Laboratory Phenomenon Research Articles

Lightning in aeronautics

It is generally accepted that a civilian aircraft is struck, on average, once or twice per year. This number tends to indicate that a lightning strike risk is far from being marginal and so requires that aircraft manufacturers have to demonstrate that their aircraft is protected against lightning. The first generation of aircrafts, which were manufactured mainly in aluminium alloy and had electromechanical and pneumatic controls, had a natural immunity to the effects of lightning. Nowadays, aircraft structures are made primarily with composite materials and flight controls are mostly electronic. This aspect of the "more composite and more electric" aircraft demands to aircraft manufacturers to pay a particular attention to the lightning protection and to its certification by testing and/or analysis. It is therefore essential to take this risk into account when designing the aircraft. Nevertheless, it is currently impossible to reproduce the entire lightning phenomenon in testing laboratories and the best way to analyse the lightning protection is to reproduce its effects. In this context, a number of standards and guides are produced by standards committees to help laboratories and aircraft manufacturers to perform realistic tests. Although the environment of a laboratory is quite different from those of a storm cloud, the rules of aircraft design, the know-how of aircraft manufacturers, the existence of international work leading to a better understanding of the lightning phenomenon and standards more precise, permit, today, to consider the risk as properly controlled.

Six strategies for generalizing software engineering theories

General theories of software engineering must balance between providing full understanding of a single case and providing partial understanding of many cases. In this paper we argue that for theories to be useful in practice, they should give sufficient understanding of a sufficiently large class of cases, without having to be universal or complete. We provide six strategies for developing such theories of the middle range.In lab-to-lab strategies, theories of laboratory phenomena are developed and generalized to other laboratory phenomena. This is a characteristic strategy for basic science. In lab-to-field strategies, theories are developed of artifacts that first operate under idealized laboratory conditions, which are then scaled up until they can operate under uncontrolled field conditions. This is the characteristic strategy for the engineering sciences.In case-based strategies, we generalize about components of real-world cases, that are supposed to exhibit less variation than the cases as a whole. In sample-based strategies, we generalize about the aggregate behavior of samples of cases, which can exhibit patterns not visible at the case level. We discuss three examples of sample-based strategies.Throughout the paper, we use examples of theories and generalization strategies from software engineering to illustrate our analysis. The paper concludes with a discussion of related work and implications for empirical software engineering research.

In vitro and in vivo activities of piperacillin-tazobactam and meropenem at different inoculum sizes of ESBL-producing Klebsiella pneumoniae

The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-Kpn) infections, the inoculum effect of ESBL-Kpn on β-lactams was studied in vitro and in vivo using an experimental model of pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on β-lactams was evaluated at standard (105 CFU/mL) and high (107 CFU/mL) organism concentrations. The MIC50 of piperacillin-tazobactam, cefotaxime and cefepime was increased eight-fold or more and that of meropenem was increased two-fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn pneumonia mouse model treated with bacteriostatic effect-adjusted doses of piperacillin-tazobactam (1000 mg/kg four times daily, %T > MIC; 32.60%) or meropenem (100 mg/kg twice daily, %T > MIC; 28.65%) at low/standard (104 CFU/mouse) and high (106 CFU/mouse) inocula. In mice administered a low inoculum, no mice died after treatment with piperacillin-tazobactam or meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the piperacillin-tazobactam-treated group died, whereas all meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion, meropenem was more resistant to the inoculum effect of ESBL-Kpn than piperacillin-tazobactam both in vitro and in vivo. In the management of severe pneumonia caused by ESBL-Kpn, carbapenems may be the drugs of choice to achieve a successful outcome.

Attention to negative emotion is related to longitudinal social network change: The moderating effect of interdependent self-construal.

Many previous studies have investigated older adults' attentional preference toward different emotions. Interdependent self-construal is identified to be an important moderator of this phenomenon. However, despite the important social functions of emotions, the social consequence of older adults' emotional preferences in attention have not yet been examined. The current study tested how older adults' attentional preferences assessed in the laboratory influenced changes in their real-life social network, and how interdependent self-construal moderated this effect. A total of 45 older adults aged 60-84 years participated in an eye-tracking session that measured their attentional preference to emotional faces versus neutral faces. After that, participants completed the Self-Construal Scale. Participants' social network was then assessed by the Social Convoy Questionnaire twice over a 2-year period. Interdependent self-construal significantly moderated the effect of attention to angry and sad faces on older adults' real-life social network changes. For older adults with a higher level of interdependent self-construal, more attention toward negative emotions was related to longitudinal decreases in the number of their emotionally close social partners. The present study shows the important role of attentional preferences in older adults' social network maintenance. It identified a real-life macro level social outcome of a micro level laboratory phenomenon, which can be an important direction for future research.

