Control experiments were performed in parallel: BLOCK-iT Alexa Fluor Red Fluorescent Oligo was incubated alone with MCF-7 to assess unspecific fluorescence, and it was also delivered with commercially available transfection medium recommended for dsRNA transfection to assess efficient delivery of the fluorescent oligo. As it can be observed in Figure 7, both lecithin dispersions at pH 5.0 and pH 7.0 are able to efficiently deliver oligos in MCF-7 cells. Fluorescent Inhibitors,research,lifescience,medical siRNA mainly

located in the cytoplasm of the cells near the nucleus (Figures 7(c) and 7(d)). In contrast, fluorescently labeled naked siRNA was not detected by fluorescence microscopy (Figure 7(b)) neither within Inhibitors,research,lifescience,medical cells nor in the extracellular medium, suggesting that siRNA is degraded or removed by washing the cells when the incubation period is finished. Figure 7 Fluo-siRNA uptake by MCF-7 cells transfected with lecithin dispersions in pH 5.0 and pH 7.0 buffers. Control dsRNA:Lipofectamine (a), dsRNA alone (b), dsRNA:lecithin 25mM pH 5.0 (c), and dsRNA:lecithin 25mM pH 7.0 (d) at N/P 8000 were … 4. Conclusions

In the present work, a siRNA lecithin-based delivery system capable to improve the disadvantages that nonviral carriers normally present, like Inhibitors,research,lifescience,medical poor cellular uptake or high cytotoxicity, was readily obtained. It was not necessary to add other components like cationic lipids or cationic surfactants, of recognized toxicity, so as to improve siRNA loading capacity. In this case, the efficiency in loading was reached by means of the optimization of the critical parameters in the elaboration, such as pH and ionic strength. It was proposed that in the Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical case of nanoparticles obtained at lower pH, an important electrostatic interaction between the oligonucleotide and the positively

charged head of the amphiphile is responsible for the formation of isolated spherical particles, while at higher pH, the interactions between charged groups of lecithin and siRNA are less relevant. When assessed in parallel with the commercial transfection reagent Lipofectamine, Sitaxentan lecithin dispersions at pH 5.0 and pH 7.0 were both able to efficiently deliver oligos in MCF-7 cells, in PLX4032 manufacturer contrast to naked siRNA. Moreover, fluorescent siRNA mainly located near its target, surrounding the nucleus of the cells. Neither other components like lipids for cell transfection nor molecular modifications were necessary. If the absence of toxicity and the significant cellular uptake exhibited are considered along with the ease of preparation, critical issues for the rest of nanocarriers that have been proposed for siRNA delivery, the present oligo delivery system represents a promising one for further investigation.

Consistent with this suggestion, neuroimaging studies of memory for previously studied pictures have revealed reactivation during retrieval of some of the same visual processing regions that were active during encoding.100 These observations dovetail nicely with an idea initially advanced by cognitive psychologists, often referred to as the sensory reactivation hypothesis, that true memories tend to contain more sensory

and perceptual information than do false memories.62,101 Consistent with this hypothesis, behavioral studies have shown that retrieval of true memories is associated with increased access to sensory and perceptual details compared with retrieval Inhibitors,research,lifescience,medical of false or imaginary memories.101-105 More recently, neuroimaging

Inhibitors,research,lifescience,medical studies in which participants are scanned during retrieval of true and false memories have provided additional evidence consistent with the sensory reactivation hypothesis. For example, in several neuroimaging studies using the DRM semantic associates Inhibitors,research,lifescience,medical paradigm, participants who were scanned during retrieval showed increased activity in sensory-perceptual regions during true recognition as compared with false recognition.44-46 However, whether or not such effects are observed may depend on subtle features of the experimental design. 13,47,106 In an attempt to examine sensory reactivation effects using material known to engage perceptual processing pathways, Slotnick and Schacter34 used novel visual shapes as target stimuli. All the shapes that participants studied were physically similar to prototype shapes that were not presented during encoding. Following presentation Inhibitors,research,lifescience,medical of the study list, participants made old/new recognition decisions about previously studied shapes, nonstudied related shapes, and nonstudied unrelated shapes. Slotnick and Schacter34 hypothesized that true recognition of previously studied shapes, as compared with false recognition of nonstudied

related Inhibitors,research,lifescience,medical shapes, would be accompanied by a sensory signature Linifanib (ABT-869) involving increased activation of visual processing regions. Consistent with this hypothesis, there was significantly greater activity during true than false recognition in regions of Talazoparib concentration primary visual cortex (eg, BA 17, 18) that are concerned with processing such features of target stimuli as orientation and color. By contrast, higher-order visual areas in occipito-temporal cortex (eg, BA 19, 37) showed comparable levels of activity during true and false recognition. Consistent with the foregoing, additional evidence supporting the sensory reactivation hypothesis has been reported in studies using fMRI to examine the widely known post-event misinformation effect.

