Inflammatory bowel diseases — like Chron’s disease and ulcerative colitis — may be associated with decreased bacterial diversity and an increased volume of bacteriophages and other viruses

© 2015 Peter Free

Citation — to study

Jason M. Norman, Scott A. Handley, Megan T. Baldridge, Lindsay Droit, Catherine Y. Liu, Brian C. Keller, Amal Kambal, Cynthia L. Monaco, Guoyan Zhao, Phillip Fleshner, Thaddeus S. Stappenbeck, Dermot P.B. McGovern, Ali Keshavarzian, Ece A. Mutlu, Jenny Sauk, Dirk Gevers, Ramnik J. Xavier, David Wang, Miles Parkes, and Herbert W. Virgin, Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease, Cell, DOI: 10.1016/j.cell.2015.01.002 (online now, 22 January 2015))

Citation — to press release

Michael C. Purdy, Viruses may play unexpected role in inflammatory bowel diseases, Washington University in St. Louis (22 January 2015)

From the arguably poorly communicated abstract

The finding in this study may boil down to the fact that the volume and diversity of “free” Caudovirales bacteriophages — meaning those outside the bacteria they usually inhabit — may be increased in patients with inflammatory bowel conditions (like Chron’s and ulcerative colitis), as compared to controls.

Alternatively, the finding may be that the volume of loose Caudovirales bacteriophages and noticeable volumes of other viruses are both increased:

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases.

We show that the enteric virome is abnormal in CD and UC patients.

In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages.

The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations.

These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis.

We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.

© 2015 Jason M. Norman, Scott A. Handley, Megan T. Baldridge, Lindsay Droit, Catherine Y. Liu, Brian C. Keller, Amal Kambal, Cynthia L. Monaco, Guoyan Zhao, Phillip Fleshner, Thaddeus S. Stappenbeck, Dermot P.B. McGovern, Ali Keshavarzian, Ece A. Mutlu, Jenny Sauk, Dirk Gevers, Ramnik J. Xavier, David Wang, Miles Parkes, and Herbert W. Virgin, Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease, Cell, DOI: 10.1016/j.cell.2015.01.002 (online now, 22 January 2015) (paragraph split, underline added)

Regarding the abstract’s opaque language

Notice that the abstract and its title loosely conflate the more general terms, “viral” load and “virome” with the more specific term, Caudovirales bacteriophages. Thus, we cannot tell whether the team found:

(a)  both an increase in viruses (of apparently many kinds) and a proportionately noticeable increase in loose Caudovirales bacteriophages

or

(b) mainly an increase in loose Caudovirales bacteriophages.

Second, the abstract adds the mildly counterintuitive statement that bacterial populations remained the same, despite the fact that a loose Caudovirales bacteriophage population(s) presumably came from dead or dying bacteria.

Given that it seems unlikely that different species of bacteria would all be equally affected by whatever causes them to lose their Caudovirales bacteriophage DNA bits, it does not make obvious sense, when the authors simultaneously suspect that “the virome may contribute to intestinal inflammation and bacterial dysbiosis.”

Note

Dysbiosis is an unnecessarily imprecise and fancy word for “microbial imbalance”.

Which in this context we can assume to mean that the research team suspects that the heightened viral load has something to do with the reduced diversity and population(s) of intestinal bacteria.

Maybe and equally, maybe not. One could just easily assume that:

(a) if the Caudovirales bacteriophage population comes from dying bacteria,

(ii) then it is whatever is killing the bacteria that causes inflammatory disease

and

(iii) not the associated change in loose bacteriophage volume/diversity that is the culprit.

One could hypothesize the same thing for many or all of the other viruses, as well.

As is it turns out, the abstract’s arguably unclear wording merely reflects the confusion that almost always attends a preliminary investigation

According to Michael Purdy’s much more informative press release, the research team has no idea which viruses it is dealing with or how they got there:

The Centers for Disease Control and Prevention estimates that inflammatory bowel diseases affect about 1 million people in the United States.

Crohn’s disease and ulcerative colitis are thought to involve misdirected immune attacks on gut tissue and can lead to weight loss, bleeding in the gut and rectum, and loss of appetite. Surgery to remove part of the bowel is often necessary to treat Crohn’s disease.

Virgin and his colleagues studied three groups of patients with Crohn’s disease or ulcerative colitis living in Chicago, Boston and the United Kingdom.

In each group, they compared viral DNA purified from the feces of participants with viral DNA from the feces of healthy people living in the same areas and, in some cases, the same homes.

The findings suggest that scientists should be studying the virome as closely as the microbiome, said senior author Herbert W. Virgin IV, MD, PhD.

