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David Plaut: Off the Cuff

Intriguing Troponin Series
July 28, 2014 11:53 AM by David Plaut

I recently was asked to comment on the following series of troponin values from a general hospital:

Day  Time  Troponin 1 
 1  1325  2.6
 1  1724  2.4
 1  2035  2.3
 2  0248  2.2
 2  0646 2.1 

Since this is a series of extremely high troponin, an MI was suspected. Although the EKG/ECG was not normal, there was no evidence of an AMI.

The apparent "change" in the TnI is probably due to the random error rather than a physiological change.

I am sorry to say that, by the time I was asked to comment on this, the sample was gone and the patient had been discharged. My response had the sample still been available was to suggest that one or more of the samples be mixed 1+1 and 1+3 with a sample with a very low TnI level (approx. 0).  Then assay the unmixed sample(s) and the dilutions. If the sample contained a heterophilic antibody (my thought) the values would not show linearity.  If the troponin were truly TnI the sample would show linearity.  Another/additional test would be to measure a not constituent measured by immunoassay such as TSH or hCG.  A high value in these would also indicate a heterophilic antibody.

An interesting article on salivary cTnI appeared recently.  In a group of 30 confirmed AMI and 28 non-MI

the cTnI were measured in both serum and saliva.  The interquartile range for the saliva was 0.08-0.23 and for the AMI patients at 12 hrs. post-admission the range was 2.7-11.6 and at 24 hrs. the range was 2.1-9.0

In a similar study by the same authors higher CK levels in saliva were also recorded.

In both cases there was a positive correlation between serum levels of both CK and cTnI and salivary levels.

Reference

  1. Indian J Med Res. Dec 2013; 138(6): 861-865

 

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Iron Deficiency and Hepcidin
July 21, 2014 11:00 AM by David Plaut

Iron deficiency (ID) is relatively common among the elderly population, contributing substantially to the high prevalence of anemia observed in the last decades of life, which in turn has important implications both on quality of life and on survival. In elderly subjects, ID is often multifactorial (i.e., due to multiple concurring causes, including inadequate dietary intake or absorption, occult bleeding, medications).

Moreover, because of the typical multi-morbidity of aged people, other conditions leading to anemia frequently coexist and make diagnosis of ID particularly challenging. Treatment of ID is also problematic in elderly, since response to oral iron is often slow, with a substantial fraction of patients showing refractoriness and requiring cumbersome intravenous administration. In the last decade, the discovery of the iron regulatory hormone hepcidin (an acute-phase reacting protein) has revolutionized our understanding of iron pathophysiology.

In serum samples, age- and gender-dependent reference values were determined using serum samples from healthy volunteers (n = 231). Hepcidin is stable for 1 day at room temperature, 6 days at +4°C and at least 42 days at -20°C. Breakfast and the type of sampling device do not affect hepcidin concentration. Reference values for females aged 18-50 years were 0.4-9.2 nmol/L, for those >50 years 0.7-16.8 nmol/L and for males ≥18 years 1.1-15.6 nmol/L.

References

  1. Front Pharmacol.2014 Apr 23;5:83.
  2. Bioanalysis.2014 Apr;6(8):1081-91
  3. Arthritis Rheum.2011 Dec;63(12):3672-80.
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The Human Gut
July 16, 2014 12:49 PM by David Plaut

The human gut is home to trillions of microbes (the intestinal microbiota) that form a symbiotic relationship with the human host. During health, this intestinal microbiota provides many benefits to the host and is generally resistant to colonization by new species; however, disruption of this complex community can lead to pathogen invasion, inflammation, and disease.

Restoration and maintenance of a healthy gut microbiota composition requires effective therapies to reduce and prevent colonization of harmful bacteria (pathogens) while simultaneously promoting growth of beneficial bacteria (probiotics). Accumulating evidence indicates that the gut microbiota plays a significant role in the development of obesity, obesity-associated inflammation and insulin resistance. 

