On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2016 Jan 23, Daniel Schwartz commented:

This paper addresses a practical consideration when providing dialysis to a patient with a toxic alcohol ingestion - the need to plan the nursing hours likely needed to run dialysis, which is often in the on-call/overnight period.

The model has been converted to a web and mobile app based tool to support easier usage: http://qxmd.com/calculate/dialysis-duration-needed-for-methanol-ingestion

Conflict of interest: Medical Director, QxMD

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent report.

Is it possible that the fistula might alternatively be described as an unusually prominent vessel of Wearn? These vessels are unusually prominent in PAIVS, probably due to the hypertensive right ventricle.

http://www.ncbi.nlm.nih.gov/pubmed/23332812

For additional commentary, please see

https://twitter.com/BrettSnodgrass1/status/412868120508788736/

Comments and suggestions are welcome.

Thank you kindly.

On 2015 Apr 02, Harri Hemila commented:

Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001 misled readers for a decade due to the errors in the extraction and analysis of data.

The Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001 has substantial errors. I found errors in the 2009 update of that review by Kaur B, 2009. My comments of the 2009 update are available as a separate document. Then I found that the errors originated in the first version by Kaur B, 2001, and they were repeated in the updates by Ram FS, 2004 and by Kaur B, 2009, until the review was withdrawn by Kaur B, 2013. Thus the Cochrane review (2001) on vitamin C and asthma misled readers for over a decade due to the errors in the extraction and analysis of data. Here I briefly describe the errors in the first version of the Cochrane review (2001) on vitamin C and asthma by Kaur B, 2001.

As relevant background knowledge, it was known long before Kaur B, 2001 that exercise can cause exercise-induced bronchoconstriction (EIB or EIA, exercise-induced asthma), eg Mahler DA, 1993, and that respiratory virus infections can cause exacerbations of asthma, eg Nicholson KG, 1993. Thus, if vitamin C influences bronchoconstriction, the effects might be most pronounced during exercise and/or viral infections.

Errors in the extraction of data

Kaur B, 2001 wrote in the Results section (p.4): “there were two studies where the protective effects of vitamin C were investigated using exercise challenge. Both these studies reported pulmonary function outcomes, but one (Cohen 1997) reported absolute mean value post-exercise, while the other (Schachter 1982) reported absolute change post-exercise .”

In Comparison 01: Outcomes 01 and 02 (p. 10), Kaur B, 2001 presented the results of those two studies. However, Cohen HA, 1997 had 20 participants, yet Kaur B, 2001 showed data for only 11 participants, without revealing to the reader that data for 9 of Cohen's participants are missing from their review. Cohen showed the data of 11 participants on the basis that vitamin C was beneficial for them. However, it is inappropriate and violates the ITT principle to show such a biased subgroup in the Cochrane review by Kaur B, 2001, without explaining that another 9 participants were excluded. Cohen HA, 1997 also reported that on the placebo day, 20/20 of the participants had EIB, whereas on the vitamin C day, 10/20 had EIB. This comparison does not need any imputations, but these data were not extracted for the Cochrane review by Kaur B, 2001.

A decade before the Kaur B, 2001 review, papers reported that “EIA symptoms start after exercise, peak 8 to 15 minutes after exercise” so that there is a delay between the end of exercise and the peak of FEV1 decline, and “a fall of 10% or more in the FEV1 after exercise is diagnostic” so that the relative change in FEV1 (in %) is the most reasonable outcome when assessing EIB, eg Mahler DA, 1993. Such facts are relevant when analyzing EIB trials.

Kaur B, 2001 considered that “exercise challenge” was a particular issue in the Cohen HA, 1997 and Schachter EN, 1982 studies, see the above extract. However, in Outcome 01 (p.10) the Cochrane review showed data on the pre-exercise FEV1 levels, which is not an outcome influenced by exercise. In Outcome 02 (p.10) the Cochrane review extracted data on the absolute post-exercise FEV1 level for Cohen HA, 1997 and absolute FEV1 change for Schachter EN, 1982. These outcomes are not relevant, since the standard outcome for EIB is the relative change in FEV1 (in %), see above.

Furthermore, the greatest decline in FEV1 occurs about 8 to 15 min after the end of exercise, above. However, in Outcome 02 (p.10), Kaur B, 2001 shows Schachter's FEV1 changes immediately after exercise in Schachter's Table II, instead of FEV1 changes 5 min after exercise which Schachter reported in Table III. The latter is much more relevant in a study on EIB, since “EIA symptoms ... peak 8 to 15 minutes after exercise”, Mahler DA, 1993.

Kaur B, 2001 (p.4) write that “Anah did not report data in a manner that permitted further analysis”. However, in the following paragraph, Kaur B, 2001 wrote that, in the Anah study, “there were 9 exacerbations in the intervention group which had 22 patients and 35 exacerbations in the placebo group which had 19 patients ”. Thus, Anah CO, 1980 did report data that can be statistically analyzed, see below.

Errors in the analysis of data

Schachter EN, 1982 and Cohen HA, 1997 were cross-over studies so that the same participants were randomly administered vitamin C or the placebo. Such data should be analyzed by the paired t-test.

In Outcomes 01 and 02 (p.10), Kaur B, 2001 analyzed Schachter and Cohen data by the unpaired t-test, which is unsound for paired data. Kaur B, 2001 reported no difference between the vitamin C and placebo days for 11 of Cohen's participants with P=0.4 (unpaired t-test), whereas the correct paired t-test yields P=0.003.

Furthermore, given that the goal was to examine the effect of vitamin C on EIB, Kaur B, 2001 should have calculated the relative changes in FEV1 (in %), see above.

Schachter EN, 1982 published the data for all their 12 participants, and Kaur B, 2001 could have used the paired t-test to analyze the relative changes.

Similarly, Kaur B, 2001 could have calculated the relative changes for the 11 participants published by Cohen HA, 1997, and could have imputed eg “no effect” for the 9 participants who had missing data.

Nevertheless, using the paired t-test is a simplistic analysis of FEV1 changes, since it is possible that the effect of vitamin C depends on the severity of EIB. Hemilä H, 2013 analyzed the two studies using linear regression. Schachter EN, 1982 showed a 55% reduction in the postexercise FEV1 decline (95%CI 32% to 78%) with vitamin C. Imputation of “no effect” to the 9 participants with missing data of Cohen HA, 1997 yielded an estimated 42% reduction in the postexercise FEV1 decline (19% to 64%) with vitamin C. Finally, Cohen HA, 1997 also published the EIB status, which has no missing data. On the placebo day, 100% (20/20) of participants suffered from EIB, whereas on the vitamin C day, only 50% (10/20) suffered from EIB. Thus vitamin C caused a 50 percentage point decrease (23 to 68) in the occurrence of EIB, see Hemilä H, 2013.

Kaur B, 2001 (p. 4) claimed that “Anah did not report data in a manner that permitted further analysis,” which is incorrect. Anah CO, 1980 reported that in the placebo group (n=19), there were 35 asthma attacks, but in the vitamin C group (n=22), only 9 attacks. By using the standard Poisson approach, these data give RR=0.22 (0.09 to 0.47). Anah did not publish the individual level data and it might be over-dispersed, see Glynn RJ, 1996. Nevertheless, Anah published partial descriptions of the asthma attack distributions which can be used to impute more realistic distributions for the treatment groups, yielding a 95%CI of 0.06 to 0.81, which is still far from the null effect, see Hemilä H, 2013. Furthermore, the exact distribution of severe and moderate asthma attacks in the vitamin C group can be inferred from Anah CO, 1980 and this outcome needs few imputations. Vitamin C reduced the incidence of severe and moderate asthma attacks by RR=0.11 (0.02 to 0.48).

In conclusion, had Kaur B, 2001 extracted data correctly, and had they properly carried out the statistical analysis, they could have concluded in 2001 that there was strong evidence that vitamin C was beneficial against EIB in Cohen HA, 1997 and in Schachter EN, 1982, and against common cold-induced asthma exacerbations in Anah CO, 1980.

Secondary analysis of the Cohen HA, 1997, Schachter EN, 1982 and Anah CO, 1980 studies has been carried out by Hemilä H, 2013, Hemilä H, 2013, and Hemilä H, 2014.

On 2015 Jan 08, David Mage commented:

Jack Finklea, first Director of the EPA Health Effects Research Laboratory, RTP/NC, wrote here as follows: "We should use what we know in preventive programs and in directing future research. We will make some mistakes when we apply incomplete knowledge, but I think that our need for an excellent scientific information base should not mask the need for society to act on what we do know to clean-up the workplace, and environmental pollution."

The five major mistakes EPA made in setting the first Particulate Matter (PM) National Ambient Air Quality Standard were as follows:

1) The PM standard was for Total Suspended Particulate (TSP) as measured by a highvol sampler that collected all PM with aerodynamic diameters (AD) ranging up to 40 microns. This included PM too large to be inhaled. It was later revised to reflect only respirable PM that were < 10 um and < 2.5 um AD.

2) The first PM NAAQS was 75 ug/m3 TSP as a 1-year geometric mean (GM) based on PMID 6017082. This was a major mistake because two values 5 and 5 have an arithmatic mean (AM) of 5 and a GM of 5 but 0 and 10 have an AM of 5 and a GM of 0! But note, the health effect of {0,10} is greater than the health effect of {5,5}. In addition the GM is not relatable to the dose of inhaled PM even if the total volume of air inhaled during the year were known.

3) The PM NAAQS were, and still are now, based upon the collected mass of the PM, not its molecular composition. From first principles, the cardio-pulmonary toxicity of any PM molecule depends upon its molecular structure and not its molecular weight. Thus if two PM samplers collect the identical number of molecules of the same AD in the same amount of time, EPA would consider the PM collection with the higher average molecular weight to produce more of a health effect (e.g., it is more toxic) than the other collection. This mistake has not been corrected and still underlies virtually all PM studies.

4) All PM NAAQS are based upon the PM concentration measured at an ambient PM monitoring station location meeting various siting and location criteria. Given that no subject spends 24-hours continuously breathing only the ambient air at the station location, the personal PM exposure of all people living in the area will not be numerically equal to the official ambient PM concentration that EPA compares to the NAAQS.

5) The PM NAAQS and all PM epidemiology studies upon which it is based assume the PM health effects follow an ambient PM concentration response relation or a personal PM exposure response relation. They follow neither! They must follow a dose response relation with dose given a value with units specific to the health effect under consideration. For instance: i) if the health effect is systemic, then the dose should be reported as mg/kg-day; ii) if the health effect is related to pulmonary airway surface irritation, then the dose should be reported as mg/m2-day where the mg might, for example, refer to the mass of PM deposited on the non-ciliated sensitive area of alveoli of the pulmonary tract, and m2 refers to that area (not the entire area of the pulmonary tract).

On 2014 Nov 19, Wei Liu commented:

After a long 20 years, the results are confirmed by another scientist Michael Bailey.

