Skinnier TVs and Heavier Kids

Posted on July 31, 2014 by gutsandgrowth

A recent study showed an association between having a TV in the bedroom with increased weight gain (JAMA Pediatrics 2014; 168: 427-34). Here’s a link: Bedroom TV and obesity study. My emphasis in bold:

Design: “We conducted a random-digit prospective telephone survey that captured children and adolescents from across the United States. Participants included 6522 boys and girls aged 10 to 14 years at baseline who were surveyed via telephone about media risk factors for obesity. Weighted regressions assessed adiposity at 2- and 4-year follow-up, controlling for television and movie viewing, video-game playing, parenting, age, sex, race or ethnicity, household income, and parental educational level.”

Results: “Distributions for age, sex, race or ethnicity, and socioeconomic status were similar to census estimates for the US population. Sample weighting methods accounted for higher dropout rates among ethnic minorities and those with lower socioeconomic status. Bedroom televisions were reported by 59.1% of participants at baseline, with boys, ethnic minorities, and those of lower socioeconomic status having significantly higher rates. In multivariate analyses, having a bedroom television was associated with an excess BMI of 0.57 (95% CI, 0.31-0.82) and 0.75 (0.38-1.12) at years 2 and 4, respectively, and a BMI gain of 0.24 (0.02-0.45) from years 2 to 4.”

Conclusion: “Having a bedroom television is associated with weight gain beyond the effect of television viewing time. This association could be the result of uncaptured effects of television viewing or of disrupted sleep patterns. With the high prevalence of bedroom televisions, the effect attributable to this risk factor among US children and adolescents is excess weight of 8.7 million kg/y.”

Comment: While this study targets TV, “screen time” has now expanded to cell phones, tablets, and computers. All of these may be detrimental to physical well-being.

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Epidemic of Aggressive Care vis-a-vis Breast Cancer

Posted on July 30, 2014 by gutsandgrowth

In many areas of medicine, the need for increased certainty of cure and diagnostic certainty leads to other problems; sometimes, “the perfect is the enemy of the good.” While this happens in pediatric gastroenterology, the frequency is probably greatest in oncology. A recent terrific article in the NY Times by Peggy Orenstein highlights an epidemic of contralateral prophylactic mastectomy (CPM) in the care of patients with breast cancer.

Here are a couple of points and the link –Wrong Approach to Breast Cancer:

According to a study published in the Journal of Clinical Oncology in 2009, among those with ductal carcinoma in situ — a non-life-threatening, “stage 0” cancer — the rates of mastectomy with C.P.M. jumped 188 percent between 1998 and 2005. Among those with early-stage invasive disease, the rates went up 150 percent between 1998 and 2003. Most of these women did not carry a genetic mutation, like the actress Angelina Jolie, that predisposes them to the disease.
Overestimation of their actual chances of contracting a second cancer. In a 2013 study conducted by the Dana-Farber Cancer Institute in Boston, for instance, women under 40 with no increased genetic risk and disease in one breast believed that within five years, 10 out of 100 of them would develop it in the other; the actual risk is about 2 to 4 percent.
Underestimated the potential complications and side effects of C.P.M. Breasts don’t just screw off, like jar lids: Infections can occur, implants can break through the skin or rupture, tissue relocated from elsewhere in the body can fail. Even if all goes well, a reconstructed breast has little sensation. Mine looks swell, and is a remarkably close match to its natural counterpart, but from the inside it feels pretty much like a glued-on tennis ball.
The most comprehensive study yet, published earlier this month in the Journal of the National Cancer Institute, showed virtually no survival benefit from the procedure — less than 1 percent over 20 years.
How can that be? Well, first of all, it is extremely rare for a tumor on one side to spread to the other. Cancer doesn’t just leap from breast to breast.

Naloxegol for Opioid-Induced Constipation

Posted on July 29, 2014 by gutsandgrowth

Opioid narcotics are ubiquitous therapeutic agents for acute and chronic pain. In the United States, more than 240 million opioid prescriptions are dispensed per year. One of the most common sided effects is constipation. The mechanism of this side effect is the binding of opioid agonists to μ-opioid receptors located in the enteric nervous system.

The recognition of this mechanism has allowed the development of μ-opioid receptor antagonists. A recent study has shown that Naloxegol helps treat constipation related to opioids in patients with noncancer pain (NEJM 2014; 370: 2387-96). Naloxegol is a pegylated derivative of the μ-opioid receptor antagonist naloxone. Pegylation limits the ability of naloxegol to cross the blood-brain barrier; hence, the central pain effects of narcotics are not blocked whereas the effects on the enteric nervous system are limited.

This study reported the results of two phase 3, double-blind studies with a combined 1352 participants. Response to treatment was defined as having ≥3 spontaneous BMs/week and an increase in baseline of ≥1 spontaneous BM/week for ≥9 of 12 week study period and for ≥3 of the final 4 weeks.