33-36 In addition to antiamyloid therapies, many other strategies are under development that would be relevant to the early-stage disease processes, not only for AD, but also for other neurodegenerative diseases. These approaches include anti-inflammatory and antioxidant approaches, as well as general neuroprotective strategies or methods to enhance the pathways involved

in learning and memory. For example, a small peptide that is derived from a neuroprotective protein is being developed by Allon Therapeutics as a drug candidate and has been shown to protect neurons from Aβ-induced insults.37 In addition, investigators are working to develop peptidomimetic compounds that activate neurotrophin Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical receptors and protect neurons from cell death.38 Other strategies that increase brain-derived neurotrophic receptor (BDNF) receptor signaling have progressed into nonhuman primates and have shown promising results, including restoring cognitive function and protecting neurons from death.39

Finally, the mitochondria has gained attention recently as a compelling target for preventing neuronal degeneration. Dimebon, a drug originally developed as an antihistamine, showed promising clinical benefit in a recent AD clinical trial in Russia and is thought to function through stabilization of the mitochondria:40,41 While the focus of this review is Inhibitors,research,lifescience,medical on preventing dementia at its earliest stages, in MCI, or even earlier, later-stage disease interventional therapies will also be necessary. As in heart disease, Inhibitors,research,lifescience,medical preventative therapies are not 100% effective, and strategies need to be developed to protect these patients from further disease progression. The amount and distribution of tangle pathology has been correlated with neuronal cell death and clinical disease severity,42 therefore preventing tau aggregation and tangle formation may prevent cell death from occurring. Currently, investigators are working on Inhibitors,research,lifescience,medical a number of therapeutic strategies to disrupt tangle formation in AD, including directly disrupting tau aggregation and/or targeting numerous pathways that regulate tau phosphorylation.43,44

In addition, many investigators are working on helping patients regain lost functionality by replacing injured neurons, either through the induction of pathways that stimulate neurogenesis or through exogenous stem cell therapies.45,46 Alzheimer’s disease in perspective These various treatment why approaches should not be considered in isolation. The future of Alzheimer’s disease therapy might be viewed as a combination approach or selleck inhibitor multitargeted therapeutic “cocktail.” In the case of cardiovascular disease, even though we have good surrogate markers like cholesterol, we still do not fully understand the underlying disease mechanisms, nor do we have a cure for the disease. We do, however, have relative effective preventative treatments, such as statins, that reduce disease prevalence.

The gender difference was opposite in a computer-pointing task (Rohr 2006), with motor times shorter in men, favoring speed, than women, highlighting accuracy. In the present study, fairly comparable results were obtained for human subjects and monkeys, as far as the hand dominance is concerned. Indeed, 62% of monkeys and 55% of human subjects did not show any statistically http://www.selleckchem.com/products/ON-01910.html significant Inhibitors,research,lifescience,medical hand dominance, as assessed by the score derived from the

modified Brinkman board task. Concerning the CTs, the results are more difficult to interpret in monkeys. The CTs were fully coherent with the score in one case only (Mk-CA), whereas for the other monkeys, there was no, or less, consistency (Table ​(Table1).1). As reminder, the CT is a parameter Inhibitors,research,lifescience,medical additional to the score, which eliminates possible biases in the score, due to inattention and/or lack of motivation of the monkey. In other words, it does not take into account the time interval between two slot manipulations. Moreover, we had taken into consideration only the last 20 sessions at plateau, to focus on the supposedly most stable daily behavioral sessions. It may, however, be interesting to consider the CT in more sessions Inhibitors,research,lifescience,medical in the plateau phase for a stricter comparison with the score for the very same sessions, although, in previous studies

