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Top tow, from left: Consumption (scale goes up to “135 and over per 1000 deaths”), diphteria (50 and over), cancer and tumors (30+), whooping cough (14+);

Middle row: Pneumonia (105+), croup (20+), malarial fever (80+), scarlet fever (11+);

Bottom row: Diarrheal diseases (100+), typhoid fever (50+), measles (20+), heart disease and dropsy (80+).

From davidrumsey.com.   

The link between influenza, and deaths from apparently-unrelated causes, has apparently been noted for well over 100 years. It’s still somewhat controversial today.

Effect on the Mortality from other Diseases.
One of the chief characteristics of an influenza epidemic is the effect it produces on the mortality from other diseases. The disorders most conspicuously affected are, as is well known, those of the respiratory system; but others are influenced in an almost equally marked degree. The annexed table gives details of the relation between the mortality due to various causes of death and that attributed primarily to influenza during the course of the 1892 epidemic.

The principal facts are contained in Table III. Besides the rise in the mortality from the respiratory diseases, the augmented fatality of phthisis, diseases of the circulatory system, and whooping-cough is noticeable, as is also the increase in the number of deaths attributed simply to ” old age.”

Another diagram (No. 1) exhibits the dependence of the mortality ascribed to the two main respiratory diseases, bronchitis and pneumonia, on the presence of influenza for the whole period from October, 1889, to July, 1892. It will be seen that in every instance of the prevalence of the latter, the curves representing the mortality from, the two former rise far above the average; The peculiar significance of these curves lies in the fact that the presence of influenza as the primary cause of death was not recognised in any of the cases which they represent; otherwise they would have appeared in the Registrar-General’s returns under the head of “influenza,” and not under that of “bronchitis ” or “pneumonia ” as the case may be.

London.  Causes of the Mortality due to the Influenza Epidemic of 1892

An increased mortality from all or most of the causes that have been mentioned characterises all influenza epidemics, and not that of 1892 alone. It is impossible to believe that the invariable coincidence between the rise of these various causes of death and influenza is accidental, and the conclusion seems inevitable that influenza itself is the determining cause, though it does not so appear in the returns furnished to the Registrar-General. This being the case, in estimating the mortality of any particular epidemic it is necessary to allow for the deaths returned under other heads than that of influenza.

–On the Influenza Epidemic of 1892 in London :: BMJ 2:353-356 (1892)

Why do a spider’s legs curl up when it dies?

The explanation was provided by Pritesh Kalantri: Spider legs extend due to hydraulic pressure, not muscular action, so when the hydraulics are turned off (as when the spider dies) the muscles that contract the legs have no opposing action, and the legs curl up.

This was new to me, and I quickly found what seems to be the original paper establishing this fascinating fact:  Parry, D. A., R. H. J. Brown: The hydraulic mechanism of the spider leg. J. Exp. Biol. 36 (1959a) 423–433.

A helpful diagram should you decide to test hydraulic pressure in your own spider’s legs. This can be used with live spiders, as needed.

A more detailed view of spider anatomy

1. The blood pressure inside the leg of the house spider Tegenaria atrica has been measured. Maintained pressures of about 5 cm. Hg and transient pressures of up to 40 cm. Hg have been found.
2. The relation between the blood pressure in the leg and the extension torque at the hinge joints has been established.
3. Considerable torques can be developed at the hinge joints during extension, for example, when accelerating a mass fixed to the leg. The transient pressures found to arise in the leg are adequate to account for these torques.
4. The hydraulic mechanism is discussed. The available evidence suggests that the pressure found in the legs occurs also in the prosoma but not in the abdomen, in which case the maintained pressure must be due to the heart. This, however, requires further investigation.

We are greatly indebted to the Cambridge Instrument Company for the loan of a photo-electric transducer; and also to many friends who have supplied us with spiders.

However, a little further research suggests that hydraulic activity is not the only mechanism for spider leg movement.