Key results:

Response to Naloxegol at 25 mg dosing: 44.4% in first study and 39.7% in second study (compared with 29% of placebo treated patients in both studies).
Most adverse effects were mild to moderate and included increased abdominal pain, diarrhea, nausea, and flatulence. Major cardiovascular events were rare and not increased compared to placebo.

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You Still Need the Data

Posted on July 28, 2014 by gutsandgrowth

A recent study (J Pediatr 2014; 165: 23-9) confirmed the obvious: “early empiric antibiotic use in preterm infants is associated with lower bacterial diversity.” That being said, you still need the data and the specific changes are of importance.

This study examined the stools from 74 preterm infants (≤32 weeks gestational age) and determined how the microbiota changed in relation to no antibiotics (18% of cohort), brief antibiotics (1-4 days) (64% of cohort), or ‘intensive’ antibiotics (5-7 days) (18% of cohort). Empiric antibiotics consisted of ampicillin and gentamicin. Stools were analyzed with the 16s ribosomal DNA community profiling.

The key findings are graphically shown in Figure 1 with pie charts showing the relative abundance of 10 bacterial genera at week 1, week 2, and week 3 in each of the three groups.

Those who received 5-7 days of antibiotics had the most changes in their microbiota with increased Enterobacter and lower bacterial diversity in the second and third weeks of life.
In those who received no empiric antibiotics there was increasing bacterial diversity noted sequentially. These changes were not seen in either of the antibiotic groups. However, the group with brief antibiotic exposure returned to their baseline diversity by week 3.
Infants receiving early antibiotics experienced more cases of necrotizing enterocolitis, sepsis and death than those who were not exposed to antibiotics (this was not proven to be casually-related).

Take-home message: This study proves that antibiotics change the microbiome in neonates and that neonates exposed to antibiotics may have complications as a result. Better biomarkers (with rapid turn around time) would allow more careful selection of which neonates need empiric antibiotics.

Medical School Student vs. Dr. Oz

Posted on July 27, 2014 by gutsandgrowth

A recent link from Vox (highlight on KT Park’s twitter feed) highlights a medical student’s actions against Dr. Oz’s pseudoscience.

Here’s an excerpt:

Benjamin Mazer is a third-year medical student at the University of Rochester. Last year, after becoming increasingly concerned with the public-health impact of Dr. Mehmet Oz’s sometimes pseudoscience health advice, he decided to ask state and national medical associations to do something about it.

“Dr. Oz has something like 4-million viewers a day,” Mazer told Vox. “The average physician doesn’t see a million patients in their lifetime. That’s why organized medicine should be taking action.”…

We had all of this first-hand experience with patients who really liked his show and trusted him quite a bit. [Dr. Oz] would give advice that was really not great or it had no medical basis. It might sound harmless when you talk about things like herbal pills or supplements. But when the physicians’ advice conflicted with Oz, the patients would believe Oz….

I wrote policy for the Medical Society of the State of New York [where Dr. Oz is licensed] and the American Medical Association asking them to more actively address medical quackery on TV and in the media—specifically Dr. Oz.

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Understanding Breast Milk Jaundice

Posted on July 26, 2014 by gutsandgrowth

A recent study of 170 Japanese infants with breast milk jaundice (BMJ) demonstrated that 52% had a homozygous mutation: UGT1A1*6 (J Pediatr 2014; 165: 36-41). The study included 55 controls without BMJ.

Defects in UGT1A1 have been associated with a number of hereditary unconjugated hyperbilirubinemias including Crigler-Najjar type 1 in which there is complete deficiency of the enzyme Crigler-Najjar type 2 in which there is limited activity of the enzyme, and Gilbert syndrome in which there is moderate activity of the enzyme (but less than general population).

In this study, none of the control population had the UGT1A1*6 homozygous mutation. The authors note that “the components of breast milk clearly contribute to the onset of neonatal jaundice. Our in vitro investigation showed the inhibitory effect of 5α-pregnane-3α, 20β-diol on UGT1A1 activity.” Thus, this may help explain why cessation of breastfeeding for a short period can improve BMJ.

Take-home message: In this Japanese population, the UGT1A1*6 homozygous mutation is an important reason for BMJ. Yet, for about half of all infants another, yet unidentified mechanism(s), is responsible.

“We Still Have More to Learn”

Posted on July 25, 2014 by gutsandgrowth

“The most beautiful thing we can experience is the mysterious, it is the source of all true art and science. He to whom this emotion is a stranger, who can no longer pause to wonder and stand rapt in awe, is as good as dead: his eyes are closed.” –Albert Einstein.

I’m not sure the above quote has much direct relevance to today’s blog, but it came to mind after reading “we still have more to learn” in a recent editorial. The editorial elaborated on another study showing that hypotonic fluids increase the risk of hyponatremia (J Pediatr 2014; 165: 163-9, editorial 14-15). The editorial cautions that “intravenous fluid therapy is a prescription much like antibiotics or chemotherapy. What we prescribe for intravenous fluids must fit the patient’s history and condition.”