“This is the tip of the iceberg,” he said.

“A significant portion of the viral DNA we identified in these patients is unfamiliar to us — it comes from newly identified viruses we don’t know much about.

We have a great deal of groundwork to do, including sequencing the genetic material of these viruses and learning how they interact with the gut and gut bacteria, before we can determine if changes in the virome cause these conditions or result from them.”

Much of the increased viral diversity in participants with inflammatory bowel diseases was in the form of bacteriophages, which are viruses that infect bacteria and can incorporate themselves into the bacteria’s genetic material,” said Virgin . . . head of the Department of Pathology and Immunology.

Changes in the gut that eliminate bacteria in inflammatory bowel diseases may unleash bacteriophages in the dying bacteria, Virgin speculated.

Or the introduction of a new bacteriophage to the gut, perhaps through the foods in a person’s diet, may trigger a reaction in the digestive system or the microbiome that causes the disorders, he said. It’s also possible that a combination of these mechanisms may contribute.

© 2015 Michael C. Purdy, Viruses may play unexpected role in inflammatory bowel diseases, Washington University in St. Louis (22 January 2015) (extracts, italics added)

The moral? — Interesting, probably valuable, but too early to say more than that

Excellent work, but somewhat clumsily reported in the abstract. Kudos to Michael Purdy for clearing the confusion with his informative press release.

Study of 290 adults appears to show that shortened telomeres and increased copies of mitochondrial DNA can result from childhood adversity — being further associated with depression, anxiety, and substance abuse

© 2015 Peter Free

Citation — to study

Audrey R. Tyrka, Stephanie H. Parade, Lawrence H. Price, Hung-Teh Kao, Barbara Porton, Noah S. Philip, Emma S. Welch, and Linda L. Carpenter, Alterations of Mitochondrial DNA Copy Number and Telomere Length with Early Adversity and Psychopathology, Biological Psychiatry, DOI: 10.1016/j.biopsych.2014.12.025 (in press, 16 January 2015)

Being less than ideally treated early in life appears to have cellular effects that represent or mimic cellular aging

From the abstract:

Methods

Two-hundred and ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews.

Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders).

Telomere length and mtDNA copy number were measured from leukocyte DNA by qPCR [quantitative real time polymerase chain reaction].

Results

Childhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001).

Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers.

Conclusion

This study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders.

We replicate prior work on telomere length and psychopathology, and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging.

© 2015 Audrey R. Tyrka, Stephanie H. Parade, Lawrence H. Price, Hung-Teh Kao, Barbara Porton, Noah S. Philip, Emma S. Welch, and Linda L. Carpenter, Alterations of Mitochondrial DNA Copy Number and Telomere Length with Early Adversity and Psychopathology, Biological Psychiatry, DOI: 10.1016/j.biopsych.2014.12.025 (in press, 16 January 2015) (at Abstract) (paragraphs split)

Caveat

It is too early in this research to draw conclusions as to the validity of the cellular aging analogy. Similarly, I am cautious (as the research team also appears to be) in inferring whether psychopathology might cause these cellular manifestations or the reverse. Or both.

With regard to the cellular aging analogy, just because shortened telomeres occur in association with generically getting cellularly old, does not mean that a similar telomeric shortening earlier in life (due to childhood adversity) represents the same process with the same results. As the authors rightly note, these are “markers” of aging. Markers are, at best, associations — with sometimes little causative and even representational merit.

The moral? — Still too early to assess these findings’ meanings and interventional significance

That said, this study joins others that demonstrate the cellular consequences of psychic adversity. “It’s not just all in my head.”

Danish-Colombian study of wheat and corn — shows that a high density, grid sowing pattern — planted with well-chosen crop seed varieties — markedly reduces weed volume — while significantly boosting crop production

© 2015 Peter Free

Citation — to Colombian prong of the study

C Marín and J Weiner, Effects of density and sowing pattern on weed suppression and grain yield in three varieties of maize under high weed pressure, Weed Research 54(5): 467–474, DOI: 10.1111/wre.12101 (October 2014)

Citation — to press more inclusive release

Rikke Pape, Crops can do their own weed control, University of Copenhagen (13 January 2015)

Not unlike high density block planting in back yard gardening

From the press release:

Research studies performed in Danish wheat fields, together with recent studies in Colombian corn fields, demonstrate that modified sowing patterns and the nearer spacing of crops results in a reduction of total weed biomass.

The amount of weeds was heavily reduced – by up to 72% – while grain yields increased by more than 45% in heavily weed-infested fields.

The trick is to increase crop-weed competition and utilize the crop’s head start, so that it gains a large competitive advantage over the neighbouring weeds.