(e.g., Kaeser et al. 2010, 2011), the CTs were largely stable during the entire plateau phase. The discrepancy between score and CTs is likely to be due to other parameters, such as diverted Inhibitors,research,lifescience,medical attention in between the grasping of two consecutive pellets. It may also originate from the different motor habits reflected by the temporal sequence followed by the animal to visit the slots (e.g., the monkey scans the board systematically from one side to the other or from the middle and then to the sides; see Kaeser et al. 2013). Moreover, at a given time point, the animal may change prehension strategy (e.g., collect two pellets at a

time). As long as the new strategy is not fully mastered, the hand dominance may vary, although the CTs Inhibitors,research,lifescience,medical remain short. In human subjects, as for the score data, the CT data showed that the hand dominance is generally consistent with the hand preference. The present study offers the opportunity to compare the hand dominance and the hand preference for both human subjects PAK6 and nonhuman primates. As reminder, the human subjects exhibiting hand dominance showed, most of the time, the same laterality for hand preference. This was not the case for the monkeys, where the laterality of the hand dominance did not systematically correspond to the one of the hand preference (Table ​(Table1).1). The same conclusion was met in a study conducted on four female M. fuscata Japanese monkeys (Kinoshita 1998). Concerning the hand preference, the results in human subjects are very consistent with their self-assessment.

Table 2 Distribution of the reasons to entry the ED recorded by using ICPC 2 classification in group E patients (N = 1244) of the Espoo EDs Discussion The implementation

of the ABCDE-triage combined with public guidance was associated with reduction in the number of patient visits to GP out-of-hours ED services by about 24%. The observed #this website keyword# reduction in GP visits in the ED may partly be due to considerable public debate and the publicity provided by the new system and rules. It is possible that some of the patients decided not to request emergency care at all due to the expected long waiting times or risk of being redirected to daytime health services. Patients were Inhibitors,research,lifescience,medical also assessed to group E by the triage nurse and redirected to homecare. This result is higher than our former experience from Vantaa City where the number of ED visits decreased by 8% after implementation of ABCDE-triage [16]. In Espoo, the population seemed to adapt very quickly to the idea that those who needed help most must go first and those whose

need is not urgent should not necessarily visit the ED at all. However, a considerable difference between Vantaa and Espoo was, that in Espoo the patient who was assessed to group E might be sent home with advice Inhibitors,research,lifescience,medical while in Vantaa the patient was allowed to stay and wait as long as the queue of more urgent patients (groups A-D) persisted [16]. This may also have explained why the decrease in patient visits was much higher in Espoo than in Vantaa. GPs were previously assumed to regulate access to the acute secondary health care by referring those patients who need specialist Inhibitors,research,lifescience,medical care. The triage was performed by primary health care in EDs but it did not diminish or increase the workload of the secondary health care in the same facility. Altogether, the present finding agrees with the former Inhibitors,research,lifescience,medical report of Vertesi [3] which suggested that triage did not automatically enhance activities in the secondary health care ED. The number of visits to primary care GPs during office hours was unchanged from March 2004

to February 2008 in Espoo (Figure ​(Figure3).3). Thus, the decrease in patient visits to the GPs in Espoo EDs did not cause an overflow of patients in the office hour GP practice. There were some hints that demand for nurse visits in daytime services increased but this could not be verified because also other changes were made in office-hour Bay 11-7085 public health to alter the workload of nurses at the same time. Furthermore, no excessive doctor resources were allocated to office-hour activities at the time of the intervention. Thus, we cannot exclude the possibility that the lack of change in the number of visits to primary care GPs during office hours was just attributable to that fact. Yet the same phenomenon was observed in Vantaa City in our previous work [16].