The article was a systemic review of published studies. Though 1634 citations were screened, only 10 studies (n=893) were included as independent randomized controlled trials. Hypotonic fluids were defined as tonicity <250 mmol/L; isotonic fluids were defined as normal saline (0.9%), Ringer lactate, Hartmann solution, and any other fluid with tonicity approaching that of normal serum. The key findings:

Hypotonic fluids increase the relative risk (RR) of hyponatremia (Na <135) with RR of 2.37
Moderate hyponatremia (Na <130) risk was increased further with RR of 6.1.
Sub-group analysis of half-normal saline showed relative risk for hyponatremia was 2.42.

The editorialists comment that much has changed in the 55+ years since Holliday and Segar’s publication in 1957 describing maintenance fluid requirements. These changes include sicker patients who are at increased risk for non-osmotic ADH release. Thus, even patients receiving isotonic fluids are at some risk for hyponatremia. However, the key point is that maintenance fluids are not appropriate for replacement of losses and in the perioperative setting.

Bottomline: Think twice before using a hypotonic fluid especially on admission or after surgery. While there is no perfect intravenous fluid for all patients at all times, in many patients, isotonic fluids will be more favorable by reducing the risk of hyponatremia.

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Drug Therapy for Celiac Disease

Posted on July 24, 2014 by gutsandgrowth

While a life-long gluten-free diet (GFD) is effective in most individuals with Celiac disease (CD), it is not effective in some. This could be related to cross contamination of food products, improper/inaccurate labeling and perhaps other factors as well. As a consequence, there is a rationale for the development of medical therapy. A recent study (Gastroenterol 2014; 146: 1649-58) has shown the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases administered orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial.

Methods: In a 6-week challenge study, adults with biopsy-proven celiac disease were divided into a treatment group with ALV003 (n=20) or a placebo group (n=21). The 2.0 g gluten dose (equivalent to 1/2 slice of bread) for the study was determined after an optimization study (using 1.5 g, 3.0 g or 6.0 g of gluten (bread crumbs) in three divided doses). Biopsies were taken before and after the gluten challenge.

Key finding:

No significant mucosal deterioration was observed in biopsies from the ALV003 group based on biopsies after the challenge period. In contrast, the placebo group did have evidence of mucosal injury.

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Putting in Place a Big Piece of the Eosinophilic Esophagitis Puzzle

Posted on July 23, 2014 by gutsandgrowth

A recent study (Nature Genetics 2014; doi:10.1038/ng.3033 -thanks to Seth Marcus for this reference) provides novel in-depth molecular and mechanistic information on eosinophilic esophagitis (EoE). Though the publication and supplemental material span only 8 pages, it is packed with information and highly technical assays and thus takes an effort to work through.

The authors performed a genome-wide association study (GWAS) of SNPs (single nucleotide polymorphisms) from >1.5 million genetic markers. In total, this study involved samples from 736 EoE patients and 9246 controls. Four prominent markers were identified at 2p23, 5q22, 8p23, adn 15q13; however, the marker at 2p23 was most highly associated with a risk for EoE. And, 2p23 included the CAPN14 gene (best SNP rs77569859).

Key Results:

CAPN14 is “specifically expressed in esophageal epithelium and is dynamically upregulated as a function of disease activity.” Though CAPN14 is expressed in other tissues, it is primarily in the esophagus and pharynx (Figure 2).
CAPN14 encodes calpain 14, a calcium-activated cysteine protease. CAPN14 showed the greatest upregulation in comparison to all members of the CAPN family. Calpain proteases mediate protein cleavage for structural proteins, signaling molecules, transcription factors, and inflammatory mediators. The latter are “germane for allergic responses.”
CAPN14 levels are >2-fold increase in individuals with active EoE.
CAPN14 gene is modified by IL-13.

Take-home message: (from the authors) This study shows the “potential centrality of CAPN14 in the etiology of EoE….We propose a model that links the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.”

Web is Better: Liver Toxicity from Herbs

Posted on July 22, 2014 by gutsandgrowth

A recent review article (Clin Gastroenterol Hepatol 2014; 1069-76) provides a good overview of herbs and liver injury; however, the NIH website http://livertox.nih.gov/ is more comprehensive.

The article notes the difficulty in assessing liver injury from herbs and dietary supplements due to the permissive regulatory environment and underreporting.

Specific products reviewed include the following:

Weight loss supplements: hydroxycut, herbalife, green tea, usnic acid
“Health-promoting” herbs: black cohosh, comfrey, kava
Joint health supplements: flavocoxid, glucosamine
Bodybuilding supplements: anabolic steroids

The article explains issues with regard to causality and the regulatory issues. However, for each of these products, I found them on the livertox website. So, that is where I would start if I needed to look up herb-induced liver injury. Reporting of adverse events can occur through FDA website: http://www.fda.gov/safety/medwatch/default.htm or through hotline: 800-FDS-1088.

A related reference –Bad Way to Lose Weight: “SlimQuickTM-Associated Hepatotoxicity Resulting in Fulminant Liver Failure and Orthotopic Liver Transplantation” ACG Case Rep J 2014;1(4):220–222. http://dx.doi.org/10.14309/crj.2014.59. Published: July 8, 2014

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