On 2017 Jun 08, Monica Green commented:

There is a typographical error in this entry (PMID: 11624264). The title of the study should correctly read: In search of an "Authentic" women's medicine: the strange fates of Trota of Salerno and Hildegard of Bingen.

On 2017 Feb 10, Romain Brette commented:

Dear authors,

I am very disappointed and rather surprised by the tone of your reply, and even more surprised by your final reflections. You consider that one should not post comments publicly. But to post comments and let authors reply is the whole point of PubMed Commons. It is not clear to me what harm is done to science since the authors's responses are published; on the contrary. There is no reason to be aggressive when discussing with a peer.

Best regards, Romain Brette

On 2017 Feb 10, David Attwell commented:

The answers to Dr Brette’s new points are as follows.

(1a) Ohmic vs Goldman dependence of current on voltage

For a cell as assumed in Attwell & Laughlin (2001) (i.e. 200 Megohm membrane measured with a 10mV hyperpolarizing step, VNa=+50mV, VK=-100mV, Vrp=-70mV, [Na]o=[K]i=140mM, T=37C), assuming a Goldman voltage dependence for the Na⁺ and K⁺ fluxes through ion channels leads to PNa/PK=0.0746 and a Na⁺ influx at the resting potential of 130pA, corresponding to an ATP consumption of 2.7x10⁸ molecules/sec. This is 21% less than the 3.42x10⁸ molecules/sec we calculated using an ohmic dependence of the currents on voltage. This difference is negligible given the variation of measured input resistances and the range of other assumptions that we needed to make. Furthermore, there are no data establishing whether the voltage-dependence of Na+ influx is better described by an ohmic or a Goldman equation.

(In a later post Dr Brette claims that the error arising is 40%. We suspect that his value arises from forgetting the contribution of the Na/K pump current to setting the resting potential, which leads erroneously to PNa/PK=0.05, and a 41.3% lower value than the ohmic dependence predicts.)

(1b) Cl^- permeability

Our point was that the Cl^- permeability was negligible. Which equation was used to derive that fact is therefore irrelevant.

(2) Pumps

We still disagree with the notion that, for a membrane with just Na⁺ and K⁺ fluxes, the system is unstable if it only has a Na/K pump. The Na pump rate is adjusted to match activity via its dependence on [Na⁺ ]i and by the insertion of more pumps when needed.

(3) Cost of Na⁺ extrusion at the mean potential

Tonic synaptic activity may depolarize cells by a mean value of ~4-8mV (Paré et al., 1998, J Neurophysiol 79, 1450). This will affect the calculation of “resting” Na+ influx negligibly (e.g. by ~6mV/120mV = 5% for a 6mV depolarization with Vrp=-70mV and VNa=+50mV). As stated in our earlier comment, this depolarization does not affect the ATP used per Na⁺ pumped by the Na/K pump. Finally the ATP used on extruding synaptic ion entry is considered separately in the calculations.

(4) What input resistance tells us

For cortical L2/3 pyramidal cells the majority of the membrane area is in the basal dendrites, which have an electrotonic length of ~0.24 space constants, while the apical dendrites have an electrotonic length of ~0.69 space constants (mean data at body temperature from Trevelyan & Jack, 2002, J Physiol 539, 623). Larkman et al. (1992, J Comp Neurol 323, 137) similarly concluded that most of the dendrites of L2/3 and L5 pyramidal cells were within 0.5 space constants of the soma.

Elementary cable theory shows that, for a cable (dendrite or local axon) with a sealed end, with current injection at one end, the ratio of the apparent conductance to the real conductance, and thus the ratio of our calculated ATP usage (on Na⁺ pumping to maintain the cable’s resting potential) to the real ATP usage, is given by (1/L).(exp(2L) - 1)/(exp(2L) + 1) where L is the electrotonic length (cable length/space constant). For L=0.24, 0.5 and 0.69, respectively, this predicts errors in the calculated ATP use of 1.9%, 7.6% and 13.3%, which are all completely negligible in the context of the other assumptions that we had to make.

For the axon collaterals near the soma, there is less information on electrotonic length, but the few measurements of axon space constant that exist (Alle & Geiger, 2006, Science 311, 1290; Shu et al., 2006, Nature 441, 761) suggest that the axon collaterals near the soma will similarly be electrically compact and thus that their conductance will be largely reflected in measurements of input resistance at the soma. We excluded the part of the axon in the white matter from our analysis, but did include the terminal axon segments in the grey matter (where the white matter axon rises back into a different cortical area. Re-reading after 16 years the source (Braitenberg & Schüz, 1991, Anatomy of the Cortex, Chapter 17) of the dimensions of these axons, it is clear that those authors were uncertain about the contribution of the terminal axon segments to the total axon length, but assumed that they contributed a similar length to that found near the soma in order to account for the total axon length they observed in cortex. It is unlikely that these distant axon segments will contribute much to the conductance of the cell measured at the soma but, partly compensating for this, part of the axon in the white matter will. This, along with the electrical compactness of the dendrites and proximal axons discussed above, implies that our calculated ATP use on the resting potential is likely to be correct to within a factor of 1/f = 1.57 (where f=0.64 is the fraction of the cell area that is electrically compact [ignoring the minor voltage non-uniformity quantified above], i.e. the soma, dendrites and proximal axons, calculated from the capacitances in Attwell & Laughlin and assuming that the proximal axons provide half of the total axon capacitance in the grey matter).

In fact the situation is likely to be better than this, because this estimate is based on membrane area, but ATP use is proportional to membrane conductance. Estimated values of the conductance of axons (Alle & Geiger, 2006, Science 311, 1290) suggest that the specific membrane conductance per unit area in axons is significantly lower than that in the soma and dendrites (see the Supplementary Information section on Granule Cells in Howarth et al. (2010) JCBFM 30, 403), which reduces the ATP used on maintaining the resting potential of axons.

General reflections on what people expect from the Attwell & Laughlin paper

Our paper tried to introduce a new way of thinking about the brain, based on energetics. Given the large number of assumptions involved it would be a mistake to expect individual values of ATP consumption to be highly accurate. Remarkably, the total energy use that we predicted for the grey matter turned out to be pretty well exactly what is measured experimentally. Nevertheless, constant updating of the assumptions and values is, of course, essential. It is interesting that the value we derived for the ATP used per cell on the action potential (3.84x10⁸ ATP) was initially revised downwards nearly 4-fold in the light of papers showing less temporal overlap of the voltage-gated Na⁺ and K⁺ currents than occurs in squid axon (Alle et al., 2009, Science 325, 1405), but has increased with more recent estimates back to be close to our original estimate (3.77-8.00x10⁸ ATP, Hallermann et al., 2012, Nature Neuroscience 15, 1007).

The most important assumption that we made was that all cells were identical, which immediately implies that this can only be an approximate analysis. We were very happy that the total energy use that we predicted from measured ionic currents, cell anatomy and cell densities was so close to the correct value.

General reflections on post-publication peer comments

We believe that if someone has questions about a paper then the most productive way to get them answered is: (i) to think about the issues; if that fails (ii) to write to the authors and ask them about the questions, rather than posting some vague and erroneous comments that will forever be linked to the paper, regardless of their validity; and if that fails (iii) to write a paper or review which goes through peer review, pointing out the problems. Peer review is crucial for determining whether the points are valid or not - it potentially saves many readers the time needed to read possibly erroneous comments.

It takes a long time to reply to such comments, and we feel that Dr Brette could have done the calculations that we have provided in our two sets of responses. We will not be posting further responses therefore.

David Attwell & Simon Laughlin, 09-02-17

On 2017 Feb 08, Romain Brette commented:

A qualification about point (2): I agree it is theoretically possible to use a single 3:2 Na/K pump and have a stable system, if firing rate is lower than a limit set by the minimum voltage at which the pump can work (from thermodynamic considerations). In this case, it is probably ok to neglect the other pumps (assuming chloride does not play a role); at least the model is consistent. As I wrote in my initial comment, point (4) seems to be the more problematic point. Point (1a) leads to a correction of about 40%.

On 2017 Feb 01, Romain Brette commented:

Thank you very much for your detailed reply. I obviously sympathize with the idea that theoretical work requires simplifying assumptions. The question is to what extent these simplifications lead to accurate estimates, and I disagree that the number of citations is a good indicator of this point.

Here is a more detailed analysis. I will respond starting from the last point, as it will hopefully be clearer.

(4) What input resistance tells us

Thank you for pointing to your more recent studies. It still remains that the assumption “that input resistance measured at the soma can give us a rough estimate of ATP use on the resting potential” cannot be correct here. I am simply using the numbers given in the paper (Attwell & Laughlin 2001), in particular in section “Energy needed for action potentials”, where it is considered that the typical unmyelinated axon has length 4 cm and diameter 0.3 µm. This means that most of the axon’s length is beyond the characteristic length of voltage attenuation (not more than a few hundred µm) and so the input resistance at the soma does not include the axon. But the membrane area of the axon is many times that of the soma, again according to the numbers used in this paper. One can simply divide the charge needed to depolarize the axon by the charge needed to depolarize the soma, as given in the text: 3.77 x 10^-11 / 1.96 x 10^-12 = about 20. So the membrane resistance (1/total conductance) should be about 20 times lower than measured at the soma. One may argue that the input resistance at the soma also includes part of that of the dendrites. But the total dendritic area is (following the numbers given in the paper) 1/3 of that of the axon, so even if we include all of it (very conservative), we still find that the membrane resistance is overestimated by a factor 3. So one needs to apply a correction factor of 3-20 (3 being very conservative).

(3) Cost of Na+ extrusion at the mean potential

I am afraid I was not clear enough. I was referring to a much more elementary point, which is that the fluxes of Na+ and K+ depend on the membrane potential, since the ionic currents depend on the membrane potential (at least through the driving force). With synaptic activity, the membrane potential is typically depolarized because of the mean synaptic current. So the balance of currents used in the methods should include the total current Isyn + INa + IK, in addition to the pump current. Unfortunately we have now three unknowns for two observables (input resistance and mean potential).

(2) Pumps

Again I apologize that my comment was apparently not clear. In a system with a single pump with 3:2 stoechiometry, equilibrium can only be achieved if the mean flux of Na+ through the channels exactly equals 3/2 of the mean flux of K+. This can only happen at a very specific potential; so the pump can only do its job around one particular membrane potential value. If the neuron is depolarized by synaptic activity, for example, the pump fails to maintain equilibrium (too much K+ leaking out). Finally it can also be seen that, because each action potential produces an equivalent flux of Na+ and K+ (electroneutrality), i.e. with 1:1 stoechiometry, a single 3:2 pump cannot maintain equilibrium at high activity.