Important to this subject is the concept of "crosstalk" (i.e., the biochemical exchange between host and microbiota that maintains the metabolic health of the superorganism and whose dysregulation is a hallmark of the obese state). Differences in community composition, functional genes and metabolic activities of the gut microbiota appear to distinguish lean vs obese individuals, suggesting that gut "dysbiosis" contributes to the development of obesity and/or its complications. The current challenge is to determine the relative importance of obesity-associated compositional and functional changes in the microbiota and to identify the relevant taxa and functional gene modules that promote leanness and metabolic health.

As diet appears to play a predominant role in shaping the microbiota and promoting obesity-associated dysbiosis, parallel initiatives are required to elucidate dietary patterns and diet components (e.g., prebiotics, probiotics) that promote healthy gut microbiota.

References

  1. Mol Aspects Med. 2013 Feb;34(1):39-58.
  2. J Mol Biol. 2014 Jun 6. pii: S0022-2836(14)00279-4.
  3. Gastroenterol Clin North Am. 2012
  4. Curr Opin Clin Nutr Metab Care. 2011
  5. Pharmacol Ther. 2011
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Quorum Sensing
July 14, 2014 11:47 AM by David Plaut

Quorum sensing (QS) is a bacterial communication process that depends on the bacterial population density. It involves small diffusible signaling molecules which activate the expression of myriad genes that control a diverse array of functions including virulence. Quorum sensing is a process of cell-cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly.

This process enables bacteria to express energetically expensive processes as a collective only when the impact of those processes on the environment or on a host will be maximized. Among the many traits controlled by quorum sensing is the expression of virulence factors by pathogenic bacteria. 

As QS is responsible for virulence in the clinically relevant bacteria, inhibition of QS appears to be a promising strategy to control these pathogenic bacteria. QS antagonists should be viewed as blockers of pathogenicity rather than as anti-microbials and because QS is not involved in bacterial growth, inhibition of QS should not yield a strong selective pressure for development of resistance. QS inhibitors hold great expectations and we may look forward to their application in fighting bacterial infections. 

References

  1. EMBO Mol Med. 2009 Jul;1(4):201-10
  2. Recent Pat Antiinfect Drug Discov. 2013 Apr;8(1):68-83.
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Biomarkers for Acute Kidney Injury
July 1, 2014 11:28 AM by David Plaut

The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery.

Acute kidney injury (AKI) is a common and serious condition in both the inpatient and outpatient settings, and its diagnosis depends on serum creatinine or cystatin C measurements.

Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers has limited our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has provided a number of potential biomarkers. For example, neutrophil gelatinase-associated lipocalin (NGAL) is emerging as an excellent stand alone biomarker in the plasma and urine for predicting and monitoring clinical trials and in the prognosis of AKI. In recent years, a number of new biomarkers of AKI with more favorable test characteristics.

The two tables indicate the utility of the newer markers, some of which are commercially available indicate the utility of these markers compared to cystatin C.  Because the pattern of appearance in the urine or serum, varies with the markers it may be necessary to use more than one marker to detect and monitor AKI.

Efforts to detect AKI in the earlier stage has resulted in some promising biomarkers such as KIM-1, NGAL, IL-18, and Clusterin. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, NAG, RBP, IL-18, NGAL, Netrin-1, KIM-1, Clusterin, Sodium Hydrogen Exchanger Isoform and Fetuin A are biomarkers for tubular reabsorption function.

For Additional Reading

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Geriatric patients and anemia
June 19, 2014 11:28 AM by David Plaut

Anemia is a common condition in the elderly (for example, in a study of .6880 individuals, 2905 men and 3975 women, aged 65-95 [mean age 72.5], mild anemia [hemoglobin levels <10 g/dL] was found in 6.1% of women and 8.1% of men.) The reason that LDH shows up is that there is 20% more LDH in red cells than serum. More than 10% of the population over 70 years have iron and/or vitamin B-12 deficiency.  Here is a flow chart that may help evaluate chronic anemia: http://asheducationbook.hematologylibrary.org/content/2012/1/183/F3.expansion.html

For Additional Reading

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Body on a Chip
June 17, 2014 10:55 AM by David Plaut
In a recent blog, I touched on some ideas and tools that are being used to build "labs on chips."  The word nano operates significantly in this area.  If you were as excited and intrigued with that blog, read on for now we are going to talk on "organs-on-a-chip" and even a "body-on-a-chip."  Just how does one model, test, and learn about the communication and control of biological systems with individual organs-on-chips that are one-thousandth or one-millionth of the size of adult organs, or even smaller, i.e., organs for a milliHuman (mHu) or microHuman (μHu)?

