Biomedical subjects

A Nordgren

Publications and source records attributed to A Nordgren.

At least 19 recordsLinked to original sources

PubMed2006

Ammonium chloride and alpha-ketoglutaric acid increase glutamine availability in the early phase of induced acute metabolic acidosis.

BACKGROUND: Glutamine deficiency in critical illness is associated with increased morbidity and mortality. We hypothesized that ammonium chloride (NH(4)Cl) and alpha-ketoglutaric acid (alpha-KGA) infusions could increase glutamine availability possibly through de novo synthesis in the liver. METHODS: Anesthetized post-absorptive pigs were allocated to four groups (n = 8). The study groups received either a 4-h intravenous infusion of alpha-KGA, 11.4 micromol/kg/min and NH(4) (+), 9.7 micromol/kg/min (group 1), or alpha-KGA, 2.85 micromol/kg/min and NH(4) (+), 46.3 micromol/kg/min (group 2), or alpha-KGA, 11.4 micromol/kg/min (group 3), or isotonic saline (control group). Plasma concentrations of glutamine and glutamine exchange in liver, intestine and skeletal muscle were investigated. RESULTS: Plasma glutamine concentrations in group 1 (58% increase) were greater (P < 0.05) compared with the control group (14% decrease) and group 3 (13% decrease), and in group 2 (91% increase) compared with the control group, group 3 (P < 0.0001) and group 1 (P < 0.05). Intestinal glutamine extractions in group 2 were significantly greater (P < 0.01) compared with all other groups. Neither the liver nor the hind leg increased its release of glutamine. Arterial pH decreased (all P < 0.001) to 7.39 +/- 0.01 in the control group, 7.30 +/- 0.01 in group 1, 7.19 +/- 0.01 in group 2 and 7.35 +/- 0.01 in group 3. CONCLUSION: Infusions of alpha-KGA and NH(4)Cl, to a pH range of 7.20-7.30, did not enhance hind leg or hepatic glutamine release. The increased plasma concentrations of glutamine were effects of NH(4)Cl, not alpha-KGA, and caused either by de novo synthesis or decreased degradation.

Acidosis↗

PubMed2005

Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles.

OBJECTIVES: To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis. METHODS: The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix. RESULTS: Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype. CONCLUSIONS: In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.

Adult↗

PubMed2003

Metaphors in behavioral genetics.

Behavioral geneticists sometimes use metaphors to describe the role of genes in human behavior. In this paper, five sample texts are analyzed: a popular book, a textbook, a scientific review article, and two original scientific articles representing different approaches in behavioral genetics. Metaphors are found in all the different kinds of sample texts, not only in the popular book and the textbook. This suggests that metaphors are used not only for rhetorical or pedagogical purposes but play a more fundamental role in scientific understanding. In the sample texts, the metaphors tend to be antideterministic, i.e., they do not imply genetic determinism but stress the interaction of multiple genes and multiple environmental factors. No conclusion can be drawn, however, as to whether antideterminism is representative of present-day behavioral geneticists in general. Certain historically important metaphors that may imply genetic determinism are qualified, avoided, or explicitly rejected. There are tensions between some of the metaphors, making them difficult to combine. All the metaphors that are used appear empirically apt, however sometimes only with certain qualifications.

Genetic Determinism↗

PubMed2003

Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia.