To compensate for arbitrary fluxes of n ions, one needs to modulate the activity of at least n pumps. In a Na/K system, theoretically a second Na/K pump with a different stoechiometry would work. Alternatively, one can use two additional cotransporters which carry Cl- in opposite directions together with K+ and/or Na+ (eg NKCC1 + KCC2). In such a system, the Na/K pump is used not only to compensate for Na+ flowing into the ionic channels, but also to provide energy for the other pumps in the form of the Na+ gradient. In any case, ensuring ionic equilibrium independently of activity (input or output) requires at least two pumps, and unfortunately this makes it impossible to estimate their activity from just the knowledge of input resistance and mean/resting potential.

(1a) Ohmic vs Goldman-Hodgkin-Katz dependence of current on voltage.

I agree that using a linear model is more convenient. My point was rather that it is not accurate. It should be recalled that the linear (or “ohmic”) model of ionic currents has no biophysical basis (in contrast with GHK, which is based on a biophysical model, although indeed a simple one). It was derived empirically by Hodgkin & Huxley in the squid axon. However in the same preparation, Hodgkin and Katz (HODGKIN AL, 1949) have shown that the resting potential is better predicted by the GHK equation.

(1b) Cl- permeability.

Thank you for these references, it is very helpful. Note however that to show that chloride permeability is low, Xu and Adams used indeed the GHK equation, not the ohmic equation. Note also that all the points I have made above still apply to a Na/K system.

Summary

In summary, these different points make it unlikely that it is possible to estimate Na+ fluxes from just the knowledge of input resistance (especially at the soma) and resting (or mean) potential. One would rather need estimates of K+ and Na+ currents at the mean potential (eg from patch-clamp measurements).

On 2017 Jan 31, David Attwell commented:

Our answers to Dr Brette’s comments are as follows.

(1a) Ohmic vs Goldman-Hodgkin-Katz dependence of current on voltage

We assumed an ohmic dependence on voltage of the ‘leak’ currents for Na⁺ and K⁺ for simplicity. The maths can also be done for a GHK dependence of Na⁺ and K⁺ current on voltage (e.g. see Johnston & Wu (1995), Foundations of Cellular Neurophysiology, Chapter 2, Example 2.3), but it is more convenient to assume an ohmic dependence because that then allows easier conversion of input resistances (1/(GNa+GK)) reported in the literature into ATP consumption (without the need to assume a value for [Na⁺ ]i). In any case, the GHK equation makes assumptions (https://en.wikipedia.org/wiki/GHK_flux_equation) that are unlikely to all be correct.

(1b) Cl^- permeability

Our paper was for the grey matter of the mammalian neocortex. The permeability of the membrane to chloride is reported to be very low in mammalian cortical neurons (see Fig 5c and p121 of the Discussion of Thompson, Deisz & Prince, 1988, J Neurophysiol 60, 105, available at http://jn.physiology.org/content/jn/60/1/105.full.pdf). Similarly, for rat parasympathetic neurons, Xu & Adams (1992, J Physiol 456, 405, https://www.ncbi.nlm.nih.gov/pubmed/1284080) found that for the resting membrane PCl/PK<0.001.

Nevertheless, we extended our analysis slightly, to include the Cl^- component of the membrane permeability, here: Howarth, Peppiatt-Wildman & Attwell (2010) JCBFM 30, 403 http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2009.231

(2) Pumps

Dr Brette states “The model considers only the Na/K pump. However, such a system cannot be stable; there has to be at least another pump”.

This is simply incorrect, and the system is stable. The pump exports 3 Na⁺ and imports 2 K⁺ for each ATP consumed. The equations in our paper are set up so that there is no net current across the membrane (the sum of the Na⁺ , K⁺ and pump currents are zero), and so that the magnitude of the pump current is 1/3 of the Na⁺ charge entry (so d[Na⁺ ]i/dt=0) and 1/2 of the K⁺ charge exit through the resting conductance (so d[K⁺ ]i/dt=0). This can be seen by evaluating the resting potential for zero net current (following equations 1-3 of Attwell & Laughlin, 2001), and then calculating the ion fluxes.

(3) Cost of Na⁺ extrusion at the mean potential

We assume this point is based on the notion that the energy needed to extrude Na⁺ should be voltage-dependent, so that the ATP needed would be smaller at a more depolarised potential. In fact the stoichiometry of the Na/K pump is apparently not significantly voltage-dependent (between 0 and -60mV), so that the ATP used is always 1/3 of the Na⁺ pumped (see Rakowski, Gadsby & de Weer, 1989, J Gen Physiol 93, 903, https://www.ncbi.nlm.nih.gov/pubmed/2544655), as we assumed.

(4) What input resistance tells us

The Attwell & Laughlin (2001) paper attempted to provide order of magnitude estimates for the ATP used on different subcellular processes in neurons, and this involved assuming that input resistance measured at the soma can give us a rough estimate of ATP use on the resting potential. The analysis addressed energy use only in the grey matter, excluding the majority of the cortical neuron axon in the white matter (which we dealt with here: https://www.ncbi.nlm.nih.gov/pubmed/22219296). Nevertheless, of course voltage is non-uniform in spatially distributed neurons, and input resistance measured at the soma will then not precisely define the resting influx of Na⁺ measured all over the cell. In later work (Howarth, Peppiatt-Wildman & Attwell (2010) JCBFM 30, 403 http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2009.231; Howarth, Gleeson & Attwell (2012) JCBFM 32, 1222, http://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2012.35) we estimated resting Na⁺ influx in different cellular locations. Thus, there is plenty of scope for improving estimates of the energy consumed on resting potentials, as more data become available.

Summary

Broadly, most of these points reflect the fact that theoretical work often requires simplifying assumptions. Clearly the assumptions that we made have been useful, because (according to Web of Science or Google Scholar respectively) the paper has been cited 1067 or 1752 times. However, there is always room for improvement and we look forward to seeing Dr Brette’s own detailed analysis.

David Attwell & Simon Laughlin, 31-1-17

On 2017 Jan 18, Romain Brette commented:

This is a seminal paper on the energetics of the brain, where the authors derive estimates of the energy (ATP) consumption of various components of the nervous system, and in particular that due to excitatory neural activity, not including myelinated axons. The methods contain theoretical reasoning to calculate the energy cost of an action potential and of maintaining the resting potential, in particular. Thus I would highly recommend anyone interested in the theory of neural energetics to read this paper. It is also a good source of relevant empirical data.

There are two theoretical approaches to derive energetic estimates. One is to estimate ATP consumption for various intracellular processes, for example using the stoechiometry of the Na/K pump (3 Na+ out, 2 K+ in, 1 ATP consumed). The problem with this approach is metabolic processes are very complex and only partially known, so any theoretical approach is bound to make more or less drastic approximations. The other is rather based on thermodynamic theory, where one calculates the change in free energy due to transmembrane ion movements. From this, one can then derive the minimal rate of ATP consumption. The disavantage of this approach is it only gives a lower bound on ATP consumption. However, if we assume that metabolic processes are quite efficient, then it should still give a correct order of magnitude. This paper chooses the first approach.

I have a few criticisms however about the calculation of the energy consumption of the resting potential (first part of the methods).

1) The calculation is based on a model with two linear currents (Na+ and K+), following the Hodgkin-Huxley formalism. However, even in the HH model, the leak current (represented here by the K+ current) is carried by several ions. It is a mixture of currents (Na+, K+, Cl-). Implicitly, the approach of the authors assumes that the neuron’s resting potential is above the reversal potential of K+ because there is a Na+ flux at rest. But according to H&H, the leak current (at least in the squid axon) is mostly carried by chloride, which has a higher reversal potential than potassium. Therefore, the fact that the resting potential is above EK tells us little about the flux of Na+ at rest. In fact, the resting potential is more accurately predicted by the GHK voltage equation, as a function of the permeabilities to Na+, K+ and Cl-. Unfortunately, the sole knowledge of resting potential and input resistance (2 observations) does not allow us to deduce the fluxes of 3 different ions.

2) The model considers only the Na/K pump. However, such a system cannot be stable; there has to be at least another pump (or three pumps if we include Cl-). Presumably, this simplification was made because the Na/K pump is the major source of energy, and because other relevant pumps are not electrogenic. Indeed there are co-transporters such as NKCC1 (moves Na+, K+, Cl- into the cell, with 1:1:2 stoechiometry) but these do not consume energy. However, including these in the model (which as mentioned is necessary for stability of ionic concentrations) changes the balance of fluxes and therefore the activity of the Na/K pump. This relates to the comment above on the approach based on the stoechiometry of a few selected processes.

3) The authors estimate the cost of Na+ extrusion at the resting potential. However, it would be more relevant to apply the calculation to the mean potential, not the resting potential. This is typically quite a bit higher.

4) This final point is in my view more problematic. The theory relates ATP consumption rate to the input resistance; that is, it is inversely proportional to Rin. This is indeed logical since the ionic fluxes are proportional to the total membrane conductance. However, the relevant quantity here is total conductance summed over the entire membrane area of the neuron (everywhere where there are ionic fluxes), but the quantity that is used in the paper is the input resistance measured at the soma, which corresponds essentially to the soma and proximal dendrites. It does not, for example, include the area of the axonal membrane, which is a least an order of magnitude larger than the soma. So the result will be incorrect by at least an order of magnitude.

Point (1) leads to substantial overestimation of ATP consumption rate; points (3) and especially (4) lead to substantial underestimation of ATP consumption rate. Together, this makes the energy consumption due to resting potentials very uncertain.

Regarding the calculation of the cost of propagated action potentials, I believe the approach is correct, except the 1/4 efficiency factor (Na+ flux is 4 times larger than necessary to charge the membrane capacitance) comes from the Hodgkin-Huxley model of the squid axon, while vertebrate axons are more efficient. But this has been corrected in subsequent studies.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2014 Jan 11, Brett Snodgrass commented:

Dear Reader,

Please provide your kind consideration to the distinction between the Thebesian veins and the vessels of Wearn.

It is possible in this report, that both connections permit drainage into the left ventricle.

The article states "Egress of blood from this vessel was observed to take place by way of the Thebesian system, through the ventricular septum and thence into the left ventricle."

The authors presume that it was taking place through the Thebesian veins and not the vessels of Wearn. Since the vessels of Wearn previously had no name, they may have been referred to as Thebesian vessels. This is problematic because if someone reads prior reports about what Thebesius studied, they will likely identify the terms "Thebesian veins" and note that Thebesius reported venular-cameral connections.

In this particular case, the venular hypoplasia probably resulted in increased backpressure and egress of blood from both the Thebesian veins and vessels of Wearn into the left ventricle.

Please see

1. http://bit.ly/JTWearn

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933738/

3. http://bit.ly/vasaThebesii

4. http://bit.ly/ThebesianByPratt

My opinion is that accurate anatomic terminology is a basic principle underlying good medical science, and I ask others to consider whether the aforementioned definitions are appropriate. If this comment is not helpful, please let me know how it might be improved.

Comments and suggestions are welcome.

Thank you very much.