T2) analysis of variance (ANOVA) with repeated measures on the second factor. Second, after checking the interrater-reliability for the three different strength ratings, by calculating intraclass correlation coefficients (ICC; Shrout and Fleiss 1979), we compared both groups referred to their find more average strength in the BDORT (after inducing their anxiety) for both times of measurement. The data were

analyzed using a 2 (group: experimental group vs. control group) Inhibitors,research,lifescience,medical × 2 (time of measurement: T1 vs. T2) ANOVA with repeated measures on the second factor. Third, we compared the experimental group and the control group in relation to the data in the STAI-G, divided into STAI-G-State Inhibitors,research,lifescience,medical and STAI-G-Trait for both times of measurement. Hence, data were analyzed using two 2 (group: experimental group vs. control group) × 2 (time of measurement: T1 vs. T2) ANOVAs with repeated measures on the second factor. Results Intensity of anxiety The ANOVA did not reveal an main effect for time of measurement (F(1, 47) = 3844) and for group (F(1, 47) = 0.472). However, there was a significant interaction between time of measurement and

group (F(1, 47) = 9.26, P < 0.008, η² = 0.16). For T1, the mean values of anxiety did not differ significantly between both groups. Inhibitors,research,lifescience,medical However, the interaction indicated that the mean values of anxiety decreased in the experimental group from the first to Inhibitors,research,lifescience,medical the second time of measurement and the mean values of anxiety in the anxiety condition were as far as possible unchanged (see Fig. ​Fig.22). Figure 2 Likert Scale (LS) for the intensity of anxiety in the experimental group (EG) and the control group (CG) for time of measurement 1 (T1) and time of measurement 2 (T2). Physical task First, the interrater-reliability coefficients were acceptable

for all judges (ranging from 0.90 to 0.96 and averaging 0.93) for both times of measurement. The subsequent 2 (group: experimental group vs. control group) × 2 (time of measurement: Inhibitors,research,lifescience,medical T1 vs. T2) ANOVA yields a main effect for time of measurement (F(1, 48) = 13.44, P < 0.001, η² = 0.21) but not for group (F(1, 48) = 3.20). In addition, we found a significant interaction between group and time of measurement (F(1, 48) = 12.96, P < 0.001, η² = 0.21). Figure ​Figure33 shows that the mean data for strength (after the anxiety induction) increased in the experimental group from T1 to T2 and the strength in the control group was as far as possible unchanged from T1 to T2. Figure Endonuclease 3 Mean strength rating and standard errors for the emotion anxiety in the experimental group (EG) and in the control group (CG) for time of measurement 1 (T1) and time of measurement 2 (T2). STAI-G-State The ANOVA revealed no significant main effect for group (F(1, 48) = 1.74) or for time of measurement (F(1, 48) = 0.54). However, we found a significant interaction between group and time of measurement (F(1, 48) = 5.73, P < 0.022).

Acute renal injury (ARI) and blood transfusion requirements There were more ARI in the selleck products coagulopathic group 25 (25.3%) patients than in the non coagulopathic group 7 (8.4%) (p=0.003). This is comparable with other studies done outside Uganda on ATC [6,7]. However the exact relationship between ARI and ATC needs to be further investigated. There was no strong association between blood transfusion requirements

and coagulopathy. A total of 41(41.4%) of patients with coagulopathy were transfused and 27 (32.5%) of patients without coagulopathy were transfused with different blood products (p=0.179). Increased transfusion requirements in major trauma patients were probably due to two events; blood loss at the scene (event) and continue Inhibitors,research,lifescience,medical loss secondary to coagulopathy. Lack of significant difference in our study could be because of non compliance to standard

protocol as far as blood transfusions practices is concerned in our setting Inhibitors,research,lifescience,medical because in part there is frequently inadequate supply of blood during the day but more so at night. Mortality The overall mortality was 38(20.9%), this is higher mortality than what has been reported in developed world. Kirya reported a mortality of 39(26%) among major trauma patients in a study of outcome of major trauma patients at Mulago hospital 10 years ago [24]. Other studies reported an overall mortality among major trauma patients ranging from 15% to 20%, however Inhibitors,research,lifescience,medical these studies where done in high resourced trauma centres [6,10,11]. The mortality was more in the coagulopathic group 29(29.3%) than in the non coagulopathic group 9(12.2%) P=0.002, this is comparable with other studies [6,10,11]. Inhibitors,research,lifescience,medical In this study, coagulopathy was a strong predictor of mortality in major trauma patients (IRR 2.7 95% CI 1.3 – 5.7, p = 0.001) and a predictor of morbidity (longer length of

stay). The Kaplan-Meier survival curves suggest Inhibitors,research,lifescience,medical a significant difference in probability of survival between patients with elevated PTT and those with normal (p=0.001). Most deaths resulting from elevated PTT occur early in the hospital stay, with the probability of survival paralleling between the two groups as time goes on. Thus PTT was a strong predictor of outcome than PT. Multiple regressions showed PTT, systolic BP, GCS were the variables that influenced outcome the most. The ability to determine whether the trauma patient at admission Cell press is coagulopathic or not is a single most important predictor of outcome. This is comparable with other studies on ATC [6,7,10]. This study was not without limitations; perhaps additional variables such as INR (International Normalized Ratio), temperature (to detect hypothermia), metabolic acidosis and fibrin break down products would have added valuable information to ascertain coagulopathy. So is the lack of blood products that is encountered often times in the late night hours we did not catergorise which patient came at night or during the day.