With serious work being done to realize functioning artificial livers, kidneys, hearts, and lungs on chips, the next step is not only to interconnect these organs but also to consider the integration of stem cell technology to create interconnected patient-specific organs. Such a patient-specific body-on-a-chip requires a sophisticated set of tools for micropattering cell cultures in 3D to create interconnected tissue-like organ structures. It seems that anticipation that such a technology would have a wide area of application, primarily benefiting drug development, chemical safety testing, and disease modeling.

We are not there, yet.  But it is certain that a large amount of work is going into these projects not just for the ‘fun' of creating, say, a kidney, on a chip but for the results will aid in drug testing and replacement medicine and individual (unique) drug treatment.

For Additional Reading

  1. Wikswo JP. Lab Chip. 2013 Sep 21;13(18):3496-511. Scaling and systems biology for integrating multiple organs-on-a-chip.
  2. Moraes C. Integr Biol (Camb). 2013 Sep;5(9):1149-61. On being the right size: scaling effects in designing a human-on-a-chip.
  3. Williamson A. Lab Chip. 2013 Sep 21;13(18):3471-80. The future of the patient-specific Body-on-a-chip.
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Middle East Repiratory Syndrome
June 11, 2014 9:56 AM by David Plaut

Middle East Repiratory Syndrome (MERS) recently was said to be a "public health emergency of international concern." The MERS virus, which appeared in the Middle East in 2012, has spread through that area; cases have been found in Asia, Europe and the United States. The mortality rate is near 30%.

Two health workers at a hospital in Orlando, Fla., who were exposed to a patient with MERS exhibited flu-like symptoms, and one was hospitalized. 

MERS, which causes coughing, fever and occasionally fatal pneumonia, is a virus from the same family as SARS, which has killed about 800 people worldwide since it first appeared in China in 2002. 

MERS, a second coronavirus, SARS being the first, is transmissible from person to person, and its close relationship with several bat coronaviruses suggests that these animals may be the ultimate source of the infection. However, many key issues need to be addressed, including identification of the proximate, presumably zoonotic, source of the infection, the prevalence of the infection in human populations, details regarding clinical and pathological features of the human infection, the establishment of a small rodent model for the infection, and the virological and immune basis for the severe disease observed in most patients. Margaret Chan, Director-General of the World Health Organization, has called MERS-CoV "a threat to the entire world." There is no vaccine for MERS.

For Additional Reading

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Helicobacter pylori
June 9, 2014 1:02 PM by David Plaut
Helicobacter pylori has been associated with the colonization of gastro duodenal mucosa of humans from millions of years. The central burden of the disease is in the developing countries, due to overcrowding and poor hygiene. Wherever it is found, if left untreated, it leads to a number of consequences from minor to sinister diseases over time (these include including extra-gastric diseases like cerebrovascular, cardiovascular, idiopathic thrombocytopenia, sideroblastic anemia, mental diseases, and collagen vascular diseases).

The major challenges that remain are prevention of H. pylori-related diseases by effective treatment and screening procedures and development of a vaccine. It is also becoming increasingly difficult to eradicate and the main reason for this is growing primary antibiotic resistance rates in a world where antibiotics are frequently prescribed and readily available. Clinicians today must be prepared to face multiple treatment failures, and should be equipped to decide the appropriate salvage therapy when antibiotic resistance occurs. Established empiric second line treatment options include both bismuth based quadruple therapy and levofloxacin based triple therapy. Antibiotic testing is recommended prior to initiating third line treatment.

The prevention of cancer of the stomach, a worst sequel of H. pylori continues to be a significant challenge despite population screening and prevention underway in many countries. In contrast, the beneficial effects of H. pylori with respect to allergic diseases and obesity are now clear. Moreover, the problem of drug resistance for eradication of H. pylori has arisen for which novel treatments are being tried. Lactobacillus reuteri having anti H. pylori action is emerging as one of the promising treatment.