On 2014 Nov 24, Ivan Oransky commented:

The second author of this paper has agreed to retract it and five others following a finding of misconduct by the Office of Research Integrity: http://retractionwatch.com/2014/11/20/former-vanderbilt-scientist-faked-nearly-70-images-will-retract-6-papers-ori/

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Apr 29, G L Francis commented:

Yes a good comment, with much better structural data for the IGF-I receptor available since this study was undertaken. The responsiveness of muscle satellite cells cultured from turkeys at various ages of maturity would also be interesting in light of recent knowledge about the role of tissue specific stem cells during development, tissue repair,and role in aging.

On 2014 Apr 29, John Wallace commented:

With more structural data now available, revisiting this topic may prove interesting.

On 2017 May 24, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only.

http://www.jbc.org/content/276/38/35280.full.pdf?sid=f3f9c372-75a2-438d-8ee9-4c20dff5c06e

"This article has been withdrawn by the authors. In Fig. 3, the CT, EGF panel contained duplicated features. Several panels shown in Fig. 3 were assembled as a composite. The Elk1 and pERK immunoblots in Fig. 4B were inappropriately manipulated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper."

On 2015 May 25, Raphael Stricker commented:

Single-Dose Antibiotic Prophylaxis of Lyme Disease: Too Little Too Late?

Over the years since the article by Nadelman et al. was published in 2001 (1), doctors have been using single-dose doxycycline prophylaxis to treat patients following a tickbite. Newer research in animals and humans suggests that this prophylaxis may be ineffective.

The study by Nadelman et al. forms the basis for the Lyme prophylactic treatment guidelines of the Infectious Diseases Society of America (IDSA), and the IDSA guidelines recommend starting prophylaxis “within 72 hours of the time that the tick was removed.” However in 2004 Zeidner et al. noted that a single dose of doxycycline prevented infection in only 43% of mice exposed to Borrelia burgdorferi, the agent of Lyme disease, and a follow-up study in 2008 showed that only 20-30% of mice were protected from combined infection with B. burgdorferi and Anaplasma phagocytophilum following single-dose doxycycline prophylaxis (2). To explain prophylactic treatment failure, Piesman and Hojgaard recently published a mouse study showing the importance of the time interval between tick removal and prophylactic treatment (3).

In commenting on the study by Nadelman et al., Piesman and Hojgaard state: “The authors enrolled subjects if the tickbite occurred within 3 days of their clinical visit, but did not analyze the data based on the exact time between tick removal and delivery of prophylaxis….We found that two treatments of doxycycline delivered by oral gavage to mice on the day of removal of a single potentially infectious nymphal I. scapularis tick protected 74% of test mice compared to controls. When treatment was delayed until 24h after tick removal, only 47% of mice were protected; prophylactic treatment was totally ineffective when delivered ≥2 days after tick removal.” The loss of prophylactic efficacy over this time interval is supported by well-documented observations of rapid transmission of Lyme disease within 24 hours of a tickbite in humans (4). A review of the pertinent literature revealed that the risk of B. burgdorferi transmission within 24 hours of a tickbite was 7% under experimental conditions in mice and up to 25% in clinical studies involving humans (5).

In summary, animal and human studies of exposure to B. burgdorferi suggest that there may be a very narrow window for prophylactic treatment following tick removal. In failing to take this narrow prophylactic window into account, the study by Nadelman et al. appears to put patients at risk of developing Lyme disease following antibiotic prophylaxis that may be too little too late.

References

1. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, Welch P, Marcus R, Aguero-Rosenfeld ME, Dennis DT, Wormser GP. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tickbite. N Engl J Med. 2001;345: 79-84.
2. Zeidner NS, Massung RF, Dolan MC, Dadey E, Gabitzsch E, Dietrich G, Levin ML. A sustained-release formulation of doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite. J Med Microbiol. 2008;57(Pt 4):463-8.
3. Piesman J, Hojgaard A. Protective value of prophylactic antibiotic treatment of tickbite for Lyme disease prevention: An animal model. Ticks Tick Borne Dis. 2012;3:193-6.
4. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
5. Cook MJ. Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med. 2014;8:1-8.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2013 Oct 30, Jamie Horder commented:

This 2001 paper was discussed in a 2010 feature in the British Medical Journal Newman M, 2010

"Study 329, a study of 275 adolescents, was one of three clinical trials conducted by SmithKline Beecham (as GSK was then known) in the mid 1990s.

Study 329’s results showed that paroxetine was no more effective than the placebo according to measurements of eight outcomes specified by Martin Keller, professor of psychiatry at Brown University, when he first drew up the trial.

Two of these were primary outcomes: the change in total Hamilton Rating Scale (HAM-D) score, and the proportion of “responders” at the end of the eight week acute treatment phase (those with a ≥50% reduction in HAM-D, or a HAM-D score ≤8). The drug also showed no significant effect for the initial six secondary outcome measures.

The drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead. Fifteen other new secondary outcome measures failed to throw up positive results.

An internal SmithKline Beecham document discussing these results and those of another trial that had failed to show paroxetine’s effectiveness noted that it would be “commercially unacceptable to include a statement that efficacy had not been demonstrated.”

SmithKline Beecham commissioned medical communications company Scientific Therapeutics Information to produce a manuscript. An employee of Scientific Therapeutics Information, Sally Laden, drew up a first draft.

The manuscript was then sent to JAMA, which rejected it after peer reviewers highlighted methodological and other problems... The paper was rewritten and sent on to JAACAP. The journal’s peer reviewers noted that the results did not “clearly demonstrate efficacy for paroxetine” and asked whether, given that 50% of placebo treated teenagers improved, selective serotonin reuptake inhibitors were “an acceptable first-line treatment.”

JAACAP nevertheless accepted the paper."

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Jul 03, Arnaud Chiolero MD PhD commented:

One of the very rare paper of major importance for clinicians, as well as for public health specialists and epidemiologists

On 2015 Jun 16, thomas samaras commented:

There's lots of evidence indicating that shorter, lighter people live longer. Throughout most of the world,shorter women live longer than taller men. In animals where the female is larger than the male, the female has a mortality rate. When I compared American males and females, I found that males were 9% taller and had a 9% shorter life expectancy.

Chan, Suzuki and Yamamoto studied Okinawan centenarians and found they were short and lean. Other centenarians studies have found similar results, including those adjusted for shrinkage with age.

In addition, US government mortality data over the entire adult age range found that that Asians had the lowest mortality. Latinos and Native Americans had a higher mortality and Whites and Blacks had the highest mortality. Asians are the shortest ethnic group, followed by Latinos and Native Americans. Blacks and Whites are the tallest.

Recent studies have found shorter people live longer. One was based on 8000 elderly Japanese-Hawaiian males tracked for over 40 years. Another involved men in a small village in Sardinia. The third one was a review of evidence from eight different types of studies. Many more papers are listed in www.humanbodysize.com

The Director of the Aging and Longevity Research Laboratory at the University of Southern Illinois also published a review paper in Gerontology and concluded that smaller body size appears to be best for good health and longevity.

These papers are listed below.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2016 May 22, Lydia Maniatis commented:

(Fifth comment). Some more thoughts: Ariely's main concepts - sets, similarity - are vague. He could have explained what, for the purpose of his claims, he intends them to mean. But he doesn't - they're just placeholders.

What, for Ariely, is a set? He refers to "a collection of items." He challenges the idea that "representations of complex scenes still consist of many individual representations" suggesting instead that in many cases where "proximal items are somewhat similar the representation of a set may contain information about...the average size, color, orientation, aspect ratio, and shape of the items in the set and essentially no information about individual items."

So it would seem that Ariely's working definition of a "set" is a collection of proximal, somewhat similar items (which may differ in pretty much any respect, including shape). So vague - the description "somewhat similar" is absolutely without content - as to be practically useless, and as noted earlier, many or most of the implications are falsifiable. As noted above, even the author's own attempt to explain the alternative Ebbinghaus groups involves a contradiction of that definition.

In my discussion of the arbitrary methodological choices, I didn't mention the main one, which is the decision to use black circles and to focus on size. The reason he gives is that "such sets have the advantage that the members do not fall into distinct categories, as they could if they varied in color, shape, or orientation." So they would be "sets," but variations other than strictly size would be "disadvantageous." In what sense would they be disadvantageous? There's no discussion about this; it seems like an evasion.

Even limiting our discussion to size, we could introduce intractable complications that even Ariely's "novel paradigms" couldn't make fit. What if each circle consisted of a set of concentric circles, variously spaced? Would we construct an average of the envelope, an average of each subset of circles? What if the large group of circles, due to a configurational accident, visually grouped into two or three subsets (as may indeed have happened)? Would we have three different averages, and would these be averaged in turn? Etc.

On 2016 May 22, Lydia Maniatis commented:

(Fourth comment) Ariely's claims that his size results (such as they are) can be extended to shape, color, aspect ratio, orientation, are falsifiable. In the simplest case, a set of rectangles that includes one item (not corresponding to the mean) that has an aspect ratio of one will be registered and remembered with precision, biasing the results in favour of the individual items. The mean of the set, on the other hand, would most likely be less precisely registered. Familiar faces in a group will be remembered precisely, their mean, huh? A set of red, white and green objects would be registered, at least categorically with precision, their "mean" probably at all. The shapes in a set of triangles, squares, circles would be remembered precisely; their "mean," not so much.

These may seem like trivial examples, but there is nothing to exclude them from Ariely's broad and vague claims. That this vagueness is used as license to perform an odd and arbitrary experiment whose hugely variable and limited datasets may be favourably (if obscurely) interpreted doesn't let him off the hook.

On 2016 May 22, Lydia Maniatis commented:

(Third comment) Arbitrary methodological choices, data presentation

The title of the paper is “Seeing sets,” and question of interest is said to be “to determine what observers know about the members of a set and what they know about the statistical properties of the set (mean and distribution)” and that “sets of objects could be represented in a qualitatively different way than single items.”

These are quite broad objectives, and don't imply any particular methodology.

The author uses a very specific methodology that places demands on subjects that go beyond straightforward perception, and imposes conditions that compromise straightforward perception.

He uses brief presentation times, 500ms for the first figure and 500s for the comparison figure, with no blank space in between.

This means that there is time for about two saccades and fixations (barely), and involves potential masking effects. How did he choose these parameters? Do they matter? Would we expect the same results with longer presentation times? With a blank interval? Also, the circles increase in size geometrically, not linearly and the mean that we are talking about is the geometric, not the arithmetic mean. Why not a linear progression and an arithmetic mean?

It's been understood for a long time that by adjusting experimental conditions we can get pretty much any result we want, which is why such conditions should come with a theoretical rationale attached. Because the author's choices here seemingly make the task much more difficult than it should be given the goal, they need to be explained, not just flatly asserted.

Another blank check is to be found in a footnote referring to a “small study” which was the basis for selecting/describing one of the parameters in the reported study (“members differed in size from non-members by at least 18%, about three times the size-discrimination threshold for sets of same-size spots [as determined in the “small study”].” In a personal communication, Ariely told me that this study used about ten subjects, and was mostly about studying “within-subject variation.” Such a study could also have given an indication of between-subject variation. Given the link between the two studies, and the oddity of using only two observers (why only two?), some more specific info on results/methods of this "small study" would seems called for.