Serum 25OH vitamin D3 level was 20 ng/ml.

Serum levels of calcitonin, α-fetoprotein and carcinoembryonic antigene (CEA) were within normal ranges. Serum concentration of parathyroid hormone-related peptide was not available to us. Treatment started with normal saline, furosemide and calcitonin. Despite aggressive hydration and continuous intake of furosemide and calcitonin, the patient’s condition gradually deteriorated during the next 48 hours with Inhibitors,research,lifescience,medical aggravation of hypercalcemia and deterioration of mental status. Therefore, 90 mg Pamidronate, which resulted in gradual Selleckchem Galunisertib decrement of serum calcium level, was prescribed. Ultrasonographic evaluation of the abdomen revealed a 150 mm lobulated mass in the upper part of abdomen which

was confirmed by CT scan (figure 1). The patient underwent surgery, during which a large, lobulated, hard, hypervascular and irregular mass occupying the body and tail of the pancreas was observed. The mass could not be totally excised Inhibitors,research,lifescience,medical because of hypervascularity and severe bleeding potentials. Histopathologic Inhibitors,research,lifescience,medical evaluation revealed that the mass was a neuroendocrine tumor. Immunohistochemistry (IHC) staining, done in Iran, was positive for synaptophysin, alpha 1 antitrypsin and vimentin. Re-evaluation of IHC, done at the Department of Pathology, St. Michael Hospital, Toronto, Ontario, Canada, disclosed cytoplasmic immunopositivity for PTHrP (figure 2), somatostatin, calcitonin, serotonin and chromogranin. Ki-67 nuclear labeling

index Inhibitors,research,lifescience,medical was estimated at 1-3%. Figure 1 Abdominal computed tomography scan showing the pancreatic tumor Figure 2 Immunohistochemical staining showing positivity for parathyroid hormone related protein. After one week, because of paresthesia and serum calcium concentration of 7.1 mg/dl, calcium carbonate and calcitriol were prescribed Inhibitors,research,lifescience,medical followed by chemotherapy with Etoposide and VP16. After six months the patient underwent surgery for a second time in another hospital. This surgery was also unsuccessful at complete removal of the pancreatic mass. The neonate was also operated on by a team of pediatric surgeons; however, unfortunately she expired the day after the surgery. Discussion Present case is unique because of the large invasive tumor spanning whole length of pregnancy, severe post partum hypercalcemia, and birth of a baby with above-mentioned isothipendyl malformations secondary to a pancreatic NET. Neuroendocrine tumors are rare neoplasms. The annual incidence is 2-3/100,000 and 30-50% of the tumors are functional.4,7 Pancreatic NET presenting with hypercalcemia secondary to PTHrP production constitute a small minority of these tumors. Because of the similarity of the clinical picture with multiple endocrine neoplasia type 1 (MEN1), the pathogenesis of hypercalcemia in patients with pancreatic NET was a real challenge.

14 They are complex, in their fine categories. They are not identical, and, national susceptibilities aside, would be much better fused to a single classification, employing the advantages of each, without the disadvantages, sometimes http://www.selleckchem.com/products/CAL-101.html different, that each has. The strong separation

into single episode and recurrent is not justified by empirical research, and Inhibitors,research,lifescience,medical it is not useful as a major division: all disorders which become recurrent are single episode on the first occasion. The DSM definitions are better. The specification in DSM-III of depressions related to medical disorder and to substance use is not helpful, since there is little to show they differ from the rest of depressions in any major ways. Bipolar and unipolar disorder Much of the discussion about the nosology of affective disorder concerns various subtypes. Depression was for many years a fertile ground for classifiers.15,16 Although much of the heat and pressure have subsided, the issues still complicate diagnostic schemes. Inhibitors,research,lifescience,medical The best-accepted and best-substantiated Inhibitors,research,lifescience,medical distinction is the bipolar-unipolar one. This was not always so. As described above, Kraepelin viewed all affective disorders as manic-depressive.