For Additional Reading

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Cancer and the Immune System
May 28, 2014 3:46 PM by David Plaut

Immunotherapy for cancer has undergone a renaissance in recent years, based both on technological developments such as the ease in introducing genes into T cells and on an improved understanding of the obstacles to eradicating cancer through immune mechanisms. Much remains to be discovered, however, there is considerable optimism that this approach can have a significant impact for patients, both alone and as an adjunct to hematopoietic stem cell transplant. For a long time doctors suspected that the immune system could affect certain cancers. Even before the immune system was well understood, William Coley, a surgeon, first noted that getting an infection after surgery seemed to help some cancer patients. In the late 1800s, he began treating cancer patients by infecting them with certain kinds of bacteria, which came to be known as Coley toxins. Although he had some success, his technique was overshadowed when other forms of cancer treatment.

Since then, doctors have learned a good deal about the immune system, deal with genetic therapy and they might be used to treat cancer. In the last few decades immunotherapy has become an important part of treating some cancers. Immunotherapy includes treatments that work in different ways. Some boost the body’s immune system in a very general way. Others help train the immune system to attack cancer cells specifically. Immunotherapy works better for some types of cancer than for others. It’s used by itself for some of these cancers, but for others it seems to work better when used with other types of treatment.

Immunotherapy Boosts Pediatric Cancer Survival

http://www.nih.gov/researchmatters/october2010/10042010cancer.htm
New Method of Gene Therapy for Treating Advanced Melanoma

http://www.nih.gov/researchmatters/september2006/09012006gene.htm   
The Best American Science Writing 2012.

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The Biology and Genetics of Obesity
May 22, 2014 1:46 PM by David Plaut

Many years ago, I came up with a sure way to lose weight – take in fewer calories than you burn. What could be simpler?

I was not alone. A study of more than 1100 adults found that 61% of U.S. adulates that “personal choices about eating and exercise” were the cause of overweight.

Over the past few years, data have been accumulating that indicate that while I might be correct in many, even most cases, there was a group of people with whom my plan would not work.

Today, molecular genetics is central to obesity research. In 2007, Mark McCarthy, Andrew Hattersley, and their colleagues in the UK identified a common variant in FTO, the fat-mass and obesity–associated gene, and gene hunters aided by the use of next-generation–sequencing technology continue to identify gene variants or mutations. These studies reinforce what some researchers have been insisting for more than a century: that obesity is innate in some people, that for them weight regulation is not governed by a uniform tally of “calories in–calories out,” Genetic predispositions, in tandem with the development of food environments that facilitate overeating and built environments requiring minimal energy expenditure, may help explain why so many Americans are obese today.

Chin Jou, N Engl J Med 2014; 370:1874-1877

 

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A Diagnostic Algorithm for Suspected Upper-Extremity Deep Venous Thrombosis
May 20, 2014 2:02 PM by David Plaut

The prevalence of upper-extremity deep venous thrombosis (DVT) has risen in conjunction with more frequent use of central venous catheters. There are clear algorithms for diagnosing lower-extremity (e.g. Wells), but not for upper-extremity, DVT. A multicenter study, a diagnostic algorithm was evaluated in 406 patients with suspected upper-extremity DVTs. The study included calculating a clinical decision score consisted of +1 point each for the presence of a central venous catheter or lead, localized pain, or unilateral edema and −1 point for a plausible alternate diagnosis. Scores of ≤1 implied that upper-extremity DVT was unlikely. The algorithm in addition to the score included D-dimer testing, and ultrasonography. The patients were follow-up after 3 months.

Fifty percent of patients (203) were assigned clinical decision scores of 0 or 1 (upper-extremity DVT unlikely); 90 had normal D-dimer tests and did not undergo further testing or treatment -- none developed symptomatic DVTs. The 113 low-scoring patients with abnormal D-dimer tests underwent ultrasonography: Ultrasonography was negative in 73 -- they did not receive treatment, and none developed symptomatic DVTs. Upper-extremity DVTs were diagnosed in 12 low-scoring patients. In the 203 patients with higher scores, ultrasonography detected no upper-extremity DVTs in 83; those patients underwent D-dimer testing and repeated ultrasonography if D-dimer test were abnormal, with a yield of 3 additional DVT diagnoses. Rates of upper-extremity DVT were significantly lower in patients with scores ≤1 than in those with scores >1 (6% vs. 44%).