OBJECTIVE: To evaluate the early myocardial biochemical inflammatory response with the microdialysis technique during porcine endotoxemia and to simultaneously monitor systemic hemodynamics. DESIGN: Prospective, randomized, placebo-controlled trial with parallel groups. SETTING: Animal research laboratory at the University Hospital of Uppsala, Sweden. SUBJECTS: Thirteen piglets aged 12-14 wks receiving general anesthesia. INTERVENTIONS: After thoracotomy and the insertion of microdialysis probes in standardized locations in the left ventricle of the heart and in the quadriceps muscle, seven pigs received a continuous infusion of endotoxin, initiating a severe endotoxemic shock. Six pigs received saline instead of endotoxin. MEASUREMENTS AND MAIN RESULTS: Endotoxemia caused a rapid and pronounced elevation of a metabolite obtained from prostaglandin degradation, 15-keto-dihydro-PGF(2alpha), in myocardial microdialysate fluid being specific of cyclooxygenase (COX)-mediated inflammation (p <.001 vs. saline-infused controls). Simultaneously, we observed a decrease in left ventricular stroke work index in the endotoxemic pigs (p <.01 vs. saline-infused controls). Endotoxemia did not alter 15-keto-dihydro-PGF(2alpha) levels in quadriceps muscle. Endotoxemia caused increases in taurine, hypoxanthine, and magnesium in myocardial microdialysate (p <.05 vs. saline-infused controls), whereas the contents of pyruvate, lactate, inosine, adenosine, and calcium were not significantly changed. CONCLUSION: Endotoxemia induced a myocardial COX-mediated inflammation without signs of ischemia. In parallel, a depletion of myocardial energy substrates and a deterioration in myocardial performance were seen.

Analysis of Variance↗

PubMed2001

Large-scale forest girdling shows that current photosynthesis drives soil respiration.

The respiratory activities of plant roots, of their mycorrhizal fungi and of the free-living microbial heterotrophs (decomposers) in soils are significant components of the global carbon balance, but their relative contributions remain uncertain. To separate mycorrhizal root respiration from heterotrophic respiration in aboreal pine forest, we conducted a large-scale tree-girdling experiment, comprising 9 plots each containing about 120 trees. Tree-girdling involves stripping the stem bark to the depth of the current xylem at breast height terminating the supply of current photosynthates to roots and their mycorrhizal fungi without physically disturbing the delicate root-microbe-soil system. Here we report that girdling reduced soil respiration within 1-2 months by about 54% relative to respiration on ungirdled control plots, and that decreases of up to 37% were detected within 5 days. These values clearly show that the flux of current assimilates to roots is a key driver of soil respiration; they are conservative estimates of root respiration, however, because girdling increased the use of starch reserves in the roots. Our results indicate that models of soil respiration should incorporate measures of photosynthesis and of seasonal patterns of photosynthate allocation to roots.

Carbon↗

PubMed2001

Limitations of chromosome classification by multicolor karyotyping.

Multicolor karyotyping technologies, such as spectral karyotyping (SKY) (Schröck et al.1996; Liyanage et al. 1996) and multiplex (M-) FISH (Speicher et al. 1996), have proved to be extremely useful in prenatal, postnatal, and cancer cytogenetics. However, these technologies have inherent limitations that, in certain situations, may result in chromosomal misclassification. In this report, we present nine cases, which fall into five categories, in which multicolor karyotyping has produced erroneous interpretations. Most errors appear to have a similar mechanistic basis.

Animals↗

PubMed2001

Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock.

PURPOSE: Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia. METHODS: Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed. RESULTS: Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group. CONCLUSIONS: Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).

Anesthetics, Intravenous↗

PubMed2001

Effects of sustained pressure application on compliance and blood gases in healthy porcine lungs.