As late as ICD -9, published in 1978, the ICD did not clearly make the separation, although hidden within the subcategories of manic-depressive disorder (296) for readers of very small print, was a distinction between Inhibitors,research,lifescience,medical 296.1, manic-depressive, depressed, which was meant to be unipolar, and 296.3, manic-depressive, circular, depressed, which was meant to

be bipolar. Most users of the classification did not realize this, so the distinction was in practice ver}’ erratically recorded. The unipolar-bipolar distinction was incorporated into DSMIII when it was issued in 1980, and later into the ICD when ICD-10 was issued. It was pathfinding work in the 1960s by Angst17 and Penis18 that established the value of the distinction. They had been influenced by descriptions by Karl Leonhard, a 20th-century German psychiatrist with a very 19th-century approach to nosology based on his mental hospital clinical experience, Inhibitors,research,lifescience,medical of monopolar whatever and bipolar cycloid psychoses.19 The bipolar-unipolar distinction is clcarcut by definition, depending on the occurrence of a manic episode. Usually it is also so in practice, although late first manic episodes lead to embarrassing changes of diagnosis, and it is hard to be sure of the nature of minor mood elevations, in some cases which are regarded as bipolar II disorder or cyclothymic disorder, or in some subjects with milder mood changes in community epidemiology studies. The status of single-episode mania is debated, but is accepted by most as indicating true bipolar disorder. Some would regard recurrent depression as related to bipolar disorder, but there is not good evidence that this is the case. TTttcrc are good validating features for the distinction.

This is exactly what a vast majority of US physicians seem to do: 93% of over 800 surgeons, obstetricians, and other specialists at high risk of litigation reported practices of recommending a diagnostic test or treatment that is not the best option for the patient, but

one that protects the physician against the patient as a potential plaintiff, including, for instance, unnecessary CT scans, biopsies, Inhibitors,research,lifescience,medical and MRIs, and more antibiotics than medically indicated.10 Similarly, in the rural Michigan hospital discussed above, of about 90% of the patients who were referred to the coronary care unit, only roughly 25% actually had a myocardial infarction. In environments where risk of being sued is high if a patient is mistakenly diagnosed and/or treated as healthy and where physicians seek to avoid potential lawsuits, it is ecologically rational for them to follow the defensive heuristic “err on the safe side,” being overcautious and prescribing more Inhibitors,research,lifescience,medical diagnostic tests and treatments than necessary. This defensive heuristic is not the same as an irrational reasoning error or a cognitive illusion, caused by people’s mental limitations. Inhibitors,research,lifescience,medical But precisely because of this, as we will discuss next, there is room for change: by changing

the environment, physicians can be led to rely on heuristics that are more beneficial to the patient. The science of fast-and-frugal heuristics Doctors and other humans cannot foresee the future, and cannot know if a diagnosis is correct for certain, or if a treatment will cure a patient for certain. Rather, they have to make decisions under uncertainty

and often under the constraints of limited time. According to the fast-and-frugal heuristics research Inhibitors,research,lifescience,medical program, these decisions can nevertheless be made successfully, because Selleck GSI-IX people can rely on a large repertoire of heuristics—an adaptive toolbox—with each heuristic (ie, each tool) being adapted to a specific decision-making environment. By relying on a heuristic that is well adapted to a particular environment, Inhibitors,research,lifescience,medical a person can make sound decisions, often based on very little information in little time (hence “fast-and-frugal”). There are different sets of mechanisms that help people to choose among the heuristics. The first depends on the workings of basic cognitive capacities, such as memory.11 The interplay of these capacities Sodium butyrate with the environment creates for each heuristic a cognitive niche in which it can be applied. For instance, the frequency and recency with which we have encountered information in our environment influences what information we remember, and how quickly we remember it. What information comes to the mental stage, and how quickly it arrives there, in turn determines what heuristics are applicable to solve a given task. A second set of mechanisms for selecting heuristics includes social and individual learning processes that can make people more prone to choose one applicable heuristic over another.