Hippo’s ‘magic’ sweat explained.


 

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The really clever thing about hippos is that they produce their own sunscreen, in the form of a sticky reddish sweat.

Now, a team from Kyoto Pharmaceutical University, Japan, has explained the chemistry of this special substance

It has told Nature magazine the oily secretion is made up of two unstable pigments – one red, the other orange.

The red pigment also has antibacterial properties, which work to protect the hippo from certain pathogens and accelerate its recovery from wounds.

River horse

The hippopotamus – or “river horse” – is a belligerent creature, which puzzled the ancient Greeks by apparently sweating blood.

In fact, the thick red substance, which oozes from glands all over its skin, is one of the hippo’s many ingenious survival tools.

The enormous relative of the pig occupies a unique amphibious niche – which requires some specialised equipment.

Hippos consume as much vegetation as they can during the night, when they are shielded from the searing heat and sun. At dawn, they retire into water and spend their days resting, squabbling and, most importantly, digesting.

“Hippos are basically fermentation vats,” Wayne Boardman, head of veterinary services at the Zoological Society of London, UK, told BBC News Online. “They are adapted to eating poor quality food stuffs, but to be able to get nutrition out of these, they need to be able to eat for long periods of time.”

Because it is so important for hippos to eat a vast amount, they must venture out in the sun from time to time, to top up on their nightly binge.

But a traditional sunscreen – like fur – is not practical if you spend half your time submerged in water.

Evolution’s answer

The answer that evolution came up with was an anti-UV secretion, which is at first colourless, then red, then finally brown as the pigment polymerizes.

“The sunscreen property of the sweat was first suspected because albino hippos are often observed – and they seem healthy,” Kyoto’s Kimiko Hashimoto told BBC News Online.

This natural skin-care product not only protects the hippo from the sun, it also regulates temperature and discourages the growth of bacteria.

http://newsimg.bbc.co.uk/shared/img/o.gif

Professor Hashimoto and his colleagues collected samples of the hippo’s sweat and examined it, to see what makes it so special.

They found it is made up of two pigments – one red, called “hipposudoric acid”; and the other orange, called “norhipposudoric acid”.

The scientists believe these two substances are produced from a metabolite of amino acids (the building blocks of proteins).

Both pigments act as sun blocks and the red one, they discovered, is a particularly good antibiotic.

At concentrations lower than that found on the hippo’s skin, it can inhibit the growth of two types of pathogenic bacteria. This is useful for hippos, because they are terrible fighters.

“Hippos are always fighting,” said Mr Boardman. “You see them in the wild and they have wounds all over them.”

Perhaps it is no wonder, then, that evolution endowed them with a handy antiseptic.

Mr Boardman added: “They get scratches and bites and cuts and yet they don’t seem to get infections.”

KNOW THE HIPPOPOTAMUS

 

Size: 1.3m shoulder height

Mass: 1600-3200kg

Lifespan: 45 years

Diet: Herbivorous

Predators: Crocodiles and lions

 

 

Source: BBC


Call to Replace Prolonged Pain Experiments in Mice.


 

mouse

A new literature review by Physicians Committee authors published in the Journal of Applied Animal Welfare Science raises serious questions about whether experimenters and institutions are appropriately implementing the 3Rs—replacement, reduction, and refinement—in mice experiments.

The review, which documents trends in experiments that subject mice to pain for at least 14 days, found that the total amount of prolonged neuropathic, inflammatory, and chronic pain experiments on mice has increased dramatically in the past decade. In the 55 studies reviewed, there were no references to the 3Rs.

The authors say that their findings suggest that researchers conducting prolonged pain research on mice are paying little, if any, heed to 3Rs principles in the planning and execution of their research.

They also stress that alternative approaches exist for replacing and reducing animal use and for refining methods to minimize pain and suffering. In the area of pain research, ethical clinical studies with human patients have the advantage that humans can reliably report their experience of pain and pain relief.

Other studies in mice have been misleading researchers for years, according to a new study just published in the Proceedings of the National Academy of Sciences. The study’s authors concluded: “New approaches need to be explored to improve the ways that human diseases are studied.”

The Physicians Committee addressed the 3Rs at its Animals, Research, and Alternatives conference, which brought together an international panel of experts to discuss how expanding knowledge of animals’ psychological and social attributes warrants their protections in research, and the latest and most promising alternatives to the use of animals in research.

To learn more about the problems with mice experiments, visit PCRM.org/Mousetrap.

Source: PCRM


EU Confirms Ban on Marketing of Animal Tested Cosmetics and Ingredients.


 

The European Union has confirmed that—taking effect March 11, 2013—the marketing, import, and sale of animal-tested cosmetics and their ingredients will no longer be legal in the EU. Congratulations to Kristie Sullivan, M.P.H., PCRM’s director of regulatory testing issues, and Aryenish Birdie, PCRM’s regulatory testing policy coordinator, who have spent years rallying support for the ban that will save the lives of countless rabbits, guinea pigs, mice, and rats who suffer and die each year for cosmetics testing.