The presentation of the data is also rather weird. For the mean-discrimination experiment, we aren't given information on the proportions of correct answers the two observers achieved. Maybe this information is hidden in the opaque measure that is provided (and which assumes normality in the data without any justification - isn't that a problem?). This measure is the "mean-discrimination threshold" derived using "a standard profit analysis (Finney, 1971) ...to determine the mean-discrimination threshold (the standard deviation of the best-fitting cumulative normal distribution." Is best-fitting the same thing as "well-fitting"?

Given the method, and assuming that it really is the case that subjects were better at guessing the mean rather than the size of individual members, I could speculate on why that might be. First of all, observers never had to play the "yes-no" game with means (why not?). All they had to do was say "larger-smaller." This seems like an inherently easier task. Further, given the time constraint, there wasn't enough time to inspect each of the four different circle sizes individually. Observers only had time for one or two. So for half of each set, at least, they were out of luck on each trial in the individual member task. For the mean estimation, if they could learn to target the middle two on each trial - not the largest, not the smallest - then they could ballpark the mean. Who knows? The situation is as Runeson (1995) has described for a different type of vision study:

"For perception and cognition research in general, it is noteworthy that the cue-based style of theorising exhibits a certain lack of inherent correctives for ineffectual experiments because of its emphasis on weak and irregular performance. Thus, an experiment that is unsuitable in design or procedure could easily provide supportive-looking data at least as long as cues, salience limits, and trade-off functions are not specified in detail....data that represent suboptimal observer performance seem to have provided spurious support for untenable theoretical commitments,... "

On 2016 May 22, Lydia Maniatis commented:

(Second comment) Comment on section titled “The Economy of Set Representations"

Ariely begins this section by saying that: “Although the exquisite sensitivity of the human visual system ...is a source of wonder and delight, a computer can be equally sensitive. Much harder to solve, and currently far beyond the abilities of computer vision systems, is the problem of knowing what information to throw away.” He considers it problematic, therefore, that “in research in spatial vision, the focus has been more on reproducing the image exactly, on compressing the representation without losing information (e.g. Watson, 1987)” and suggests that “”If our models do not lose any of the original data, then no decisions have been made, no information has been extracted.”

These statements are strikingly naive with respect to basic theoretical and empirical facts of perception.

By “the original data” Ariely can only be referring to the photons hitting the retina. If the visual system accurately encoded the intensity of each and every one of these, then the only information it would possess would be the intensity of each and every one of these. If it recorded the relative intensities of each and every one of these, then that would the only information it would possess. Something is missing, and that is the understanding that to be informative, the “original data” must be massively leveraged, organised via complex principles which group, inflate, complete, emphasize or de-emphasize - in general interpret these points to create 3D impressions of shape, light, movement, space. The fundamental problem is not compression but “going beyond the information given.” This is a very old misunderstanding for which there's no longer any excuse, and which should not be recycled, decade after decade. To correct Ariely's statement above, “If our models do not interpret the original data, no information has been created.” The processes Ariely is positing are actually post-organisation, his "original data" are the visual system's perceptual constructs, that are then to be averaged, or whatever. This is not less work, it is more.

Finally, “The reduction of a set of similar items to a mean (or prototypical value), a range, and a few other important statistical properties may preserve just the information needed to navigate in the real world, to form a global percept, and to identify candidate locations of interest.”

Leaving aside the vagueness of the term “set,” the idea that sets of “similar” (how similar?) objects – a set of chairs, a group of kids – is reduced to a group mean and a range defies both experience and logic. The most important units in our environment are objects, not loose collections thereof. We see items, groups of items, but I have never seen a mean of a group of items. The idea that our perception of such groups turns into a random hall of mirrors of sizes, colors, shapes when they are simply near each other...where does that come from?

On 2016 May 18, Lydia Maniatis commented:

This highly-cited article is celebrated as seminal, pioneering, influential. (See for example Bauer, 2015). In contrast, I find the arguments facile, incomplete, and inadequate to support a bold but very vague and seemingly implausible proposal. I'll deal with separate issues in separate comments here, beginning with the one that is easiest for me to make. It deals with the second to last section of the paper, titled "Visual Contrast Illusions and Set Representations." The style of argument of this section is a good illustration of the casualness of the authors arguments in general.

Here's my comment:

Ariely argues that the Ebbinghaus illusion is amenable to explanation in terms of “set representation.” Specifically, he says that the circle surrounded by large circles appears smaller than the one surrounded by small circles because each is “judged relative to the set properties of the circles surrounding it. If the basic representation of a set contains the relationship of an object to the mean of its set, it follows that the [former] will be judged smaller than the [latter].”

Assuming that what applies to the central circle applies to every circle, Ariely is saying that the “basic representation of a set” includes, in its composition, the relationship of each object to the mean of the set. That means five sub-representations in addition to the representation of the mean size of the set and of each individual member (adjusted for set mean). And since he also suggests that mean representations are created for other features as well, e.g. color, shape, we would have to add these to the hypothetical representations. (If efficiency of representation is the goal, this does not seem to fit the bill.)

Ariely even presents a kind of test of his claim by citing a study that showed that when the central circles are surrounded by triangles, the effect is attenuated. This is no where near good enough. Many logical and empirical falsifications of his thesis are close to hand.

Ariely overlooks the fundamental fact that the Ebbinghaus illusion is contingent on configuration. It should be pretty clear that it would be a trivial project create sets of circles (putting them in a row, for example, and adjusting which is adjacent to which) for which his prediction would fail.

In addition, while he only focusses on size, Ariely does not limit his claims to size. But it is also trivial to show that it doesn't work for, e.g. lightness, color, or shape even to the extent that it might be can be made to appear to work for size. There are countless demonstrations, involving sets of discrete figures, of so-called assimilation effects in which this explanation, involving a “contrast” effect, would fail. And it obviously fails for shape.

So we are dealing with a facile, ad hoc explanation that should at least have been challenged during review, and certainly not have been admitted as a serious argument after the fact.

Finally, it's worth pointing out that the Ebbinghaus effect is evident and robust under leisurely inspection. If the effects Ariely is proposing are this salient, why does he choose to present his multi-item stimuli using only brief presentation times (thus allowing time for only a couple of saccades) and without a blank period before (briefly) presenting the comparison figures (thus incurring possible masking effects)? Why use sub-optimal conditions rather than make his case using longer presentation times and clear and robust perceptual effects such as the Ebbinghaus? Nowhere does he explain his methodological choices.

But the priority is to explain the easy falsifications, otherwise the there is no viable hypothesis.

p.s. More conceptual inconsistencies: In his account of the Ebbinghaus, Ariely is saying that the triangles are not perceived as part of a set including the central circle. Yet a. they do group with it visually, and b. earlier in the article he says that "orientation, aspect ration, mean hue, and shape (however represented" may all be set properties." So why don't we see the circle changing shape, and why does shape difference preclude set affiliation?

On 2017 May 23, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only

http://www.jbc.org/content/276/27/24490.full.pdf?sid=192794b9-fa3c-402f-b9d0-e2643b9c92ae

"This article has been withdrawn by the authors. One cell from the 12-h, -TPA panel was duplicated in the 6-h, +TPA panel in Fig. 1A. The 12-h, -TPA panel from Fig. 1A was duplicated in the ERK2, +TPA panel from Fig. 5. Also in Fig. 5, the cells shown in the ALC, -TPA panel were duplicated. The phosphorylated MBP panel from Fig. 4 was inappropriately manipulated. In Fig. 9, the ALC, -TPA and the 183A, +TPA panels were inappropriately manipulated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper."

On 2017 Oct 24, Tamás Ferenci commented:

Weisser K, 2017 provides a reimplementation of the model presented in this paper using more standard notation.

On 2013 Jul 10, Matthew Stephens commented:

I'm interested in whether anyone has explored connections between the ideas here, and the "empirical null" ideas of Efron (eg Large-scale simultaneous hypothesis testing: the choice of a null hypothesis, JASA 2004) http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.179.2729

It seems the two have a similar goal - here one of the ideas (and probably the one that has most influence in practice, since it is now widely used) is to use the median of the test statistics to estimate an inflation factor (lambda). Efron also uses the test statistics near the center of the empirical distribution to do a similar thing, but in a different way. It might be interesting to compare the two approaches.

On 2013 Jun 18, Jill Barnholz-Sloan commented:

This paper proposes a computationally simple approach for adjustment for potential population stratification bias in case control studies. Genomic control and structured association methods, such as STRUCTURE, are widely used to test for and adjust for potential population stratification bias. Genomic control has been compared and contrasted with STRUCTURE (http://www.ncbi.nlm.nih.gov/pubmed/18852890)

On 2013 Jun 13, Robert Tibshirani commented:

This paper came about by happenstance. Prof Gil Chu and his bright young grad student Virginia Goss contacted me, and asked my advice on how to analyse their data measured on this new technology called "microarrays". I had never heard of microarrays, and together we formulated a simple approach based in t-tests and FDR, estimated by permutations. My colleague Narasimhan Balasubramanian and I built some software--- an Excel-addin called SAM (Significance Analysis of Microarrays). [Trevor Hastie suggested the convenient Excel interface.) SAM became popular at Stanford and around the world. This paper, although simple in its ideas, has become one of my most cited papers.

On 2013 Nov 24, John Sotos commented:

If this were 1903, I would diagnose ochronosis in the woman shown in the April 5 “Medical Mystery” (1). It would be the eighth case in the world’s literature. But if this were 1904, and if I were William Osler (alas!), then I would consider alkaptonuria as an additional diagnosis.

Before 1904, the diagnosis of alkaptonuria applied only to urine. Chemical properties, not color, made the diagnosis. A link with ochronosis had been proposed (2), but Osler was the first to describe ochronosis and alkaptonuria coexisting in patients, thereby bringing alkaptonuria “within the realm of the clinical physician” (3). Today, ochronotic pigmentation is considered a feature of the metabolic disease alkaptonuria (4).

Osler’s paper also lets us ponder the man and his times. Osler describes the examination of his index patient, then states: “As he left the room my attention was directed to the deep blue color of the inner surface of the ears” (3). Even if we were all Oslers (alas!), most physicians are now too busy completing reimbursement forms to watch their patients walk out of the examination room.

(1) Nikkels AF, Pierard GE. Images in clinical medicine. A medical mystery. N Engl J Med. 2001;344:1057.

(2) Albrecht H. Ueber ochronose. Zeitschrift fur Heilkunde. 1902;23:366.

(3) Osler W. Ochronosis: the pigmentation of cartilages, sclerotics, and skin in alkaptonuria. Lancet 1904;i:10-11.

