependent were: root canal size, both vertical and horizontal alveolar bone resorption, visualisation of the lamina dura dentis, and detection of hypercementosis. Understanding of these ageing changes is necessary to avoid over-diagnosis of disease.

Studies in the beagle dog have clearly established the usefulness of this breed in periodontal disease research. However, little is known about the progressive nature of the disease with advancing age. It is the purpose of this paper to describe frequency and distribution of radiographically detectable lesions in an aging population of 166 colony dogs. 3 grades of alveolar bone loss were determined on high-quality postmortem radiographs. The number of teeth involved was similar in male and female and was age-dependent. Disease was more frequent in the maxillary arcades, with the 2nd upper premolar most frequently involved. Most extensive bone loss was noted around the 3rd and 4th upper premolars, and 1st and 2nd lower molars. It is felt that by the study of such a large group of older colony dogs, a better understanding can be gained of the expected alveolar bone loss with age as determined radiographically.

A long-term radiographic follow-up study was conducted on 24 patients (34 hips) who underwent core decompression of the femoral head for avascular necrosis (AVN). The purpose of the study was to assess the potential correlation between the extent of AVN, as determined with preoperative magnetic resonance (MR) imaging, and development of collapse. The preoperative MR results were classified into four categories: group A, no AVN; group B, less than 25% involvement of the weight-bearing portion of the femoral head; group C, 25%-50% involvement; and group D, more than 50% involvement. Histologic evidence of AVN was found in all 34 hips. Collapse occurred in none of the hips in groups A and B (n = 12), in three of seven hips (43%) in group C, and in 13 of 15 hips (87%) in group D. It is concluded that MR estimation of the extent of femoral head involvement with AVN may help in predicting which femoral heads will collapse shortly after core decompression, so that this invasive procedure can be avoided in patients at risk.