© 2015 Rikke Pape, Crops can do their own weed control, University of Copenhagen (13 January 2015) (paragraph split)

From the abstract — regarding the Colombian experiment with corn (maize):

Field experiments on three varieties of maize sown at three densities (5, 7 and 10.5 seeds m−2) and in two spatial patterns (grid pattern and rows) under very high weed pressure from Brachiaria brizantha were performed in 2012 and 2013.

We measured weed biomass 1 month after sowing and at harvest, and grain yield at harvest. Density, variety and sowing pattern all had strong and significant effects on both weed biomass and yield.

On average, weed biomass was reduced (by 72% in the first year and 58% in the second year), and grain yield was increased (by 48% and 44%) at the highest density in the grid pattern compared with standard sowing practices (medium density, row pattern).

There was a significant density × variety interaction, which is evidence for genetic differences in the response of the varieties to density in characteristics that influence weed suppression.

© 2014 C Marín and J Weiner, Effects of density and sowing pattern on weed suppression and grain yield in three varieties of maize under high weed pressure, Weed Research 54(5): 467–474, DOI: 10.1111/wre.12101 (October 2014)

Caveats

Obviously these results might vary, depending upon the weed and soil type(s) in question.

Additionally, one would think that grid planting might negatively affect some farmers’ existing investments in row-type harvest equipment.

The moral? — Made sense in home gardening, probably should also in agronomy

Agricultural experiments are often comparatively simple in concept, but large in useful results.

Before the Great Oxygenation Event — iron-supplying underwater volcanism may have slowed cyanobacteria in supplying oxygen to the atmosphere

© 2015 Peter Free

Citation — to modeling study

Elizabeth D. Swanner, Aleksandra M. Mloszewska, Olaf A. Cirpka, Ronny Schoenberg, Kurt O. Konhauser, and Andreas Kappler, Modulation of oxygen production in Archaean oceans by episodes of Fe(II) toxicity, Nature Geoscience, DOI:10.1038/ngeo2327 (advance online publication, 05 January 2015)

Citation — to press release

Janna Eberhardt, Iron toxicity for cyanobacteria delayed oxygen accumulation in early Earth’s atmosphere, Universität Tübingen (05 January 2015)

Trying to answer the question of why transition to a 20 percent oxygen atmosphere was interrupted after the first appearance of oxygen-generating cyanobacteria

From the press release:

Today’s seawater contains little iron. But more than three billion years ago, the oceans contained abundant reduced iron.

This is partially because oxygen, which causes the iron to precipitate, had not yet entered the ocean to great depths, and also because the seafloor at that time contained abundant iron released by bursts of hydrothermal activity.

“In these periods, we often find no indicators of oxygen release,” says Elizabeth Swanner, the study’s lead author.

The researchers carried out lab experiments seeking a link between high concentrations of iron and low cyanobacteria growth.

© 2015 Janna Eberhardt, Iron toxicity for cyanobacteria delayed oxygen accumulation in early Earth’s atmosphere, Universität Tübingen (05 January 2015) (paragraph split)

From the excellently written abstract:

Oxygen accumulated in the surface waters of the Earth’s oceans and atmosphere several hundred million years before the Great Oxidation Event [see here] between 2.4 and 2.3 billion years ago.

Before the Great Oxidation Event, periods of enhanced submarine volcanism associated with mantle plume events supplied Fe(II) to sea water. These periods generally coincide with the disappearance of indicators of the presence of molecular oxygen in Archaean sedimentary records.

The presence of Fe(II) in the water column can lead to oxidative stress in some organisms as a result of reactions between Fe(II) and oxygen that produce reactive oxygen species. Here we test the hypothesis that the upwelling of Fe(II)-rich, anoxic water into the photic zone during the late Archaean subjected oxygenic phototrophic bacteria to Fe(II) toxicity.

In laboratory experiments, we found that supplying Fe(II) to the anoxic growth medium housing a common species of planktonic cyanobacteria decreased both the efficiency of oxygenic photosynthesis and their growth rates.

We suggest that this occurs because of increasing intracellular concentrations of reactive oxygen species.

We use geochemical modelling to show that Fe(II) toxicity in conditions found in the late Archaean photic zone could have substantially inhibited water column oxygen production, thus decreasing fluxes of oxygen to the atmosphere.

We therefore propose that the timing of atmospheric oxygenation was controlled by the timing of submarine, plume-type volcanism, with Fe(II) toxicity as the modulating factor.