Hemolyzed Samples Should be Processed for Coagulation Studies: The Study of Hemolysis Effects on Coagulation Parameters.

Background:Rejecting hemolyzed specimens received for coagulation studies is advised by the Clinical and Laboratory Standards Institute. Receiving such specimens is a common phenomenon in many laboratories. The true impact of hemolysis on coagulation studies is little studied in clinical practice. Aim: The aim of this work is to study the changes occurring in readings of prothrombin time (PT) and activated partial thromboplastin time (aPTT) in hemolyzed samples.Subjects and Methods:A total of 45 blood samples were collected from two groups of healthy donors and patient population. Samples were run for PT and aPTT and then were hemolyzed and again rerun for PT and aPTT. GraphPad Prism 5 (Version 5, USA) was the software used for statistical analysis and paired “t” test was applied with significance level at 0.05.Results:There was trend of increase in the readings of PT and aPTT in normal population and there was trend of decrease in the reading in patient population. The difference between paired samples from group one was not statistically significant, but it was significant in samples from second group.Conclusion:Samples sent for routine screening of coagulation studies with visible hemolysis can be processed for coagulation. There was no difference observed in hemolyzed and non-hemolyzed samples.

Reply to Kaye and Sobel

To the Editor—In their letter [1], Kaye and Sobel express concern regarding the model described in our recent review [2] in which we suggest that recurrent urinary tract infections (UTIs) may in part be attributable to the ability of uropathogenic Escherichia coli (UPEC) to invade and persist within the bladder epithelium. This idea is based on results from numerous studies dating back to 1998 that used bladder cell cultures and mouse models of UTI [3]. In mice, persistent bacterial populations within the bladder are often intracellular, as assessed by gentamicin protection assays and microscopy, and unfazed by antibiotic treatments that effectively sterilize the urine. Ongoing studies in our lab and published work using mice indicate that these intracellular bacteria can reemerge sporadically and grow to high titers within the bladder lumen days to weeks after the cessation of antibiotic treatments (eg, [4–6]). The statement in our review that UPEC can persist intracellularly within the bladders of mice “without any overt clinical symptoms” was not the best choice of words and was perhaps too anthropomorphic [2]. We simply meant that mice could harbor intracellular UPEC reservoirs without displaying any obvious signs of inflammation and in the absence of any detectable bacteria within the urine. Epidemiological studies support the possibility that intracellular bacterial reservoirs within the urinary tract are responsible for many recurrent UTIs in women, but these data may also be explained by the persistence of UPEC reservoirs within local environments outside of the urinary tract (discussed in [7]). Ex vivo assays show that UPEC can invade human urothelial cells in tissue explants from volunteers, and the analysis of shed human urothelial cells collected from the urine of women with UTI symptoms indicates the presence of intracellular E. coli [8, 9]. Together, these sorts of observations suggest that intracellular UPEC reservoirs are likely more than a mouse-specific laboratory phenomenon. However, Kaye and Sobel are correct in noting that the ability of UPEC to persist long-term intracellularly within the human urinary tract has not been established. Determining if intracellular UPEC reservoirs contribute to recurrent UTIs within the human population is a daunting task, plagued by issues of tissue procurement and contamination, possible reinoculation of the bladder by UPEC from niches outside of the urinary tract, and limited means to accurately detect small numbers of bacteria within a relatively enormous tissue. Ultimately, defining the relevance of intracellular UPEC reservoirs to the etiology of recurrent UTIs may only come to light with the development of approaches that can eradicate the reservoirs. We of course agree with Kaye and Sobel that it is premature to alter treatment protocols for recurrent or chronic UTIs outside of controlled clinical investigations based solely on results from mice, but we also feel that it is important to consider alternate rational explanations for recalcitrant UTIs, whether or not they gibe with the traditional view that UPEC act as strictly extracellular pathogens.

