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David Plaut: Off the Cuff

Noteworthy SARS Treatment and Prevention Reviews
April 24, 2014 1:51 PM by David Plaut

Two recent reviews on the prevention and treatment of SARS Severe Acute Respiratory Syndromes and RSV respiratory syncytial virus and influenza virus are worth noting. One of them cautiously rejected some review articles as being biased using the Cochrane Handbook. Four other criteria were used randomized controlled trial, particular effective compound or derivative, reproducible result and animal test. The remaining reviews suggested to the authors that “Traditional Chinese herbs could directly inhibit pathogens infecting respiratory tract, or coordinate the activity of immune system to avoid or relieve infections. With the emergence of antidrug pathogens or new variants, Chinese herbs give strong evidence to protect human health.” (1)

Another meta-analysis in the Cochrane Database System Review included 18 studies with more than 2500 participants. Although many of the studies were lacking in adequate research, enough good data led the authors to state that “Most Chinese medical herbs in the included studies showed similar effects to antiviral drugs in preventing or treating influenza. Few were shown to be superior to antiviral drugs. No obvious adverse events were reported in the included studies.” However, current evidence remains weak due to methodological limitations of the trials. More high-quality RCTs with larger numbers of participants and clear reporting are needed (2).

1.            Chin Med J (Engl). 2014 Apr;127(7):1344-50.
2.            Cochrane Database Syst Rev. 2013 Mar 28;3:CD004559

Kidney Diagnostic Markers
April 22, 2014 4:46 PM by David Plaut

Unlike the progressive development of biomarkers in cardiology, there have been few changes in kidney diagnostic markers. Creatinine is still used as an indicator of kidney function, but not of the parenchymal kidney injury. Serum creatinine concentration does not change until around 50% of kidney function is lost, and varies with muscle mass, age, sex, medications and hydration status. The lag time between injury and loss of function and the risks missing a therapeutic opportunity may explain the high associated mortality.

It is clear that patient NGAL level is an appropriate, sensitive and specific -- early biomarker of AKI caused by a variety of different etiologies. It is advised that a multidisciplinary group of experts come together to make recommendations and propose a consensus of clinical procedures to advance the most efficacious NGAL monitoring protocol for early detection and treatment of patients with AKI.1 It is important to note that NGAL, in the absence of diagnostic increases in serum creatinine, is able to detect some patients affected by subclinical AKI who have an increased risk of adverse outcome.2

Another marker that has been found useful is cystatin c. For example, Cha et al. found chronic kidney disease stages were more sensitively differentiated by cystatin C compared to sCr, especially in moderate and severe kidney dysfunction. Sex and body mass index did not affect cystatin C level.3

1.   Postgrad Med. 2013 Nov;125(6):82-93. Peacock WF et al.

2.   Clin Chem Lab Med. 2012 Feb 15;50(9):1505-17,Clerico A

3.   Nephrology (Carlton). 2010 Dec;15(8):768-76. Cha RH

Sensitivity of Troponin Assays
April 17, 2014 1:50 PM by David Plaut

One of my concerns regarding the increased sensitivity of the available troponin  assays (both T and I) is the number of patients with measureable cTn with the newer methods. To a great extent, this concern has been alleviated by a recent study of several commercial assays in a 90 minute window. Of 465 ER patients, there were 12 AMIs. At presentation, the clinical sensitivity and specificity were 83% and 82% for hs-cTnI. The sensitivity and specificity were 100% and 82% for hs-cTnI at 90 min. A change of a 30% increase from baseline to 90 min improved the specificity to 94% without lowering the sensitivity. When AMI was defined as a 30% change of hs-cTnI at t=0 and 90 min and one hs-cTnI result >99th percentile cutoff, more than 3 times as many patients met the diagnostic criteria for AMI compared to results from the normal sensitive troponin assay; 28 hs-cTnI vs. 9 with cTnI. This data coincides with the concept that an AMI can be ruled in (or out) in a considerably shorter time than what many hospitals use today. While this may put a burden on the laboratory, it is a better protocol than a 6 hour version. And if the protocol uses no more than 2 samples in most of the cases (as this data argues), the laboratory and phlebotomists will have fewer samples to process.