(4) La Du BN. Alkaptonuria. Chapter 39 (pages 1371-1386) in: The Metabolic Basis of Inherited Disease. 7th ed. Scriver CR, Beaudet AL, Sly WS, Valle D (eds). New York: McGraw-Hill, 1995.

On 2017 May 23, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only.

http://www.jbc.org/content/276/17/13957.full.pdf?sid=2afabc16-c492-434c-9abd-91ed6949ef13

"This article has been withdrawn by the authors. The authors were recently made aware of an issue in Fig. 4, in which the sequence of treatment groups in the blot of rFSHR-17 cells was reorganized by cut-and-paste to align treatment groups with the companion blot of rLHR-4 cells. This rearrangement was not acknowledged in the original figure legend. Because the original data generated 16 years ago are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper and have replicated the findings in subsequent work. The authors apologize for not recording the manipulation noted in Fig. 4."

On 2013 Nov 16, Ellen M Goudsmit commented:

This paper does not report the data from the motion sensing device used (Van Essen and De Winter). These showed no significant differences between the groups after treatment. Thus any improvement can not be attributed to increases in activity as was later supported by Wiborg and several other papers from this team (see comment Kindlon, T). A letter discussing the data by Goudsmit was rejected for publication by the Lancet.

The reasons for the documented improvements remain unclear. Of note is that all the trials used a broadly-defined samples (i.e., selected using the Oxford or CDC criteria) and there is no data on the effect of CBT on symptoms other than fatigue and sleep. There has been no trial of CBT on patients with acute onset post-viral syndromes.

The current protocols for CBT promoted for CFS are aimed primarily at increasing activity. There is evidence that pacing, an alternative strategy to manage activity is of help in stabilising the condition and avoiding exertion-related exacerbations. This strategy can be used alongside CBT or any other intervention (for review, see Goudsmit et al).

1. Van Essen M, de Winter LJM. Cognitieve gedragstherapie by het chronisch vermoeidheidssyndroom (cognitive behavior therapy for chronic fatigue syndrome). (Report No. 02/111, Appendix B). Amstelveen, Netherlands: College voor Zorgverzekeringen (CVZ). 2002.

2. Goudsmit, EM., Jason, LA, Nijs, J and Wallman, KE. Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: A consensus document. Disability and Rehabilitation, 2012, 34, 13, 1140-1147. doi: 10.3109/09638288.2011.635746.

On 2013 Oct 24, Tom Kindlon commented:

Actometer data from this trial was published in 2010 - no improvements were found in this objective outcome measure for the CBT group over controls

Subjective improvements following cognitive behavioural therapy (CBT) for chronic fatigue syndrome (CFS) do not necessarily mean objective improvements were obtained.

This trial is an example of this.

Nine years after this paper was published, the mean (standard deviations) for the CBT and Control groups were released:¹ 67.4 (21.8) and 64.5 (19.7) before treatment and 68.8 (25.2) and 64.9 (21.7) at the second assessment. Different devices can be used to measure activity levels; for the actometers used in this study, healthy controls were previously found to have a mean Actometer score of 91 (S.D.=25).² That study found that the mean Actometer score of tested CFS patients was 66 (S.D.=22).²

References:

1 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1-7.

2 Van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G (2000). Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. Journal of Psychosomatic Research 49, 373-379.

On 2015 Dec 08, Michael Doube commented:

Structure model index does not measure rods and plates in trabecular bone

Structure model index (SMI) works by dilating a surface mesh a very small distance and measuring the change in surface area that occurs, then forming a ratio with volume and surface area squared. On convex surfaces, area increases during dilation, however, on concave surfaces area decreases during dilation. The negative change in surface area from the dilation of concave surfaces leads to a negative contribution to SMI, which is an aberration from its theoretical formulation. The authors recognise this and state that "the intersections between structure elements, e.g. between rods and plates, are not accounted for", but do not attempt to assess the degree of distortion such "intersections" would have on the final SMI value.

In recent work (Salmon PL, 2015) my colleagues and I quantified the amount of concave surface in trabecular bone and its contribution to SMI. We found that the assumption that the negative contribution from concave surfaces is negligible, is almost never correct in real bone samples, typically being ~20-70% of the surface. The negative contribution to SMI is substantial and renders the final SMI measurement very difficult to interpret at best, and misleading at worst. SMI's correlation with bone volume fraction has led to the false observation of a rod-like transition during bone loss, but this is little more than an artefact relating to a strong correlation between bone volume fraction and the fraction of the surface that is concave, which itself artificially depresses SMI.

We conclude that SMI should not be used for the measurement of rods and plates in trabecular bone, and that research which relies on SMI should be treated with caution.

On 2015 Jun 24, Bill Cayley commented:

A great example of when "Less" is "more": https://lessismoreebm.wordpress.com/2015/06/24/is-it-necessary-to-suture-all-lacerations-after-a-vaginal-delivery/

On 2014 Jan 07, Brett Snodgrass commented:

Dear Reader,

Please provide your attention to the distinction between the Thebesian veins and the vessels of Wearn (arteriosinusoidal & arterioluminal vessels). For additional commentary please see the following link.

https://twitter.com/BrettSnodgrass1/status/419207726455996416

Comments and suggestions are welcome.

Thank you kindly.

On 2015 Dec 05, S A Ostroumov commented:

Full text of this article, online free: https://www.researchgate.net/publication/226287633

On 2015 Nov 29, S A Ostroumov commented:

The term 'amphiphilic substance' here means 'a surfactant' or 'a surface active substance', namely, sodium dodecylsulfate (SDS).

On 2015 Nov 29, S A Ostroumov commented:

Similar results were obtained with/at lower concentrations of SDS. The results on the lower concentrations were published in the book 'Biological Effects of Surfactants'. More info on the book see here: https://www.researchgate.net/publication/200637626

On 2015 Jan 28, Donald Forsdyke commented:

SIMILARITY BETWEEN EPSTEIN-BARR VIRUS AND PLASMODIUM FALCIPARUM. A key observation in this paper (Cristillo et al. 2001) is that the EBNA-1 protein is longer than necessary because of the need to contain a low complexity GLY-ALA repeat region between functional domains. This allows purine-loading at the nucleic acid level. Essentially the same observation was reported by Pizzi and Frontali (Genome Research 2001 11, 218-229). They noted:

"Proteins from Plasmodium falciparum, the etiological agent of the most severe form of human malaria, are often larger than homologous proteins from other organisms. When multiple alignment is possible, the size difference can be seen to be due to the presence of long insertions separating well-conserved blocks that are adjacent in the homologous proteins.... The insertions are characterized by highly recurrent amino acid usage" and correspond to "low complexity regions ... believed to encode non-globular domains of unknown function that are extruded from the protein core and do not impair the functional folding of the protein."... The recurrent amino acids "correlate with A-richness in codons."

This quotation from Pizzi and Frontali is the first of a series of End Notes that were added to the version of the Cristillo paper displayed on one of Forsdyke's webpages http://post.queensu.ca/~forsdyke/EBV.htm

On 2016 Jan 05, Morten Oksvold commented:

Please not that this article contains fraudulent data, which was concluded from an investigation by the University of Alabama at Birmingham in 2009 (!):

http://www.uab.edu/reporterarchive/71570-uab-statement-on-protein-data-bank-issues

The case was recently discussed at Retraction Watch: http://retractionwatch.com/2016/01/04/nature-retracts-paper-six-years-after-it-was-flagged-for-fraud/

Cell was informed about this case in 2009, but as far as I can see there has still not been published any retraction.

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2016 Aug 15, ALAN HOWE commented:

After 15 years, this remains one of my favorite papers. The simplicity of the methodology - pulsed growth factor treatment, followed by kinase assays or measurement of 3H-thymidine incorporation - is sublime and matched only by the solidity of the experimental design and the accuracy and understated power of the interpretation of the results. I re-read this article every few months and, in the midst of a constant drive towards 'innovation' and reliance on increasingly complex experimental approaches, it shines even brighter as an example of the power of that simple assays, perfectly executed and interpreted, have in scientific discovery.

On 2016 Jun 27, Martine Crasnier-Mednansky commented:

It is worthwhile revisiting this article considering the strategy described by Müller-Hill B, 1998 was recently reaffirmed Becker NA, 2013, namely, DNA looping in the lactose operon occurs via an increase in local concentration thereby enhancing repression (see figure 1 in Becker NA, 2013).

The authors established the existence of a 2:1 complex between CAP and tetrameric LacI in the absence of DNA. Therefore, one may argue operator occupancy by such complex increases CAP local concentration at the CAP sites. Interestingly, formation of the complex was found to be cAMP-dependent thus local concentration of CAP-cAMP at the CAP sites increases with increasing concentration of cAMP (in the physiological micromolar range).

Because higher cAMP levels (as compared to glucose level) do not interfere with LacI repression (in the absence of induction), it can be inferred formation of a cytoplasmic complex between CAP and LacI would not prevent binding neither to the operator nor the auxiliary operators.

On 2013 Jun 19, Robert Tibshirani commented:

This paper presents an interesting idea for fitting a curved manifold to a set of data points. The first author-- Sam Roweis, was a beloved researcher in machine learning, who died prematurely in 2010. This was one of his best known papers. In the same issue of Science, Tenenbaum et al propose a different procedure with the same goal: "ISOMAP" http://www.ncbi.nlm.nih.gov/pubmed/?term=A+Global+Geometric+Framework+for+Nonlinear+Dimensionality+Reduction. A third approach that relates the problem to local multidimensional scaling, is presented in "Local Multidimensional Scaling for Nonlinear Dimension Reduction, Graph Drawing and Proximity Analysis (Chen and Buja; JASA 2009). This last paper also makes comparisons to local linear embedding and ISOMAP.

On 2013 Jun 19, Robert Tibshirani commented:

See my comment to Roweis and Saul http://www.ncbi.nlm.nih.gov/pubmed/11125150

On 2014 Mar 04, KEVIN BLACK commented:

Readers of this article may be interested in the following letter: http://works.bepress.com/kjb/28/

On 2014 Mar 04, KEVIN BLACK commented:

Readers of this article may be interested in the following letter: http://works.bepress.com/kjb/28/

On 2015 Dec 12, S A Ostroumov commented:

WorldCat Review 1 of the article: An aquatic ecosystem: a large-scale diversified bioreactor with a water self-purification function.

https://www.researchgate.net/publication/286582518 ;

Full text of the reviewed article, free: https://www.researchgate.net/publication/12225361;  https://www.researchgate.net/publication/215907363;

This review with evaluation (favorable) was published on WorldCat, the global largest catalog.