Short‐term Effect of Upstream Administration in Comparison to Deferred Injection of Tirofiban on Patients with Acute ST‐Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

High bolus dose tirofiban has been demonstrated to provide greater inhibition of platelet aggregation, but the most appropriate timing of its administration remains unknown. To evaluate the efficacy of upstream vs. deferred administration of tirofiban in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) on clinical outcomes. The 660 patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were divided into upstream (n=330, administration of tirofiban to all patients in emergency room) and deferred groups (n=330, treatment of patients with large thrombus burden or no-reflow phenomenon in cardiac catheterization laboratory during PCI). The primary end-points were death, nonfatal myocardial infarction (MI), stent thrombosis (ST), revascularization of targeted vessels (TVR) or major adverse cardiac events (MACE) at 1 month and 6 months following PCI, with safety end-point at 7 days. Compared with that of the deferred group, there was a significant increase of left ventricular ejection fraction (LVEF) in the upstream group within 7 days (55.5 ± 6.6% vs. 54.6 ± 7.9%, P=0.011). The rates of 7-day and 1-month MACE in the upstream group were lower than those in the deferred group (1.5% vs. 4.2%, 3.3% vs. 7.0%, P=0.037 and 0.034, respectively). However, there were higher tendencies for major and minor bleedings in the upstream group (1.8% vs. 0.9%, 2.7% vs. 1.5%, P=0.315 and 0.280, respectively). To the Chinese patients with acute myocardial infarction undergoing primary PCI, upstream administration of tirofiban was slightly superior to deferred injection for short-term clinical outcomes.

Further Insight into the Nature of Ball-Lightning-Like Atmospheric Pressure Plasmoids

Known since antiquity, ball lightning is a natural, long-lived plasma-like phenomenon associated with thunderstorms and is not well understood due to its rarity and unpredictability. A recently discovered laboratory phenomenon with striking similarity to ball lightning is observed when a high-power spark is discharged from a cathode protruding from a grounded electrolyte solution. Whereas several investigations of these long-lived plasmas have been reported over the past decade, the underlying chemical and physical processes are still unknown. The present work attempts to gain further insight into this phenomenon by examining the effect of electrolyte pH on the plasmoid and observing the chemical and physical structure of the plasmoid using high-speed schlieren videography and FTIR absorption spectroscopy. The results indicate that the lifetime and size of the plasmoid slightly increase as the pH of isoohmic electrolyte solutions deviate from neutrality. The observed absorption spectra of the plasmoids exhibit absorption cross sections in the 620-700, 1500-1560, 2280-2390, and 3650-4000 cm(-1) ranges, the last attributed to the presence of water clusters. Finally, schlieren images revealed a single, sharp density gradient at the boundary layer of the top and sides of the expanding ball-shaped plasmoid, and turbulent mixing below the ball.

EXCITATION OF KINETIC ALFVÉN WAVES BY DENSITY STRIATION IN MAGNETO-PLASMAS

Field-aligned density striation is one of the most common inhomogeneity phenomena in magneto-plasmas, such as in the solar coronal plasma and terrestrial auroral plasma. Kinetic Alfven waves (KAWs) can play an important role in the inhomogeneous heating of coronal magneto-plasmas as well as in the local acceleration of auroral energetic electrons. In this paper, we study the dispersion and instability of KAWs in a magneto-plasma with density striation structures. Results show that KAWs become unstable in the presence of the density striation and the corresponding instability has a maximal growth rate at the perpendicular wavelength close to the spatial scale of the density gradient. Related experimental phenomena in both laboratory and space plasmas are discussed. It is suggested that the excitation of KAWs by the density striation of magneto-plasmas can be of potential importance in understanding the physics of the formation of magneto-plasma filaments and their heating mechanisms, which are often present in the terrestrial auroral plasma, the solar coronal plasma, and other astrophysical plasmas.