Use of cTn and BNP in Atrial Fibrillation (AF)-associated Stroke Risk
April 8, 2014 10:17 AM by David Plaut

Cardiac troponin (cTn), due to its superior clinical sensitivity and tissue specificity, has replaced cardiac enzymes, and is the biomarker of choice in making the critical diagnosis of an acute coronary syndrome (ACS). With increases in analytical, cTn has found utility in a number of other situations once ACS has been ruled out. Assessment of atrial fibrillation (AF)-associated stroke risk is at present mainly based on clinical risk scores such as CHADS2 and CHA2DS2-VASc, although these scores provide only modest discrimination of risk for individual patients. A recent study of cTn in patients at risk for AF-stroke stratified them based on troponin I concentrations: <0.10 ng/L, n=2663; 10-19 ng/L, n=2006; 20-39 ng/L, n=1023; ≥40 ng/L, n=497. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040). The study also found the NT-proBNP was related to AF-stroke with 2.30%/year versus 0.92% in the highest versus quartile groups. Other biomarkers including von Willebrand factor and D-dimer in blood and proteinuria, estimated glomerular filtration rate, or creatinine clearance in urine, have also been found helpful in these patients.

Going Beyond Lab on a Chip
April 1, 2014 2:30 PM by David Plaut

In my last blog, I touched on some ideas and tools that are being used to build “labs on chips.”  The word “nano” (1.10-9) operates significantly in this area. If you were as excited and intrigued with that blog, read on! For now, we are going to discuss “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 the anticipation is 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 because the results will aid in drug testing and replacement medicine and individual (unique) drug treatment.


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

Lab on a Chip
March 25, 2014 11:54 AM by David Plaut

This is such a fascinating and significant area of our work that I am going to devote both this and the next blog to some recent articles that discuss Lab on a Chip. [There is a journal (Lab Chip) devoted to this. In the last 6 months at PubMed, there were over 400 articles abstracted by PubMed from the key words Lab on a Chip!] Because of intensive developments in recent years, the microfluidic system has become a powerful tool for biological analysis. Entire analytic protocols including sample pretreatment, sample/reagent manipulation, separation, reaction and detection can be integrated into a single chip platform. A lot of demonstrations on the diagnostic applications related to genes, proteins and cells have been reported because of their advantages associated with miniaturization, automation, sensitivity and specificity

Here are 4 short synopses from some of the articles I found most intriguing to us.

1.            New in-the-field-deployable diagnostic modalities are urgently needed in first-responder and point-of-care applications. Researchers have utilized innovative approaches using the unique properties of nano (1*10 -9) materials in order to achieve detection of infectious agents, even in complex media like blood. With gold nanoparticles and iron oxide nanoparticles and changes in magnetic properties, detection of pathogens, toxins, antigens and nucleic acids has been achieved with impressive nano-detection thresholds. Additionally, as bacteria become resistant to antibiotics, nanotechnology has achieved the rapid determination of bacterial drug susceptibility and resistance using these novel methods.

2.            Accurate detection and profiling of circulating tumor cells (CTCs). The rarity of CTCs, approximated at 1 CTC for every billion peripheral blood cells poses significant challenges to sensitive and reliable detection. The authors recently developed a new micro-nuclear magnetic resonance (μNMR) platform for biosensing. This μNMR platform offers high detection sensitivity and point-of-care operation, overcoming technical barriers in CTC research.

3.            By making use of the microarray format, the lab-on-chip system also addresses new trends in biomedicine. Research topics such as personalized medicine or companion diagnostics show that multiparameter analyses are an added value for diagnostics and therapy, as well as therapy control. Since reagents, microfluidic actuators and various sensors are integrated within the cartridge, these goals are addressed with a low-cost and self-contained cartridge. In combination with a fully automated instrumentation (read-out and processing unit), a diagnostic assay can be performed in about 15 min. So far, example assays for nucleic acids (detection of different pathogens) and protein markers (such as CRP and PSA) have been established. Recent developments are the integration of sample preparation and polymerase chain reaction (PCR) on-chip between diagnostic needs and available technologies can be closed.

4.            Active monitoring of the immune system in both HIV patients and individuals who are regarded as "at-risk" is critical in the decision making process for when to start a patient on ART. A reliable and common method for such monitoring is to observe any decline in the number of CD4 expressing T-helper cells in the blood of a patient. However, the technology, expertise, infrastructure and costs to carry out such a diagnostic cannot be handled by medical services in resource-poor regions where HIV is endemic. A number of new devices will soon be on the market. Many of the current and imminent devices are enabled by microfluidic solutions.


1.            Adv Drug Deliv Rev. 2010 Mar 18;62(4-5):408-23. Emerging nanotechnology-based strategies for the identification of microbial pathogenesis.Kaittanis C1, Santra S, Perez JM.