On 2015 Dec 05, S A Ostroumov commented:

Abstract: An aquatic ecosystem: a large-scale diversified bioreactor with a water self-purification function. — Doklady Biological Sciences, 2000. Vol. 374, P. 514-516. 3 tables. Bibliogr. 15. ISSN 0012-4966. Distributed by Springer, orderdept@springer-sbm.com. ** Innovative conceptualization: The author developed a new fundamental concept of aquatic ecosystem as a multi-functional bioreactor. One of the key functions of that bioreactor is upgrading water quality via a multi-component biomachinery of water self-purification. ** New facts: Contribution of the main groups of aquatic organisms (heterotrophic bacteria, fungi, cyanobacteria and microalgae, protozoans, higher plants, invertebrates, fish and amphibians) to water self-purification: comparison and analysis (Tabl.1). Relatively small effects of a synthetic non-ionic surfactant (Triton X-100 or TX100, 4-5 mg/L) on marine bacteria Hyphomonas sp. MHS-3 (5 mg/L), and on bacteria Hyphomonas sp. VP-6 (5-10 mg/L), a significant inhibition by the synthetic surfactant Triton X-100 of the water filtration by the marine mussels Mytilus edulis (4 mg/L), and by the freshwater mussels Unio tumidus (5 mg/L). The negative (inhibitory) effects of a synthetic cationic surfactant TDTMA 1 mg/L on the marine mussels M. galloprovincialis (Tabl.2); the inhibition of feeding: effects of the synthetic surfactant TX100 1-5 mg/L on the freshwater mussels Unio tumidus, inhibitory effects of the synthetic surfactant TDTMA 1-2 mg/L on the freshwater mussels U. pictorum; effects of a number of synthetic surfactant and detergents, namely, TDTMA 1 mg/L, anionic surfactant SDS 1.7 mg/L, detergents 6.7 – 50 mg/L, shampoo (namely, the shampoo) AHC 5-60 mg/L (sublethal concentrations) on the marine mussels M. galloprovincialis; TX100, TDTMA (2 mg/L), laundry detergent (Tide-Lemon, 75 mg/L) on the freshwater mollusk (the pond snail Lymnaea stagnalis) (Tabl.3).

** A fragment of the text: "Sublethal concentrations of contaminants may inhibit vital activities of other organisms involved in the function of an ecosystem as an analogue of a bioreactor. This finding provides a deeper insight into the mechanisms of anthropogenic impact on biosphere. The concept put forward in this work emphasizes that intactness of the whole range of biological diversity of hydrobionts [aquatic organisms] is required to provide effective functioning of an ecosystem as an analog of a water self-purification bioreactor. Therefore, the monetary cost estimates of ecosystems and the biota should be increased" (p. 516).

On 2015 Dec 05, S A Ostroumov commented:

Full text of this article, online free: https://www.researchgate.net/publication/12225361; and another link: https://www.researchgate.net/publication/215907363;

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2015 Nov 07, Christopher Southan commented:

For a 2013 update on BACE2 and BACE1 evolution see http://www.ncbi.nlm.nih.gov/pubmed/24381583

On 2017 May 23, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only.

http://www.jbc.org/content/276/7/4554.full.pdf?sid=7bb135bf-4164-4739-a1ec-e89b57c5148f

"This article has been withdrawn by the authors. The DP immunoblot in Fig. 1A, the DP immunoblot on the right in Fig. 2B, the DP immunoblot in Fig. 6, the DP immunoblot on the left in Fig. 7, and the DP immunoblot in Fig. 8 were inappropriately manipulated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper and have replicated the findings in subsequent work."

On 2016 Feb 05, J A Whitworth commented:

Cortisol is not a pure glucocorticoid. It binds to the mineralocorticoid receptor and thus can cause salt and water retention.

On 2016 Jan 09, Chao Liu commented:

Instead of causing renal water and sodium retention, there are a good body evidence, both from animal and human, shows that glucocorticoids could promote renal water and sodium excretion.

1. Hunter RW, Ivy JR, Bailey MA. Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity. J Physiol. 2014 Apr 15;592(Pt8):1731-44.

2. Landínez RAS, Romero MFL, Maurice EH (2014). Efectos de la prednisona sobre la función renal a corto plazo en pacientes con Insuficiencia Cardíaca Descompensada. Venezolana de Medicina Interna 30(3): 176-192.

3. Liu C, Chen Y, Kang Y, Ni Z, Xiu H, Guan J, et al. (2011). Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure. J Pharmacol Exp Ther 339(1): 203-209.

4. Liu C, Liu G, Zhou C, Ji Z, Zhen Y, Liu K (2007). Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 23(11): 865-868.

5. Liu C, Liu K (2014a). Effects of glucocorticoids in potentiating diuresis in heart failure patients with diuretic resistance. Journal of cardiac failure 20(9): 625-629.

6. Liu C, Liu K (2014b). Reply to Day et al.--hypouricemic effect of prednisone in heart failure: possible mechanisms. Can J Cardiol 30(3): 376 e373.

7. Liu C, Zhao Q, Zhen Y, Gao Y, Tian L, Wang L, et al. (2013). Prednisone in Uric Acid lowering in Symptomatic Heart Failure Patients With Hyperuricemia (PUSH-PATH) study. Can J Cardiol 29(9): 1048-1054.

8. Liu C, Zhao Q, Zhen Y, Zhai J, Liu G, Zheng M, et al. (2015). Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study. J Cardiovasc Pharmacol 66(3): 316-322.

9. Meng H, Liu G, Zhai J, Zhen Y, Zhao Q, Zheng M, et al. (2015). Prednisone in Uric Acid Lowering in Symptomatic Heart Failure Patients with Hyperuricemia - The PUSH-PATH3 Study. The Journal of rheumatology 42(5): 866-869.

On 2016 Jan 09, Chao Liu commented:

None

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Feb 20, Egon Willighagen commented:

Figure 5 is available as WikiPathway at http://www.wikipathways.org/index.php/Pathway:WP2633

On 2014 Feb 20, Egon Willighagen commented:

None

On 2017 Nov 10, Anne Niknejad commented:

erroneous information

'C69652(B. subtilis LipB)'

https://www.ncbi.nlm.nih.gov/nucest/C69652?report=genbank

C69652 Yuji Kohara unpublished cDNA Caenorhabditis elegans cDNA clone yk365f3 5-, mRNA sequence

Link should be instead:

http://pir.georgetown.edu/cgi-bin/nbrfget?uid=C69652

The UniProt entry corresponding to the enzyme B. subtilis LipB described in this paper is Q79F14

http://www.uniprot.org/uniprot/Q79F14

On 2014 Apr 17, Ivan Oransky commented:

This paper, which has been cited more than 100 times, has been retracted: http://retractionwatch.com/2014/04/17/data-highjinx-forces-retraction-of-tumor-paper-in-jbc/

On 2015 Dec 05, S A Ostroumov commented:

The full text of the article, and the abstract, online free: https://www.researchgate.net/publication/12309563; also here: https://www.researchgate.net/publication/265127167;

On 2014 Oct 10, EDWARD BERRY commented:

Correction- the second anomalous scattering site, assigned to Zn site 2, is actually due to iodine present as part of an inhibitor co-crystallized with the protein. Circumstances leading to this mis-assignment are described in a REMARK in the pdb entry 3H1K, which has the corrected structure.

On 2014 Nov 07, F W Lipfert commented:

This paper is primarily statistical in nature and makes no claims about the physiology/etiology of SIDS. We show that PM10 is not responsible for excess SIDS and that using Woodruff et al.'s protocol predicts beneficial effects of SO4, which is one of the main constituents of PM2.5. In any event, 24 years have elapsed since our paper was published and uncertainties remain about the causes of SIDS. Perhaps new statistical analyses are warranted.

Fred Lipfert

On 2014 Nov 03, David Mage commented:

Higher SIDS rates in winter are not related to indoor or outdoor sources of PM2.5 (particles with aerodynamic diameter < 2.5 microns) because Hawaii with minimal (if any) seasonal variation has a SIDS maximum rate in the winter which is related to the ARI/RSV virus brought to Hawaii by the tourists from the mainland and Japan that maximizes there in the winter. The only known PM2.5 component associated with SIDS is tobacco smoke associated with parental smoking both during pregnancy and during the first year of life and that has no seasonal variation (PMID 15483306).

On 2013 Dec 31, Gerhard Nebe-von-Caron commented:

the whole issue was part of a meeting on microbial analysis on the single cell level and should be available by open access. Get this full text available from http://bitc2-preview.sr.unh.edu/TRC/REFERENCES/FC/NebevonCaron2000.pdf

On 2015 May 19, Laura Newman commented:

This record needs to be corrected. I am the correct author of this article, NOT Rob Cunningham. He edited the newsletter Medicine and Health, but I wrote this feature story. I am in the process of having this corrected, which involves contacting a publisher of a no-longer-existing newsletter.

On 2016 Feb 01, Morten Oksvold commented:

Please note that this article is 1 out of 15 publications for which an independent investigation initiated by the University of Copenhagen has found suspicion of scientific dishonesty. The conclusion from the report was published July 23, 2012:

http://news.ku.dk/all_news/2012/2012.8/indications_of_fraud_in_penkowas_early_research/

This articles should therefore not be cited.

On 2014 Mar 26, Tom Kindlon commented:

I posted a comment in reply to this paper here: http://jnnp.bmj.com/content/69/3/302.long/reply#jnnp_el_4153

On 2015 Dec 19, S A Ostroumov commented:

A review of this article was published on WorldCatalog, the largest global catalog: http://5bio5.blogspot.com/2015/12/repost-jul-17-32-reviews-explanation-of.html

On 2015 Dec 05, S A Ostroumov commented:

The full text of the article, and the abstract, online free: https://www.researchgate.net/publication/12375514; also here, another link: https://www.researchgate.net/publication/215906004;

On 2017 Nov 04, Arnaud Chiolero MD PhD commented:

A clear explanation of why 5-years survival is such a bad statistic

On 2015 Dec 05, S A Ostroumov commented:

Full text online free, and the abstract: https://www.researchgate.net/publication/12483844; Reference: Criteria of ecological hazards due to anthropogenic effects on the biota: searching for a system. - Dokl Biol Sci (Doklady Biological Sciences). 2000; 371:204-206.

On 2014 Dec 06, Harri Hemila commented:

Jackson JL, 2000 found statistically highly significant heterogeneity between the zinc lozenge trials (P<0.00001 ). They calculated a pooled estimate of effect, although firm evidence of heterogeneity introduces serious doubt about the relevance of any one overall estimate. Instead, the main focus should be on trying to understand the sources of heterogeneity, Thompson SG, 1994. Although Jackson noted that some of the negative results might have been caused by low zinc availability, they did not carry out subgroup analysis by zinc doses. Jackson concluded in the Discussion that their “meta-analysis suggests that the evidence of zinc effectiveness is still lacking” , which is based on their inappropriate pooling of the low and high dose trials together.

Two further RCTs on zinc acetate lozenges were published after the review and both of them found significant benefit of zinc, Prasad AS, 2000 and Prasad AS, 2008.

Hemilä H, 2011 analyzed the dose-response in the zinc lozenge trials and found that five trials that used the lowest doses of zinc uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, and the pooled result indicated a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Most of the studies had been published before 2000, and the dose response would have been evident then.