Computer sound card as a tool to study of fast changing electromagnetic phenomena

AbstractThis paper presents an original undergraduate experiment which use capabilities of the PC sound device for observation and data acquisition. We study the rapid changing electromagnetic (EM) phenomena in the undergraduate physics laboratory. These phenomena are often encountered in the standard electro dynamical experiments like as electromagnetic induction and oscillation in LC circuit. The comparison of theoretical study within experimental output shows that the usage of PC sound card as digital oscilloscope is suitable in the undergraduate laboratory. For this purpose, an experiment that analyzes Faraday's law of electromagnetic induction using PC sound cards as digital oscilloscope was described. Then we apply the computer sound card to measure damped electromagnetic oscillation in the LC circuit. By using this measurement technique we were able to visualize theoretical expectation and to extract some of the parameter values from the recorded data. Moreover, combining the theoretical description of the problem with an appropriate laboratory experiment and computational procedures gives students a clearer view of the physical problem as a whole. © 2010 Wiley Periodicals, Inc. Comput Appl Eng Educ 21: 158–163, 2013

Fast Sequential Computer Model Calibration of Large Nonstationary Spatial-Temporal Processes

Computer models enable scientists to investigate real-world phenomena in a virtual laboratory using computer experiments. Statistical calibration enables scientists to incorporate field data in this analysis. However, the practical application is hardly straightforward for data structures such as spatial-temporal fields, which are usually large or not well represented by a stationary process model. We present a computationally efficient approach to estimating the calibration parameters using a criterion that measures discrepancy between the computer model output and field data. One can then construct empirical distributions for the calibration parameters and propose new computer model trials using sequential design. The approach is relatively simple to implement using existing algorithms and is able to estimate calibration parameters for large and nonstationary data. Supplementary R code is available online.

Etioplasts with protochlorophyll and protochlorophyllide forms in the under-soil epicotyl segments of pea (Pisum sativum) seedlings grown under natural light conditions.

To study if etiolation symptoms exist in plants grown under natural illumination conditions, under-soil epicotyl segments of light-grown pea (Pisum sativum) plants were examined and compared to those of hydroponically dark-grown plants. Light-, fluorescence- and electron microscopy, 77 K fluorescence spectroscopy, pigment extraction and pigment content determination methods were used. Etioplasts with prolamellar bodies and/or prothylakoids, protochlorophyll (Pchl) and protochlorophyllide (Pchlide) forms (including the flash-photoactive 655 nm emitting form) were found in the (pro)chlorenchyma of epicotyl segments under 3 cm soil depth; their spectral properties were similar to those of hydroponically grown seedlings. However, differences were found in etioplast sizes and Pchlide:Pchl molar ratios, which indicate differences in the developmental rates of the under-soil and of hydroponically developed cells. Tissue regions closer to the soil surface showed gradual accumulation of chlorophyll, and in parallel, decrease of Pchl and Pchlide. These results proved that etioplasts and Pchlide exist in soil-covered parts of seedlings even if they have a 3-4-cm long photosynthetically active shoot above the soil surface. This underlines that etiolation symptoms do develop under natural growing conditions, so they are not merely artificial, laboratory phenomena. Consequently, dark-grown laboratory plants are good models to study the early stages of etioplast differentiation and the Pchlide-chlorophyllide phototransformation.

Evolving role of platelet function testing in coronary artery interventions

The substantial reduction in ischemic events provided by the dual antiplatelet regimen with aspirin and clopidogrel is well documented in patients with acute coronary syndrome and patients undergoing percutaneous coronary intervention. Recently the variable response to the antiplatelet agents has received considerable attention after several “boxed warnings” on clopidogrel. This led to intense controversy on pharmacokinetic, pharmacodynamic, and pharmacogenomic issues of antiplatelet drugs, especially clopidogrel. Research use of platelet function testing has been successfully validated in identifying new antiplatelet drugs like prasugrel and ticagrelor. These platelet function assays are no longer regarded just as a laboratory phenomenon but rather as tools that have been shown to predict mortality in several clinical trials. It is believed that suboptimal response to an antiplatelet regimen (pharmacodynamic effect) may be associated with cardiovascular, cerebrovascular, and peripheral arterial events. There has been intense controversy about this variable response of antiplatelet drugs and the role of platelet function testing to guide antiplatelet therapy. While the importance of routine platelet function testing may be uncertain, it may be useful in high-risk patients such as those with diabetes mellitus, diffuse three vessels coronary artery disease, left main stenosis, diffuse atherosclerotic disease, and those with chronic renal failure undergoing percutaneous coronary intervention. It could also be useful in patients with suspected pharmacodynamic interaction with other drugs to assure the adequacy of platelet inhibition. While we wait for definitive trials, a predictive prognostic algorithm is necessary to individualize antiplatelet therapy with P2Y12 inhibitors based on platelet function assays and genetic testing.