In large spiders such as A. concolor, the advantage of strong leg flexion remains valid. Here, during jumps and starts, the net propulsive power is shifted more to their front legs. In contrast to jumping spiders, the ground reaction forces of the frontal legs and the second legs are as strong as those exerted by the hind legs.  … It seems that depending on the spider’s body size both hydraulics and muscular leg flexion contribute, to variable degrees, to the propulsion of the hind legs.

– Hydraulic leg extension is not necessarily the main drive in large spiders.
J Exp Biol. 2012 Feb 15;215(Pt 4):578-83. doi: 10.1242/jeb.054585.
Weihmann T, Günther M, Blickhan R.

This led inevitably to the next question:  If you accidentally sever a spider’s leg, will the leg bleed?

It does bleed, but there is a special mechanism that prevents too much loss of fluid.  Here is an explanation from a 1957 paper:

Figure 3.  Anatomy of a spider leg, showing the mechanism by which fluid loss is minimized if the leg is severed

Unlike Crustacea and insects, spiders autotomize their legs at a functional
joint and an account is given of the interesting mechanism by which the joint is severed and bleeding restricted. …

THE AUTOTOMY MECHANISM
‘Autotomie’ was defined by Fredericq (1883) as ‘mutilation par voie reflexe comme moyen de defense chez les animaux’. Usage has since widened the term to embrace all cases of fracture of limbs and other structures at a specific point where structural adaptations associated with the fracture mechanism and reduction of bleeding are found to occur.

… I have shown above (see fig. 3, A-D) that in Tegenaria the coxal muscles are all inserted on to a ring of sclerites which fit into a groove in the proximal rim of the trochanter. The joint fractures between these sclerites and the trochanter, and the coxal muscles then pull the articular membrane proximally while at the same time the sclerites converge on one another (fig. 3, E) so that a comparatively small hole is left in which the blood rapidly clots and which after a day or two is sealed by a brown plate.

– Spider Leg-muscles and the Autotomy Mechanism
D. A. PARRY
Quarterly Journal of Microscopical Science, Vol. 98, part 3, pp. 331-340, Sept. 1957.

Is the world becoming sicker or are we just better able to detect disease? The last decades have seen dramatic improvements in biological disease detection with dozens of new potential pathogens anticipated by 2020. At the same time innovations in information management are increasing awareness of disease outbreaks. Perry et al. (2011)¹ explore this in a recent review and conclude that there is overall evidence for increased emergence of disease in recent decades, and not just improvements in diagnosis and surveillance. The current increase in disease emergence is not historically unprecedented: major epidemiological transitions also occurred during the Neolithic when livestock were domesticated on a wide-scale, during the age of exploration when Old World pathogens were introduced to the New World, and to a lesser extent with increased global travel in the nineteenth century).

–Grace, D. et al. 2012. Mapping of poverty and likely zoonoses hotspots: Report to the Department for International Development. Nairobi, Kenya: ILRI 

1. Perry, B.D., Grace, D. Sones, K., 2011. Current drivers and future directions of global livestock disease dynamics. Proceedings of the National Academy of Sciences of the United States of America, 16 May 2011. doi 10.1073/pnas.1012953108

On the evening of October 21st only a few animals were affected, but on the morning of the 22d there was scarcely an animal of the equine species that was not affected.  Horses, mules, and even a zebra.  More than twenty thousand were suffering in different degrees. ¹

(See also Influenza before 1918, part II: 1872)

1. Annual report of the Department of Health of the State of New Jersey. By The New Jersey State Dept. of Health, 1877 (“Epizootic influenza”, p. 160) 

Even the most lethal pathogens we know of don’t kill every single infected individual.¹. Sometimes this is because the pathogen that infects the person is relatively weak. Sometimes it’s because the dose was low. And sometimes it’s because of something intrinsic to the patient. Some people are genetically resistant to HIV, because they have a mutated receptor, for example.

The opposite is also true. Sometimes people are more intrinsically susceptible to a pathogen. That became terribly clear during the AIDS epidemic, when quite innocuous agents started killing people, but there are probably many, many natural genetic variants that make us susceptible to some pathogens, just as some make us resistant. When epidemiologists look for “risk factors” that increase mortality or disease severity, this is part of the information they’re trying to tease out, in a rather crude way Sorting this out is part of the goal of the whole personalized medicine movement.