BACKGROUND: Short periods of sustained increase in airway pressures (Press(up)) are believed to re-open lung areas that collapsed upon induction of anaesthesia. Recruitment of alveolar surface is usually assessed in terms of changes in the pressure-volume (PV) curve. The purpose of this study was to analyse PV-curves before and after a Press(up) and to ascertain whether such changes are compatible with the concept of recruitment of lung volume. METHODS: During ketamine anaesthesia, 12 healthy piglets were subjected to a Press(up) with end-expiratory pressure (PEEP) of 12 cmH2O and end-inspiratory pressure of 40 cmH2O. Before and after Press(up), PV-curves were obtained from a slow insufflation of 630 ml at zero PEEP (ZEEP). RESULTS: Compliance was non-linear both before and after Press(up) increasing up to 300 ml and sharply decreasing thereafter. After Press(up), the entire compliance curve was shifted to a higher absolute level. Up to 100 ml and a pressure level corresponding to the lower inflection point on the PV-curve (LIP), compliance was higher before Press(up). No effects on blood gases could be observed. CONCLUSION: If the similar shape of the compliance curve corresponds to a similar chain of re-opening and overdistension events, this would imply that all volume gained by Press(up) is lost within 10 min, without explaining the higher absolute compliance following Press(up). We speculate that a) re-opening of rapidly collapsing small airways determines the initial compliance increase; b) the lower compliance after Press(up) until LIP indicates reduced intratidal re-opening of lung regions; and c) changes in bronchomotor tone induced by Press(up) raise the absolute compliance, with a similar scenario of alveolar and small airway recruitment now taking place but at different degrees of airway stiffness.

Airway Resistance↗

PubMed2001

Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping.

Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G-banding analysis. In all cases the numerical changes could be fully characterized, and a non-random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G-banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der(1)t(1;14)(q32;q21), der(2)t(2;8)(q36;?), der(3)t(2;3)(q21;?), der(8)t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements.

Child↗

PubMed2001

Interphase fluorescence in situ hybridization and spectral karyotyping reveals hidden genetic aberrations in children with acute lymphoblastic leukaemia and a normal banded karyotype.

Twenty-two cases of childhood acute lymphoblastic leukaemia (ALL) with normal G- or Q-banded karyotypes were studied by interphase fluorescence in situ hybridization (FISH) and spectral karyotyping. Probes detecting MLL, BCR/ABL and TEL/AML1 rearrangements were used for the interphase studies, along with centromere-specific probes from chromosomes 17 and X. In 10 patients (45%), previously undetected aberrations were demonstrable. Specific gene rearrangements and structural changes were found in six cases and numerical changes in five. Five of these aberrations have previously been reported to have an impact on prognosis. Three cases were massively hyperdiploid and, in one, the prognostically important BCR/ABL fusion was detected. In addition, a near-haploid karyotype with 27 chromosomes was found in one patient and TEL/AML1 rearrangements were detected in two cases. This study indicates that about half of childhood ALL cases with apparently normal karyotypes harbour genetic aberrations that may be detected using interphase FISH and spectral karyotyping.

Adolescent↗

PubMed2000

Chromosomal alterations in 15 breast cancer cell lines by comparative genomic hybridization and spectral karyotyping.

Breast cancer cell lines have been widely used as models in functional and therapeutical studies, but their chromosomal alterations are not well known. We characterized the chromosomal aberrations in 15 commonly used human breast carcinoma cell lines (BT-474, BT-549, CAMA-1, DU4475, MCF7, MDA-MB-134, MDA-MB-157, MDA-MB-361, MDA-MB-436, MPE600, SK-BR-3, T-47D, UACC-812, UACC-893, and ZR-75-1) by comparative genomic hybridization (CGH) and spectral karyotyping (SKY). By CGH the most frequent gains were detected at 1q, 8q, 20q, 7, 11q13, 17q, 9q, and 16p, whereas losses were most common at 8p, 11q14-qter, 18q, and Xq. SKY revealed a multitude of structural and numerical chromosomal aberrations. Simple translocations, typically consisting of entire translocated chromosome arms, were the most common structural aberrations. Complex marker chromosomes included material from up to seven different chromosomes. Evidence for a cytogenetic aberration not previously described in breast cancer, the isoderivative chromosome, was found in two cell lines. Translocations t(8;11), t(12;16), t(1;16), and t(15;17) were frequently found, although the resulting derivative chromosomes and their breakpoints were strikingly dissimilar. The chromosomes most frequently involved in translocations were 8, 1, 17, 16, and 20. An excellent correlation was found between the number of translocation events found by SKY in the individual cell lines, and the copy number gains and losses detected by CGH, indicating that the majority of translocations are unbalanced. Genes Chromosomes Cancer 28:308-317, 2000.