Case report and evaluation of the frequency of the prozone phenomenon in syphilis serology - an infrequent but important laboratory phenomenon

Treponema pallidum specific serology generally remains reactive for life. Therefore, the diagnosis of syphilis reinfection relies on clinical assessment and nontreponemal (reagin) serologic testing. The prozone phenomenon can lead to a falsely nonreactive rapid plasma reagin (RPR) assay result. We report a case of secondary syphilis in a HIV infected patient with a previous history of syphilis infection, where a falsely nonreactive RPR assay was associated with a delayed diagnosis of reinfection and infectious syphilis. The prozone phenomenon was detected in several of the patient's serum samples collected around this time. We subsequently undertook a prospective evaluation for the prozone phenomenon in 3222 consecutive sera, which were assayed using the RPR assay for clinical purposes over a 10-month period. The overall rate of the prozone phenomenon was 2 out of 3222 samples (0.06%; 95% confidence interval (CI): 0.02-0.22%) and the rate per reactive sample was 2 out of 397 (0.5%; 95% CI: 0.14-1.81%). Clinicians should request RPR testing at dilutions of sera when syphilis is suspected clinically and the RPR assay is nonreactive.

A NEW STELLAR MIXING PROCESS OPERATING BELOW SHELL CONVECTION ZONES FOLLOWING OFF-CENTER IGNITION

During most stages of stellar evolution the nuclear burning of lighter to heavier elements results in a radial composition profile which is stabilizing against buoyant acceleration, with light material residing above heavier material. However, under some circumstances, such as off-center ignition, the composition profile resulting from nuclear burning can be destabilizing, and characterized by an outwardly increasing mean molecular weight. The potential for instabilities under these circumstances, and the consequences that they may have on stellar structural evolution, remain largely unexplored. In this paper we study the development and evolution of instabilities associated with unstable composition gradients in regions which are initially stable according to linear Schwarzschild and Ledoux criteria. In particular, we explore the mixing taking place under various conditions with multi-dimensional hydrodynamic convection models based on stellar evolutionary calculations of the core helium flash in a 1.25 \Msun star, the core carbon flash in a 9.3\,\Msun star, and of oxygen shell burning in a star with a mass of 23\,\Msun. The results of our simulations reveal a mixing process associated with regions having outwardly increasing mean molecular weight that reside below convection zones. The mixing is not due to overshooting from the convection zone, nor is it due directly to thermohaline mixing which operates on a timescale several orders of magnitude larger than the simulated flows. Instead, the mixing appears to be due to the presence of a wave field induced in the stable layers residing beneath the convection zone which enhances the mixing rate by many orders of magnitude and allows a thermohaline type mixing process to operate on a dynamical, rather than thermal, timescale. We discuss our results in terms of related laboratory phenomena and associated theoretical developments.

Anesthetic Neurotoxicity

Anesthetic Neurotoxicity

Moisture-Induced TBC Spallation on Turbine Blade Samples

Delayed failure of TBCs is a widely observed laboratory phenomenon, although many of the early observations went unreported. “The weekend effect” or “DeskTop Spallation” (DTS) is characterized by initial survival of a TBC after accelerated laboratory thermal cycling, followed by failure when exposed to ambient humidity or water. Once initiated, failure can progress to completion quite dramatically in less than a second. To this end, the water drop test and digital video recordings have become useful techniques in studies at NASA (Smialek, Zhu, Cuy), DECHMA (Rudolphi, Renusch, Schütze), and CNRS Toulouse/SNECMA (Déneux, Cadoret, Hervier, Monceau). In the present study the results for a commercial turbine blade, with a standard EB-PVD 7YSZ TBC top coat and Pt-aluminide diffusion bond coat are reported. Cut sections were intermittently oxidized at 1100°, 1150°, and 1200°C and monitored by weight change and visual appearance. Failures were distributed widely over a 5–100hr time range, decreasing with oxidation temperature. At some opportune times, failure was captured by video recording, documenting the appearance and speed of the moisture-induced spallation process. The failure interfaces exhibited, on the TBC side, alumina scale grains (decorated with Ta-rich oxide particles) and, on the exposed bare metal surface of the blade, imprints from the scale grains (with alumina islands and streamers). The phenomenon is based on moisture-induced delamination at the alumina scale - bond coat interface. Cycling damage is a contributing factor as cracking allows access of moisture to this interface, while high strain energy provides the driving force for spallation. It has been proposed that moisture reacts with aluminum in the bond coat and releases hydrogen atoms that ‘embrittle’ the interface. A modified chemical viewpoint of scale adhesion results, including a negative synergistic effect with interfacial sulfur.