On 2016 Sep 18, Lydia Maniatis commented:

Please see comments on PubPeer.

On 2015 Jul 07, Bill Cayley commented:

A good example of when "less" is "more": https://lessismoreebm.wordpress.com/2015/07/07/costs-and-effectiveness-of-spacer-versus-nebulizer-in-young-children-with-moderate-and-severe-acute-asthma/

On 2017 May 23, Morten Oksvold commented:

This article was retracted April 27 2017 together with eight other articles from the same group due to data manipulations.

Please note that the retraction notice is visible in the PDF document only.

http://www.jbc.org/content/275/21/15799.full.pdf?sid=0143148f-ee6b-413f-ae9b-711e946793fd

"This article has been withdrawn by the authors. In Fig. 5, the band shown in lane 6 was pasted in. In Fig. 7A, the ERK1b bands in the EJ cells and Rat1 cells lanes were duplicated. Because the original data are no longer available, in the interest of maintaining accuracy in the published scientific literature, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper."

On 2015 Mar 20, Daniel Haft commented:

The authors demonstrate that HcpA, a cysteine-rich repeat protein from Helicobacter pylori, slowly hydrolyzes 6-aminopenicillinic acid and 7-aminocephalosporanic acid derivatives, and therefore has some beta-lactamase activity. However, low-level beta-lactamase activity is inherent in penicillin-binding proteins involved in cell wall biosynthesis (the natural targets of beta-lactam antibiotics) and in a number of proteins whose biological role likewise is something other than antibiotic resistance. Works citing this paper tend not to dwell on the observed weak beta-lactamase activity or on the authors' suggestion that HcpA might contribute to insensitivity to amoxicillin in resistant strains. An apparent role for HcpA as a secreted pro-inflammatory virulence factor is described in PMID:16040986. I suggest that this protein be named "cysteine-rich repeat protein HcpA" rather than "beta-lactamase HcpA" for purposes of genome annotation. Beta-lactamases conferring antimicrobial resistance but outside the Ambler classes A, B, C, and D are still not known as of early 2015.

On 2015 Jul 03, Bill Cayley commented:

A good example of when Less is More: https://lessismoreebm.wordpress.com/2015/07/03/randomized-trial-of-salbutamol-via-metered-dose-inhaler-with-spacer-versus-nebulizer-for-acute-wheezing-in-children-less-than-2-years-of-age/

On 2013 Dec 14, Rafael Najmanovich commented:

A more in-depth analysis appears in Gaudreault F, 2012.

On 2016 Dec 07, Anne Niknejad commented:

link to the erratum:

http://www.jbc.org/content/275/50/39799.full

On 2014 Nov 24, Ivan Oransky commented:

The first author of this paper has agreed to retract it and five others following a finding of misconduct by the Office of Research Integrity: http://retractionwatch.com/2014/11/20/former-vanderbilt-scientist-faked-nearly-70-images-will-retract-6-papers-ori/

On 2015 Jan 14, Pertti Hakkinen commented:

As noted later by the publisher, my name is is incorrect. See: http://toxsci.oxfordjournals.org/content/60/1/0.full.pdf "ERRATUM In 'Profiles in Toxicology. Harold Carpenter Hodge (1904 –1990),' (Toxicological Sciences 53, 157–158, 2000), one author’s name was incorrect. The correct name is P. J. Hakkinen."

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2015 Nov 07, Christopher Southan commented:

For a 2013 update on BACE1 and BACE2 evolution see http://www.ncbi.nlm.nih.gov/pubmed/24381583

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Mar 26, Jonathan Wren commented:

Appears to be relocated to: http://www.ecogene.org/

On 2014 Mar 17, Swaroop Revannasiddaiah commented:

Pain relief was the primary endpoint of treatment benefit as per this particular study. Given that palliative radiotherapy for bone metastases is often intended for fracture prevention (along with pain control), could the single 8Gy fraction not be inferior to 22Gy/5Fc, or 30Gy/10Fc? From the perspective of fracture prevention.

On 2014 Sep 08, Jonathan Eisen commented:

I wrote a blog post about how difficult it was to get access to this paper via the link to Science magazine. See AAAS - Blocking Access to the Scientific Literature Even When They Say It Is "Free". After writing the post, I found the original author's version of the paper (pre-editing by Science) and submitted that to Pubmed Central. So now there is a link to that version here as well.

On 2014 Dec 31, DAVID ALLISON commented:

Methodologic issues with this paper have been identified and discussed in a paper by Flegal et al. See: http://www.ncbi.nlm.nih.gov/pubmed/20107197. PMID: 20107197.

On 2014 Dec 07, Eric Vallabh Minikel commented:

Please see our recent work in which we have provided evidence that the apparent anticipation in E200K families is driven by ascertainment bias: Minikel EV, 2014

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Feb 23, Valeria Fadda commented:

Incremental benefit of warfarin over placebo in patients with atrial fibrillation

Valeria Fadda, Roberta Gatto, Dario Maratea - HTA Unit, Regional Health System, 50100 Firenze (Italy)

One important section of the study by Hart and co-workers (1999) is represented by the meta-analytical comparison between warfarin and placebo in patients with atrial fibrillation (6 trials shown in Table 2 of Hart's article; end point = stroke). These data have in fact been used in recent times to determine the sample size enrolled in the three pivotal trials that have compared dabigatran or rivaroxaban or apixaban with warfarin (trials RE-LY, ROCKET AF, and ARISTOTLE, respectively). While the model of Hart's meta-analysis was based on the Peto method, most meta-analyses published thereafter have employed the random-effect model, which has in fact become the most widely recognised standard. Another point that deserves to be re-examined is that at least two outcome measures can be considered in analyzing these data (relative risk, RR, which is a relative outcome measure; risk difference, RD, which is an absolute outcome measure), but Hart and co-workers considered only RR and not RD. We have therefore re-analysed the above mentioned 6 trials by conducting two separate random-effect meta-analyses which employed, respectively RR and RD as outcome measures. Our re-analysis generated the two Forest plots shown in Figure 1.

Figure 1. Forest plot: repetition of the meta-analysis of Hart and co-workers. The random-effect model has been used according to a relative outcome measure (RR, Panel A) and an absolute outcome measure (RD, Panel B). The two Forest plots show the outcome measures (RR in Panel A, RD in Panel B) calculated for individual trials (squares = outcome measure; horizontal bars = 95%CIs of the outcome measure) and for the pooled analysis (diamond in blue and vertical dotted line in red). I² is a measure of heterogeneity. Statistical calculations were performed by the OMA software (Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/). The complete references for the 6 randomized trials can be found in the article by Hart et al. (1999). Abbreviations: Ev, number of events; Trt, number of patients receiving treatment.

NOTE: Figure 1 can be downloaded from the following link: http://www.osservatorioinnovazione.net/papers/aim1999reanalysis.jpg

References

Hart RG, Benavente O, McBride R, Pearce LA (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999 Oct 5;131(7):492-501.

On 2017 Mar 29, Lydia Maniatis commented:

This explanation of the Cornsweet effect, in terms of the assumption of uneven illumination, has fundamental theoretical problems.

The explanation involves a particular variant of the figure, in which the luminance gradient occurs after a stretch of homogeneous luminance. The authors construct a figure that looks like a pair of adjacent, curved and receding surfaces. Each surface contains the luminance pattern of one rectangle of the Cornsweet. The pictorial context in which the authors have embedded them produces a percept in which the luminance changes are explicitly (that is, perceptually) attributed to illumination changes occurring over two differently-colored surfaces. The authors argue that this more complex context and the physical situation corresponding to the associated percept is the most “probable” cause of the simpler, two-rectangle version, and that the visual system therefore interprets it as such. There are several serious problems with this argument.

First, Purves et al's (1999) figure can be described as anything but "probable." I have rarely or never seen anything structured remotely like it in the human or natural environment. And, while in the published images the apparently brightly-lit side is oriented either upwards or sideways, the apparent colors of the two sides DON"T CHANGE if we view it upside-down, even though illumination from directly below is, of course, highly improbable. So the argument from probability doesn't seem valid on its face. (Also, see below)

Second, the Purves et al (1991) figure is very different in form from the two simple Cornsweet rectangles lying side-by-side. To say that this pair of rectangles is being interpreted as a very different structure - while continuing to look just the way they do - e.g. flat and coplanar, rather than curved and sharply bent at the common edge - is awkward. We are in effect dealing with the converse of the notion of “unnoticed sensations.” Here, it is a complex, 3D figural interpretation which is supposed occur but go unnoticed. And it is supposed occur even though the right angles and parallel sides of the Cornsweet figures are not typically perceived as, and as retinal projections do not typically correspond to, receding surfaces. Here, the probability argument works against the authors account; in their figure, they take care to use converging edges.

Third, Purves et al still haven’t addressed, let alone explained, the Kersten-Knill (1991) version of the Cornsweet illusion, which, within each rectangle, grades evenly from left-to-right and is perfectly consistent with two half-cylinders lit from one side (as is evidenced by the right half of the Kersten-Knill demonstration). Luminance variations consistent with cylindrical surfaces are typically perceived as such, even when lacking the type of formal cues added by Kersten and Knill. We see this in the case of the "sinusoidal patches" commonly employed in the vision literature, sometimes referred to as "sinusoidally-corrugated surfaces" (e.g. Chen and Tyler 2015, PLOS one) because of the strong impression of 3D relief they create. On the basis of Purves et al's explanation of their Cornsweet variant, the two halves of the Kersten-Knill variant should appear similarly-colored. But they don't.

It should be clear that the explanation offered by Purves et al (1999) is no explanation at all, but a purely ad hoc account, a pictorial bagatelle which simply turns a blind eye to theoretical difficulties and inconsistencies.

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2016 Oct 11, Casey M Bergman commented:

The online appendix for this paper is no longer available at the location listed in the paper (http://www.pubs.royalsoc.ac.uk/publish/pro_bs/rpbl428.htm). The appendix is now located at: http://rspb.royalsocietypublishing.org/content/266/1428/1555.figures-only

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2014 Jul 24, Albert Erives commented:

This classic paper is a description and coining of the "selector" gene model for homeotic regulators.

On 2014 Feb 20, Egon Willighagen commented:

Figure 5 is available as WikiPathway at http://www.wikipathways.org/index.php/Pathway:WP2634

On 2015 Jun 02, thomas samaras commented:

Additional information on height, CHD, and longevity is available from these recent publications.

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

On 2013 Jun 18, Jill Barnholz-Sloan commented:

This article describes the STRUCTURE program that is commonly used for population stratification testing and estimation of individual ancestry estimates for case control studies. Population stratification is an important potential bias that needs to be measured in case control studies, especially in recently admixed populations. STRUCTURE is an easy to use program that has just been recently reviewed in this paper with a detailed description of parameter settings and their impact on results (http://www.frontiersin.org/Statistical_Genetics_and_Methodology/10.3389/fgene.2013.00098/abstract)