A fascinating example was just documented in MMWR. ² Here a researcher was working with a genetically modified form of Black Plague bacteria (Yersinia pestis). This bacteria should have been harmless, because it had had its ability to grab iron from the host removed. ³. But the researcher became infected, and died, of an infection with the weakened strain.

We now learn that this was probably because the researcher had his own genetic mutation, hereditary hematochromatosis, which leads to increased levels of iron in the blood. He may⁴ have been uniquely susceptible to this strain,⁵ which could only infect people who conveniently made extra iron available to it:

Conceivably, hemochromatosis-induced iron overload might have a similar effect, enhancing the virulence of the infecting KIM D27 strain by compensating for its iron-acquisition defects⁶

Patients and pathogens are ecosystems; you need to understand both of them, or you don’t understand either.

1. Even rabies virus, for example, which kills well over 99.999% of the people it infects, has had a half-dozen people survive. Myxomatosis virus let a few rabbits survive, and their progeny became relatively resistant; there are a handful of long-term survivors of HIV treatment; and when we get down to things like ebola and smallpox, 10-30% of infected people survive.
2. Steve Silberman’s twitter account first drew my attention to the report.
3. The quest for iron is a constant struggle for pathogenic (and other) bacteria, and they have evolved all kinds of mechanisms to seize it from the host, while at the same time animals have evolved more and more ways to keep iron away from invading bacteria.
4. Note that this is speculation, not proven!
5. He also had diabetes, which may have made him more susceptible as well
6. Centers for Disease Control and Prevention (CDC) (2011). Fatal Laboratory-Acquired Infection with an Attenuated Yersinia pestis Strain — Chicago, Illinois, 2009. MMWR. Morbidity and mortality weekly report, 60 (7), 201-5 PMID: 21346706

Then, it would seem to have been all but unanimous; and now, one would think, at first sight, that it were almost an insult to human understanding to be obliged to collect statistics to prove that vaccination confers a large exemption from attacks of small pox, and almost absolute security against death from that disease. … The general ignorance of the community, especially of the lower orders, as to the aim and object of vaccination, is lamentably great, and has still to be overcome.

–William Aitken
The Science and Practice of Medicine, Vol. I (Second edition)
Charles Griffin and Company, London, 1863

Eliminating TRegs, in mouse models of cancer, often allows a strong immune response to the tumor. An interesting spin on this was shown in a recent J Immunol paper.¹ It seems that the TRegs don’t generally suppress all the response, they shut down the responses to some targets harder than others:

Our results indicate, therefore, that depletion of Tregs uncovers cryptic responses to Ags that are shared among different tumor cell lines. CT26-specific T cell responses can be elicited by different forms of vaccination in the presence of regulatory cells, but in these cases T cell responses are highly focused on a single tumor-specific epitope …Taken together, these data suggest that immune responses to some Ags are more tightly regulated than others.  ¹

In other words, even though you might be able to force a protective immune response to a tumor by vaccinating in the presence of TRegs, when you get rid of TRegs the response is broader, and targets T cell epitopes that otherwise wouldn’t look like they’re epitopes at all.

I wonder if this goes on with “normal” (say, viral or other non-tumor) epitopes – whether this sort of thing might help explain some forms of immunodominance. I kind of doubt it, but the phenomenon does sounds a little like revealing a subdominant response.

I wonder also how this ties in with a recent paper that suggested TRegs in tumors are highly focused on a small subset of tumor epitopes. Could they be more broadly-based, but on epitopes that are otherwise invisible? Again, I kind of doubt it, but it’s an intriguing idea.  Maybe the universe of tumor epitopes available for attack is much larger than we realize.

1. James, E., Yeh, A., King, C., Korangy, F., Bailey, I., Boulanger, D., Van den Eynde, B., Murray, N., & Elliott, T. (2010). Differential Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells The Journal of Immunology, 185 (9), 5048-5055 DOI: 10.4049/jimmunol.1000134