Aspirin resistance in off-pump coronary artery bypass grafting.

Anti-platelet therapy with aspirin is the cornerstone of treatment after coronary artery bypass grafting (CABG). Aspirin resistance describes the clinical observation of the inability of aspirin to prevent thrombotic complications or the laboratory phenomenon of absence of the effect of aspirin on platelet inhibition tests. Off-pump CABG (OPCAB) is associated with reduced platelet activation and turnover compared to on-pump surgery which may indicate that aspirin is more effective after OPCAB. Our aim was to evaluate the efficacy of aspirin and incidence of aspirin resistance in patients undergoing OPCAB. A total of 331 patients was recruited, of which 111 underwent primary OPCAB (group A) and 220 controls with ischaemic heart disease received medical therapy. Arachidonic acid-induced platelet aggregation and urinary 11-dehydro thromboxane B2 (11-dehydroTxB2) were measured at baseline and following aspirin administration on days 1, 4 and 10. A 6-month follow-up was completed in patients who developed aspirin resistance. On the first postoperative day, 78 patients (70.3%) were aspirin sensitive (AS) and 33 (29.7%) were aspirin resistant (AR). Of the latter, 18 (16.2%) and five (4.5%) patients remained resistant on days 4 and 10, respectively. AR patients had significantly greater platelet aggregation and urinary 11-dehydroTxB2 levels at all time points than those in the AS group. All patients in the AR group were AS by 6 months. All controls were sensitive to aspirin with similar platelet aggregation and 11-dehydroTxB2 to those in the AS group. Aspirin resistance is a transient phenomenon during the early postoperative period in approximately 30% of patients undergoing OPCAB.

Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena

The terminal complement inhibitor eculizumab has become the standard of treatment in patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). In this retrospective study, 19 PNH patients received chronic therapy with eculizumab with a median duration of 16 months (range 6-46 months). Parameters of hemolysis, transfusion requirements, and serum iron parameters were analyzed. Lactate dehydrogenase levels were significantly decreased by 85% from a median of 1897 U/l (range 293-3360) to 283 U/l (range 143-667), with an 86% reduction of transfusion requirements, whereas other parameters of hemolysis remained abnormal. Six patients (31.6%) became completely transfusion independent. A significant increase in ferritin levels from a median of 104 μg/l before to a median of 528 μg/l (p = 0.011) during treatment with eculizumab was observed. This was more pronounced in patients with low reticulocyte production index and/or requiring blood transfusions. Monospecific direct Coombs test was positive in most PNH patients, indicating a shift to extravascular hemolysis. Positive immunofixation for IgG kappa was observed, due to the presence of eculizumab in the serum. Eculizumab was safe and well tolerated long term in our study population. Iron should not be routinely supplemented in PNH patients treated with eculizumab without close monitoring of iron parameters, and iron depletion therapy should be considered in the case of overload.

Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is ‘too big to fail’

With each failure of anti-amyloid-β therapy in clinical trials, new trials are initiated with no hint of slowing down. This may be due, in part, to the fact that the amyloid cascade hypothesis has been so modified over time that it is now impossible to confirm or deny. The hypothesis now states, in effect, that invisible molecules target invisible structures. Still relevant, however, are multiple factors that surely cast some doubt but have either been rationalized or overlooked. Among these are the poor correlation between amyloid-β deposits and disease, the substantial differences between familial and sporadic disease, pathological assessment that indicates the secondary nature of lesions/proteins/cascades, the fact that soluble species are poorly reproducible laboratory phenomena, and the irrelevance of synaptic assessment to pathological interpretation. Although not yet dogma, the premature addition of mild cognitive impairment as the implied in vivo homologue to the soluble toxin-synapse interaction is also problematic. In either case, the amyloid cascade hypothesis continues to dominate the Alzheimer's disease literature and grant applications. The more the neuroscience community perseverates along these lines in the face of accumulating outcome data to the contrary, the more one is left to wonder whether the hypothesis is too big to fail.