2.            Lab Chip. 2014 Jan 7;14(1):14-23. 8.Miniaturized nuclear magnetic resonance platform for detection and profiling of circulating tumor cells. Castro CM1, Ghazani AA, Chung J, et al.

3.            Lab Chip. 2013 Jul 21;13(14):2731-48. Highly-integrated lab-on-chip system for point-of-care multiparameter analysis. Schumacher S1, Nestler J, Otto T, et al.

4.            Lab Chip. 2012 Feb 7;12(3):464-73. CD4 counting technologies for HIV therapy monitoring in resource-poor settings--state-of-the-art and emerging microtechnologies. Glynn MT1, Kinahan DJ, Ducrée J.

rging microtechnologies. Glynn MT1, Kinahan DJ, Ducrée J.


Another Blood Glucose Marker?
March 20, 2014 3:24 PM by David Plaut

It is well known that both HbA1c is an excellent marker to assess 2-3 month blood glucose levels and that measuring the blood glucose is good for the past few hours.  This is certainly true for most people.  But ... there are situations where another marker may be of use. 

For example, in patients where hemoglobin A does not represent most of the hemoglobin in the blood stream (e.g. in newborns where HbF still contributes significant levels or patients with HbS or other hemoglobinopathies in which the hemoglobin does not bind glucose). Another group of patients consists of diabetic who are being treated for diabetic kidney disease and undergoing iron or erythropoietin treatment. 

It has been found that another marker can be of value in these patients. Glycated albumin, fructosamine and 1,5 anhydroglucitol, the first two of which are readily available have been proposed for these patients. GA is especially helpful in patients with chronic kidney disease (CKD) stages 4 and 5.

In pregnancy, HbA1c is reduced due to iron deficiency but GA remains normal throughout in non-diabetic women. The consequences of uncontrolled gestational diabetes are severe to both maternal and fetal well-being. An ideal laboratory test to monitor gestational diabetes should accurately reflect short-term glucose changes. Glycated albumin, by virtue of its short half-life of 14-19 days, lends itself to monitor and control gestational diabetes.
Rule In, Rule Out
March 18, 2014 11:42 AM by David Plaut

Are two measurements of troponin alone sufficient to rule in and rule out acute myocardial infaction?

There has been a flurry of articles discussing the utility of more sensitive troponin assays.  Many of these report increases in situations that were not generally seen before -- following surgery, in persons doing certain athletic events, in renal disease and other pathologies.  This may create difficulties (lower specificity) in the ED.

Here I address the question "What is THE current protocol for possible AMI?"  This question has been asked since CK and the CK-MB became popular and it seems to have reappeared. 

This puzzles me, as data have existed since the early troponin I with a cut-off of 0.2 ng/mL. Studies then indicated that two, sometimes three values of troponin alone at T0, T45 and T90 min were adequate to rule out an MI and in most cases rule it in.  Half of the MI patients had an increased TnI at T0 and 95% were elevated within 2 hours.

Recently a number of papers have proposed much the same protocol.  For example, Aldous et al, claimed that an "accleratated diagnostic protococal consisting of a TIMI risk score of 0, no new ECG changes, and negative troponin at 0 and 2 hours post presentation safely identifies patients at low risk of ACS, in whom discharge without further evaluation can be considered."  The sensitivity of this protocol to rule out an MI was greater than 99%,

As far as ruling in an ACS, samples from 850 patients were studied by Collinson and others and found that the measurement of admission myoglobin [area under the curve (AUC) 0.76] and CK-MB (AUC 0.84) were diagnostically inferior and did not add to the diagnostic efficiency of cTnI (AUC 0.90-0.94) or cTnT (AUC 0.92) measurement on admission and 90 min.

The Heated CKD Debate
March 4, 2014 12:25 PM by David Plaut

Whether to screen for chronic kidney disease (CKD) is being rather heatedly debated these days. This is not a trivial question -- one in 10 American adults, more than 20 million, have some level of CKD, making CKD the eighth leading cause of death in the US. On one side is the American College of Physicians (ACP) which recommends:

  1. ACP recommends against screening for CKD in asymptomatic adults without risk factors for CKD. (Grade: weak recommendation, low-quality evidence).
  2. ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker. (Grade: weak recommendation, low-quality evidence).
  3. ACP recommends that clinicians select pharmacologic therapy (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation).
  4. ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence).