© 2015 Elizabeth D. Swanner, Aleksandra M. Mloszewska, Olaf A. Cirpka, Ronny Schoenberg, Kurt O. Konhauser, and Andreas Kappler, Modulation of oxygen production in Archaean oceans by episodes of Fe(II) toxicity, Nature Geoscience, DOI:10.1038/ngeo2327 (advance online publication, 05 January 2015) (at Abstract) (paragraph split, underlines added)

The moral? — The interaction between geological dynamics (volcanism), water column chemical composition and biochemistry seems reasonable

And there is this metaphorical twist, which has loosely parallel implications for today’s human interactions with Earth:

“Too much iron in the presence of oxygen was harmful. You could say the early cyanobacteria poisoned themselves,” Andreas Kappler says.

© 2015 Janna Eberhardt, Iron toxicity for cyanobacteria delayed oxygen accumulation in early Earth’s atmosphere, Universität Tübingen (05 January 2015)

Doing expensively more of what is unnecessary and potentially dangerous in American medicine — this time with headaches

© 2015 Peter Free

09 January 2015

Citation — to study

John N. Mafi, Samuel T. Edwards, Nigel P. Pedersen, Roger B. Davis, Ellen P. McCarthy, and Bruce E. Landon, Trends in the Ambulatory Management of Headache: Analysis of NAMCS and NHAMCS Data 1999–2010, Journal of General Internal Medicine, DOI: 10.1007/s11606-014-3107-3 (online first, 08 January 2015) (PDF is here)

Citation — to press release

Jerry Berger, BIDMC Study Suggests Worsening Trends in Headache Management, Beth Israel Deaconess Medical Center (08 January 2015)

Figuratively — if we don’t get paid big time, we ain’t gonna talk to ya

And we’ll order some expensively useless tests, including some with radiation (like CT and MRI) that can pose hazards to your health.

Cynics will smile:

A new study of more than 9,000 physician visits for headaches between 1999 and 2010 found that, rather than talking to patients about the causes and potential sources of relief from headache pain, clinicians are increasingly ordering advanced imaging and providing specialist referrals, both of which are considered to be of little value in the treatment of routine headaches.

The assessment of headaches depends on identifying the relatively rare instances where serious underlying causes are suspected, says lead author John N. Mafi, MD . . . who notes that evidence-based guidelines for routine headache, including those from the American Academy of Neurology, suggest conservative treatments such as counseling on stress reduction or avoiding dietary triggers.

“I was particularly alarmed about the overall trend of more imaging tests, medications, and referrals alongside less counseling,” says Mafi.

“These findings seem to reflect a larger trend in the US healthcare system beyond just headache: over-hurried doctors seem to be spending less time connecting with their patients and more time ordering tests and treatments.

“To me, this study suggests that the current 20 minute visit-based model of healthcare is broken and that we need to move towards promoting and reimbursing innovative solutions such as doctors and patients electronically collaborating on their healthcare outside the office visit.”

The study, which analyzed an estimated 144 million patient visits, found a persistent overuse of low-value, high-cost services such as advanced imaging, as well as prescriptions of opioids and barbiturates. In contrast, the study found clinician counseling declined from 23.5 percent to 18.5 percent between 1999 and 2010.

© 2015 Jerry Berger, BIDMC Study Suggests Worsening Trends in Headache Management, Beth Israel Deaconess Medical Center (08 January 2015) (paragraphs split)

I remember being trained to avoid prescribing unnecessary tests for headaches. That was 19 years ago.

Judging by the data presented in the above cited study, we have gone noticeably backward. Not only do these unnecessary tests cost substantial amounts of money, CTs and MRIs come with known health risks:

A recent report found that 62 % of CT head/brain studies are inappropriate, according to evidence-based guidelines, most frequently ordered inappropriately for chronic headache, and this overuse has significant consequences.

Incidental findings provoke unnecessary patient anxiety, can lead to more invasive procedures, and often require follow-up testing.

Susceptible individuals carry the risk of anaphylaxis or acute kidney injury due to contrast dye, and in patients with chronic kidney disease, gadolinium contrast poses the risk of nephrogenic systemic fibrosis.

Finally, ionizing radiation poses yet another hazard: in 2007, an estimated 4,000 additional cancers were created by the 18 million cranial CT studies performed in the U.S.

© 2015 John N. Mafi, Samuel T. Edwards, Nigel P. Pedersen, Roger B. Davis, Ellen P. McCarthy, and Bruce E. Landon, Trends in the Ambulatory Management of Headache: Analysis of NAMCS and NHAMCS Data 1999–2010, Journal of General Internal Medicine, DOI: 10.1007/s11606-014-3107-3 (online first, 08 January 2015) (PDF is here) (at second paragraph under Discussion in the PDF) (paragraph split)

Causes for retrograde clinical trend?

