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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).

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.