On the other side the American Society of Nephrology (ASN) strongly disagrees. Their argument is that CKD is usually asymptomatic but once discovered, can be treated and, while not cured, can provide a better quality of life for some time. Blood and/or urine tests such as eGFR with cystatin or creatinine can often detect CKD in an early state.

The USPSTF has made the following comments: "There is no generally accepted risk assessment tool for CKD or risk for complications of CKD. Diabetes and hypertension are well-established risk factors with strong links to CKD. Other risk factors for CKD include older age, cardiovascular disease, obesity, and family history. While there is insufficient evidence to recommend routine screening, the tests often suggested for screening that are feasible in primary care. The USPSTF could not determine the balance between the benefits and harms of screening for CKD in asymptomatic adults."

Two CF Victories
February 27, 2014 9:00 AM by David Plaut

There are an estimated 30 000 patients (1 in 3900 births) in the US with cystic fibrosis (CF). This is a life-limiting, multisystem disease characterized by thick viscous secretions leading to recurrent lung infections, bronchiectasis, and progressive deterioration in lung function. CF is caused by loss or dysfunction of the CF transmembrane conductance regulator (CFTR) protein -- it is an inborn disease caused by at least 1900 different mutations in one gene. CF has been difficult to treat since it was first found. 

In the past several years, two giant victories have been made on two fronts. On one was the development of the first truly breakthrough drugs -- VX-770 (now called Kalydeco) and VX-809.  These are now in Phase III trials.  While targeting only about 5% of CF patients, they provide a basis for developing other ‘personal' drugs. 

The victory on the second front is the continued progress in developing gene therapy with the hope that it will essentially curve the disease.  For example last year "a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity". Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy.  And another study concluded "that CFTR-mRNA transfection could comprise a novel alternative for gene therapy to restore impaired CFTR function."

Chimeric Antigen Receptors
February 25, 2014 11:18 AM by David Plaut

Many years ago, I gave a lecture on enzyme assays in the laboratory. When I was done talking about LDH, CPK, GGT, SGOT and SGPT; it occurred to me that anyone walking into that room who wasn't a laboratorian would wonder what language we were speaking. Sometimes I feel that way when I wander too far from chemistry.

But this is such an important topic I am going try to make it understandable to all the readers. The key is the first sentence. At a recent meeting of American Society of Hematology, a study (PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Fedorov VD, Themeli M, Sadelain M. Sci Transl Med. 2013 Dec 11;5(215):215ra172) was presented illustrating that 45 of 75 leukemia patients saw complete regressions with CARs. CARS are chimeric antigen receptors that are types of T-cells. Research at the NIH, Sloan Kettering and the University of Pennsylvania have been working toward this for a number of years. They still admittedly have more to do as at present, the cells they use are highly specific for only a few cancers.

We know also that T-cells can be very destructive when they attack targets found on both tumors and healthy cells. One large pharmaceutical company has invested heavily in the project and this year there will be clinical trials at the three research institutions on other cancers.

Two Bright Lights
February 17, 2014 11:46 AM by David Plaut

At this time there about 16,000 Americans awaiting liver transplants. This year only about 7000 will receive them due to a shortage of viable livers.

A team in Japan, where only 1 in 10 patients needing a liver will get one, described the beginning to generating livers from stem cells. The group were able to ‘reprogram' human skin cells into embryonic cells (which are often used in stem cell research as they are able to be coaxed into almost any type of cells). After combining these cells with two other types of cells, the new cells organized themselves into three-dimensional cells with blood vessels. When transplanted into a mouse, the cells exhibited many (but not all) of the functions of a liver.

At this time, a number of problems must be solved before an "off the shelf" liver is ready for humans. One of these is the size of these "liver buds." They are about 5 mm. long and too large to infuse into the blood stream. The missing functions of the human liver will need to be included. It is, however, an exciting step.

The FDA has authorized Investigational New Drug application for clinical testing of the human neural stem cells as a treatment for spinal cord injury. As a first action under this IND, the Company is working to open U.S. sites for its Phase 1/2 clinical trial for chronic spinal cord injury, which is currently underway in Switzerland and Canada. With the IND, the study will be open in the US. At this time there are seven patients being treated with the reprogrammed stem cells.

Vitamin D Intoxication
February 12, 2014 11:58 PM by David Plaut
The current interest in vitamin D has increased significantly the number of persons supplementing their diet with vitamin D preparations (More than 50% of Americans use dietary).  While rare, vitamin D intoxication can be life-threatening.  Three cases of acute vitamin D intoxication possibly due to faulty production of a multivitamin preparation were recently reported.  The symptoms of vitamin D intoxication include elevated levels of high levels of serum and urine calcium and low levels of parathyroid hormone (PTH).