The team wrote that:

We also find that while clinicians increasingly prescribe medications, order advanced imaging, and refer to other physicians, they are less often providing lifestyle modification counseling during headache visits.

Although ambulatory visit length has slightly increased over time, primary care clinicians consistently report increasing time pressures, due to several factors:

1) a greater number of recommended treatments and preventive services;

2) more informed, assertive, and inquisitive patients, including increased patient inquiries about prescription drug advertisements;

and

3) increased documentation demands.

This perception is bolstered by a rise in the number of clinical items addressed in each U.S. primary care visit, which has led to a marked decline in the amount of time allotted per clinical item, falling from a mean of 4.4 minutes per item in 1997 to 3.8 minutes per item in 2005.

Studies have demonstrated that increased time pressures in primary care lead to inappropriate prescribing, increased malpractice claims, and reduced patient and physician satisfaction.

Taken in this context, our findings suggest that the traditional 20-minute-visit-based care model may discourage the use of time-intensive tasks such as counseling.

Further research should investigate whether increasingly hurried clinicians are less likely to counsel their patients and more likely to order costly tests.

© 2015 John N. Mafi, Samuel T. Edwards, Nigel P. Pedersen, Roger B. Davis, Ellen P. McCarthy, and Bruce E. Landon, Trends in the Ambulatory Management of Headache: Analysis of NAMCS and NHAMCS Data 1999–2010, Journal of General Internal Medicine, DOI: 10.1007/s11606-014-3107-3 (online first, 08 January 2015) (PDF is here) (at fourth paragraph under Discussion in the PDF) (paragraph split)

Less time, less opportunity to think and persuade.

Caveats

The researchers noted that the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey that they drew their data from are not set up to follow individual patients. Which means that one has to assume that the averages among the entire sample, over time, are representative of the general prescribing reality:

[A]lthough some visits classified as guideline discordant may, in fact, have been considered appropriate if additional clinical data (e.g., “worst headache of my life”) had been available, our focus is less on the proportion of guideline-discordant treatments and more on treatment trends over time, and we have no reason to suspect that the proportion of headaches due to serious intracranial pathology has increased over the past decade.

© 2015 John N. Mafi, Samuel T. Edwards, Nigel P. Pedersen, Roger B. Davis, Ellen P. McCarthy, and Bruce E. Landon, Trends in the Ambulatory Management of Headache: Analysis of NAMCS and NHAMCS Data 1999–2010, Journal of General Internal Medicine, DOI: 10.1007/s11606-014-3107-3 (online first, 08 January 2015) (PDF is here) (at sixth paragraph under Discussion in the PDF)

The authors conclude that the healthcare system needs work

How headaches are investigated and treated is not a trivial issue:

The lifetime prevalence of headache exceeds 95 %, and nearly one-quarter of the population suffers from recurrent severe headaches. It is among the most common chronic pain conditions resulting in lost productivity, leading to 5.4 % of the U.S. workforce missing work each year, and is one of the chief causes of disability worldwide.

Headache is among the most frequent reasons for visiting a physician, accounting for 12 million visits per year in the U.S., and costing upwards of $31 billion per year. Most cases of headache presenting to clinicians are either acute presentations of a known chronic clinical condition or an acute self-limiting condition. Thus, the assessment of headache depends on identifying the relatively rare instances when serious underlying causes are suspected, which frequently require further investigation.

Evidence-based guidelines for primary headache suggest conservative treatments such as counseling on stress reduction or avoiding dietary triggers, and reserve imaging or specialty referrals for circumstances such as neurologic deficits, cancer, trauma, human immunodeficiency virus (HIV), or other “red flags”.

The Choosing Wisely campaign of the American Board of Internal Medicine has recently identified reducing the use of advanced imaging and prescriptions for opioids and barbiturates for headache as important opportunities to improve value in our healthcare system.

© 2015 John N. Mafi, Samuel T. Edwards, Nigel P. Pedersen, Roger B. Davis, Ellen P. McCarthy, and Bruce E. Landon, Trends in the Ambulatory Management of Headache: Analysis of NAMCS and NHAMCS Data 1999–2010, Journal of General Internal Medicine, DOI: 10.1007/s11606-014-3107-3 (online first, 08 January 2015) (PDF is here) (at first paragraph under Abstract in the PDF)

The moral? — Guidelines are not enough to fix a system warped by volume and frequently intrusive greed

Skewed as our medical system is toward procedures, expensive technology, and arguably excessive profit — sensible medicine frequently loses out.

Until we revise the assumptions that underlie profit-oriented medicine — or reorient them toward providing rewards for practicing efficacious medicine — we are going to continue with more of the same.