Breast Neoplasms↗

PubMed2000

Detailed characterization of a complex karyotype in a patient with primary plasma cell leukaemia using multicolour spectral karyotyping and micro-FISH.

INTRODUCTION: Plasma cell leukaemia is a rare disorder that usually carries an aggressive course with a rapidly fatal outcome. A variety of chromosomal abnormalities have been reported in plasma cell leukaemia but the clinical significance of an abnormal karyotype is still unclear. MATERIALS AND METHODS: We have applied the molecular cytogenetic techniques multicolour spectral karyotyping and microdissection in combination with fluorescence in situ hybridization on metaphases from a patient with primary plasma cell leukaemia and a fatal outcome. RESULTS AND CONCLUSION: The chromosome analysis showed severe hypodiploidy and 12 marker chromosomes. Identification of the structural rearrangements was not possible using routine cytogenetic methods. Utilizing the methods above, all marker chromosomes could be identified in detail and the karyotype was shown to be very complex. Forty-three breakpoints were found, and 25 could be identified at the band level, among others 14q32 where the immunoglobulin heavy chain locus is situated. Thus, these techniques provide the opportunity to resolve very complex chromosomal changes in a way that has not been previously possible and will consequently be of great importance in the search for hot spots that may harbour new cancer genes.

Adult↗

PubMed2000

Impact of different inspiratory flow patterns on arterial C02-tension.

Ventilation with decelerating inspiratory flow is known to reduce the dead space fraction and to decrease PaCO2. Constant inspiratory flow with an end-inspiratory pause (EIP) is also known to increase the removal of CO2. The aim of the study was to elucidate the effect of the pause/no-flow period while both the pattern and rate of inspiratory flow was unchanged, and when the lung was ventilated with sufficient PEEP to prevent end-expiratory collapse. Surfactant depleted piglets were assigned to decelerating or constant inspiratory flow with 24 breaths per minute (bpm) or 12 bpm, or to constant flow, without and with an end-inspiratory pause of 25%. By adding an EIP the total time without active inspiratory flow of the respiratory cycle was kept unchanged. Gas exchange, airway pressures, functional residual capacity (using sulfurhexafluoride) and haemodynamics (thermo-dye indicator dilution technique) were measured. Irrespective of ventilatory frequency, PaCO2 was lower and serial dead space reduced with decelerating flow, compared with constant inspiratory flow. With an end-inspiratory pause added to constant inspiratory flow, serial dead space was reduced but did not decrease PaCO2. The results of this study corroborate the assumption that total time without active inspiratory flow is important for arterial CO2-tension.

Animals↗

PubMed2000

Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock.

Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.

Animals↗

PubMed2000

New chromosomal breakpoints in non-Hodgkin's lymphomas revealed by spectral karyotyping and G-banding.

Chromosomal rearrangements in short term cultures from nine cases of non-Hodgkin's lymphomas (NHL) were characterized by G-banding, spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH). Eight of the nine cases showed complex karyotypes with chromosomal aberrations which, in most cases, could not be fully characterized by traditional G-banding analysis alone. Karyotypic abnormalities of special interest were marker chromosomes and chromosomes with added unidentified chromosomal material, as previously non-identified chromosomal translocations were hidden behind these aberrations. SKY and FISH analysis, as a complement to banding analysis, significantly improved the karyotypes in seven of the nine cases and unveiled 21 previously unidentified rearrangements with novel translocation breakpoints. Traditional G-banding alone revealed seven new rearrangements, which were all confirmed by SKY. None of these new aberrations occurred as single clonal rearrangements but as parts of complex karyotypes. Nevertheless, the chromosomal break-point regions identified should be considered as potential hot spots for genes involved in the tumorigenesis of the malignancy.

Adult↗

PubMed1999

Maximisation of cerebral blood flow during experimental cardiopulmonary resuscitation does not ameliorate post-resuscitation hypoperfusion.