One of the three cases involved 19-month-old girl who presented with abdominal pain, vomiting, and poor appetite. She was taking a multivitamin preparation once daily (the label indicated 200 IU) for a month, Laboratory parameters were Ca: 19.4 mg/dL (N=8.4-10.2), PTH: 3.3 pg/mL (N=15-65), 25(OH) vitamin D: 760 ng/mL (N=25-80), Her serum levels for inorganic phosphorus and creatinine were within the normal range. After 4 days of treatment her serum Ca level was still elevated (12.8 mg/dL), and the patient was discharged on day 7 with a serum Ca level of 10.5 mg/dL. The preparation she had been taking was not available to test, but it was possible to test another bottle of the same manufacturer. Assays of it indicted that the label was correct, leading to the possibility that there was different amount in her preparation.  [The manufacturer of the vitamin D preparation was not contacted to verify the amount in her preparation.]1

Toxic levels of vitamin D due to errors in labeling and manufacturing have also been reported. Araki reported on two patients who had been consuming more than 1000 (sic) times the recommended daily dose. It took approximately 1 year to normalize the vitamin) D levels.2 However, once the levels decreased below 400 ng/mL, both patients became normocalcemic and asymptomatic without long-term consequences.


  1. J Clin Res Pediatr Endocrinol.2013;5(2):136-9
  2. J Clin Endocrinol Metab. 2011;96:3603-3608.
How Significant is ‘Significant'?
January 29, 2014 4:38 PM by David Plaut

Here are 12 hemoglobin values from each of two instruments including the means, minimum and maximum as well as the difference between the pairs and the % difference between the pairs:

   Instr. A Instr. B  A-B  %(A-B) 
 1  13.5  13.4 0.1   0.3
 2  11.0  10.9  0.2  1.0
 3  14.5  14.5  0.0  0.1
 4  15.9  15.8  0.1  0.5
5 9.7 9.7 0.0 -0.1
6 14.2 14.1 0.0 0.1
7 15.3 15.2 0.1 0.5
8 13.9 13.7 0.2 0.9
9 14.3 14.3 0.0 0.2
10 15.1 14.9 0.1 0.6
11 16.1 16.0 0.1 0.4
 12  15.0 14.8   0.2 0.8 
Mean 14.0 13.9 0.1 0.4
Min 9.7 9.7
Max 16.1 16.0
t-test = 0.000516

According to the t-test (paired) these two instruments are "highly significantly" different.  Although the average difference between them is about 0.1 gm/dL (0.4%).  Barely the CV of the methods.  Too often you will see data being significant in a statistical sense, when clinically it is not of clinical significance.  Since the editors and authors are not likely to change, we must be careful readeers. 

Oh, and by the way, using the t-test (unpaired) there is no difference between the two methods.  It seems that in some cases, the statistic chosen has a significant effect on the interpretation of the data.

Blacklegged Nymphs
January 14, 2014 4:09 PM by David Plaut

In 2009, Diaz (1) remarked that "both Lyme Disease and Rocky Mountain Spotted Fever are endemic in Louisiana and the Gulf South." In 2012 Stromdahl and Hickling (2)  noted that "publications on tick-pathogen systems in the south-eastern United States are primarily at risk from emerging diseases caused by tick-borne pathogens other than B. burgdorferi.

Wendy Orent, in an article titled Southern Gothic: The Confounding Debate Over Lyme Disease in the South, wrote that "many Lyme researchers, including some from the NIH and the CDC, won't believe a word of it. There is little or no true Lyme Disease anywhere in the South."

Thus the question, "If there is Lyme or one like it, what is spreading it, as it is most likely not blacklegged nymphs (Ixodes scaprlaris). It appears that the most likely culprit is the Amblyomma americanum  or the lone star tick.  Since few researchers think that the lone star tick transmits Lyme Borrelia, the disease in the South is called STARI, for Southern Tick-Associated Rash Illness.  At this point, the cause of STARI is unknown.

This is not simply an argument among researchers, but the many patients who insist that they have Lyme disease or something very much like it.  But they continue that they are treated late if at all and thus are sliding into an untreated chronic syndrome as are many Lyme disease patients in the North.


  1. J La State Med Soc. 2009 Nov-Dec;161(6):325-6, 328, 330-1 passim.
  2. Zoonoses Public Health. 2012 Sep;59 Suppl 2:48-64


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