This study verifies the value of using d-dimer measurements to rule out DVT.

Jamaluddin Moloo, reviewing Kleinjan A et al. Ann Intern Med 2014 Apr 1.

 

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Mammography Screening, Part 2
May 13, 2014 12:45 PM by David Plaut

This is the second of two blogs in which I discuss a response to the Swiss Medical Boards recommendation to stop mammography screening for breast cancer. In a separate essay, two of the members of the committee that wrote the recommendation brought up four aspects of it.

Regarding their third concern, they wrote, “We were disconcerted by the pronounced discrepancy between womens’ perceptions of the benefits of mammography screening and the benefits to be expected in reality. How can women make an informed decision if they overestimate the benefit of mammography so grossly?”

They referred to studies in the US and Switzerland indicating that, when asked about the efficacy of screening, overestimated the outcomes. For example, in one survey about U.S. women's perceptions, in which 717 of 1003 women (72%) said they believed that mammography reduced the risk of breast-cancer deaths by at least half. In reality, “Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care. 0verall, 22% (106/484) of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received screening.” (1)

Lastly, they wrote that “the board therefore recommended that no new systematic mammography screening programs be introduced, and that a time limit be placed on existing programs. In addition, it stipulated that the quality of all forms of mammography screening should be evaluated and that clear and balanced information should be provided to women regarding the benefits and harms of screening.”

References

1.            BMJ 2014; 348 (Published 11 February 2014.

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Mammography Screening: To Screen or Not to Screen?
May 8, 2014 1:29 PM by David Plaut

Recently, the Swiss Medical Board proposed discontinuing screening of women for breast cancer using mammography. The report did not suggest an alternate. The board included a medical ethicist, a clinical epidemiologist, a clinical pharma-cologist, an oncologic surgeon, a nurse scientist, a lawyer and a health economist. Two of the board, the ethicist and epidemiologist, have written about the report, pointing out four particular concerns they had (none of the four argued for screening). In both this and the next blog, I want to quote extensively from their report (the entire report and the text from the two members are available) (1,2).

The first point addressed the fact “that the ongoing debate [over screening with mammograms] was based on a series of re-analyses of the same, predominantly outdated trials. The first trial started more than 50 years ago in New York City and the last trial in 1991 in the United Kingdom. None of these trials were initiated in the era of modern breast-cancer treatment, which has dramatically improved the prognosis of women with breast cancer.”

In 2011, a study from the UK showed an increasing effectiveness -- from a 28% reduction in breast cancer mortality in the period 1975-1991 to 65% in the period 1992-2008. The article did not report on the mortality in the population at large (3). It was this that led to the second issue the board raised – “over diagnosis.” The two members of the board said that they “were struck by how non-obvious it was that the benefits of mammography screening outweighed the harms. The relative risk reduction of approximately 20% in breast-cancer mortality associated with mammography that is currently described by most expert panels came at the price of a considerable diagnostic cascade, with repeat mammography, subsequent biopsies and over diagnosis of breast cancers — cancers that would never have become clinically apparent. The recently published extended follow-up of the Canadian National Breast Screening Study is likely to provide reliable estimates of the extent of over-diagnosis. chemotherapy or some combination of these therapies.”

In my next blog, I will discuss the third and fourth comments that the ethicist and epidemiologist brought to our attention.

References:

1.            N Engl J Med. 2014 Apr 16.

2.            www.medical-board.ch

3.            Br J Cancer. 2011 Mar 15;104(6):910-4.

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A New Supply of Blood?
May 6, 2014 2:17 PM by David Plaut

It is possible that, in two to three years, we may have a new source of blood. Studies from U. Edinburgh and the Scottish National Blood Transfusion Service have been able to reprogrammed red cells grown from fibroblasts into mature red cells. This blood is Type O negative (the universal donor). This “artificial blood would consist entirely of young, healthy and infection-free cells, avoiding the issues of pathogen contamination that have in the past plagued the donor blood supply."

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