Continuous intra-aortic balloon occlusion has been reported to improve cerebral blood flow during cardiopulmonary resuscitation (CPR) but not to ameliorate the impaired blood recirculation occurring after restoration of spontaneous circulation (ROSC). Volume expansion with hypertonic solutions may improve recovery of brain function by enhancing post-resuscitation cerebral blood flow. We hypothesised that the combination of these treatments with open-chest CPR would improve cerebral blood flow during CPR, and attenuate post-resuscitation flow disturbances. In 32 anaesthetised piglets, catheters were placed for haemodynamic and blood gas monitoring. Open-chest CPR was initiated after 9 min of ventricular fibrillation. The piglets were treated either with 3 ml kg(-1) hypertonic saline and dextran (HSD) (n = 10), HSD and balloon occlusion (n = 10) or with normal saline (n = 12). After 7 min of CPR, internal defibrillatory shocks were administered to restore spontaneous circulation. Haemodynamic variables, continuous cerebral cortical blood flow, cerebral tissue pH and pCO2 and blood gas parameters were measured during CPR and up to 210 min after ROSC. Higher cerebral perfusion pressure was found in the balloon-HSD group during CPR. This group exhibited less arterial hypertension immediately after ROSC compared with the other groups. Thereafter, a fairly rapid decrease of the perfusion pressures was observed in all groups reaching a minimum level approximately 30 min after ROSC. Cerebral cortical blood flow was significantly higher and cerebral oxygen extraction ratio significantly lower in the balloon-HSD group during CPR, but not after ROSC. In conclusion, a combination of intra-aortic balloon occlusion and HSD administration improves cerebral blood flow and brain oxygen supply during experimental open-chest CPR. In contrast, cerebral blood flow after ROSC was not shown to be influenced by this treatment.

Animals↗

PubMed1999

An inhibitor of angiotensin converting enzyme (enalapril) augments endotoxin-induced hypotension in the pig.

Septic shock causes an extensive inflammatory reaction including increased capillary leakage and a decrease in systemic blood pressure. Human septic shock can be replicated in the endotoxaemic pig. Angiotensin converting enzyme (ACE) is involved in the degradation of bradykinin, an inflammatory mediator, and in the regulation of blood pressure. Inhibition of ACE is a common approach to reduce hypertension as well as left ventricular insufficiency. Fifteen anaesthetised pigs received a continuous 3 h endotoxin infusion. The animals were randomly given an inhibitor of ACE (enalpril) [at a dose (0.5 mg x kg-1) that did not per se reduce mean arterial blood pressure (MAP); (n = 7)], or the corresponding volume of saline (n = 8). Another seven pigs were randomised for treatment with enalapril (0.5 mg x kg-1) + saline (n = 3). Four pigs were randomised to serve as untreated controls (saline + saline). Basic physiologic variables were registered. Endotoxaemia progressively reduced MAP. This decrease was significantly augmented by enalapril. Hypovolemia caused by increased permeability or salt/water excretion did not seem to explain this effect as neither blood haemoglobin nor plasma sodium differed between the two groups of endotoxaemic pigs. Inhibitors of ACE are known to potentiate the cardio-depressant effect of bradykinin. This may explain the reduction in MAP by enalapril during porcine endotoxaemia.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Ethics and imagination. Implications of cognitive semantics for medical ethics.

Cognitive semantics has made important empirical findings about human conceptualization. In this paper some findings concerning moral concepts are analyzed and their implications for medical ethics discussed. The key idea is that morality has to do with metaphors and imagination rather than with well-defined concepts and deduction. It is argued that normative medical ethics to be psychologically realistic should take these findings seriously. This means that an "imaginative casuistry" is to be preferred compared to principlism and to other forms of casuistry. Furthermore, the metaphorical character of central principles in medical ethics such as autonomy, utility, justice, and integrity is indicated. Such principles are interpreted as rules of thumb summarizing the collective wisdom concerning prototype cases.

Beneficence↗