Last year, PCRM delivered nearly 25,000 letters from EU residents and people around the world to the European Commission. The letters called on the EC to maintain its 2013 deadline for a ban on the marketing of cosmetic products tested on animals. PCRM supporters Alicia Silverstone and True Blood’s Kristin Bauer also wrote letters calling for the ban.

This ban follows Israel’s Jan. 1 ban that no longer allows the import and marketing of cosmetics, toiletries, or detergents that were tested on animals.

But we’re not resting until the United States joins the EU and Israel. We’re talking with U.S. lawmakers and working cosmetics manufacturers. Our new Come Clean campaign is working to end excruciating skin irritation and corrosion tests on animals. Come Clean asks cosmetics companies to reveal whether they perform these tests, so PCRM scientists can help them transition to superior, cruelty-free test methods.
Source: PCRM ( Physician Committee for Responsible Medicine)

FDA halts pediatric clinical trials of Sensipar following death.


 

The FDA has stopped all pediatric clinical trials of cinacalcet hydrochloride following the death of a pediatric patient (aged 14 years) in a trial, according to a press release on the agency’s website today.

In a separate press release, the FDA wrote that they continue to collect information on the circumstances surrounding the death.

Cinacalcet hydrochloride (Sensipar, Amgen) is a calcium-sensing receptor agonist indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis; hypercalcemia in patients with parathyroid cancer; and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. It is not currently approved for children aged younger than 18 years. According to the press release, clinical trials had been underway to determine the safety and efficacy of therapy in pediatric patients.

The drug works by decreasing the release of parathyroid hormone (PTH) from the parathyroid gland. It lowers high PTH levels leading to lower calcium levels in the blood; when calcium levels are too low it can result in health problems, according to the press release.

The FDA cautions that this announcement does not conclude that cinacalcet hydrochloride caused the death in a pediatric patient. However, they communicate that evaluations are ongoing and final recommendations will be released when review of this circumstance is complete.

In the press release, the FDA reminds health care professionals of the following:

  • Cinacalcet hydrochloride lowers calcium levels in the blood. Patients should be monitored for the development of low serum calcium levels (hypocalcemia).
  • The potential signs of low serum calcium levels include muscular problems such as muscle cramping, tetany, convulsions, paresthesias, and myalgias.
  • If serum calcium levels decrease below the normal range, appropriate steps should be taken to increase calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of a calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with cinacalcet hydrochloride.
  • Serum calcium levels should be measured within 1 week after initiation or dose adjustment of cinacalcet hydrochloride. Once a maintenance dose has been established, serum calcium should be measured monthly.
  • The most frequently reported side effects in adult clinical trials of cinacalcet hydrochloride were nausea, vomiting, and diarrhea.

·         Source: Endocrine Today.

When to biopsy: A taller-than-wide nodule lacking worrisome sonographic features .


 

 

Two patients were sent to the endocrine clinic for the evaluation of a thyroid nodule. A 67-year-old female was sent for an asymptomatic 1-cm thyroid nodule found during an MRI for neck pain. A 28-year-old female was referred because of a 2-cm thyroid nodule felt during an initial evaluation for infertility.

They had no history of head and neck radiation and no family history of thyroid disease, including thyroid cancer.

The patients were unaware of the thyroid nodule and had no symptoms of dysphagia, change in voice or anterior neck pressure. The 1-cm nodule could not be felt, whereas the larger 2-cm nodule was easily palpable in the left lobe. The nodule was mobile and nontender. Neither woman had palpable adenopathy in the neck. Laboratory testing showed both women had normal thyroid-stimulating hormone values <1.9 mU/L.

IMGANLY_1

Stephanie L. Lee

Both women had a thyroid ultrasound, including a nodal survey of the neck. There were no abnormal or enlarged nodes seen in the bilateral neck in levels 2, 3, 4, 5 or 6.

Nodule features

The older woman had a heterogeneous, minimally hypoechoic/isoechoic 0.9 cm x 0.6 cm x 0.3 cm (sagittal x anteroposterior x transverse) nodule in the left lobe of an otherwise normal thyroid (Figures 1A and 1B). This nodule had a shape that is taller than wide, defined as an anteroposterior/transverse diameter (A/T) ratio >1 in the transverse view. This nodule had an A/T ratio of 2 with a border that was blurred, suggesting varying thickness. There were a few nonshadowing hyperechoic foci that were not punctate and appeared to be posterior to microcytic areas of the nodule. The nodule did not have any vascular flow by Doppler (grade 1) and no calcification.

The younger woman had a mostly isoechoic/hyperechoic 2.9 cm x 2.4 cm x 2 cm (sagittal x anteroposterior x transverse) nodule in the left lobe of an otherwise normal-appearing thyroid (Figures 1C and 1D). The margins of this nodule were well defined. The nodule had an A/T ratio of 1.2 with peripheral and low-volume intranodular vascular flow (grade 3) by Doppler and no calcification. This nodule also contained nonshadowing hyperechoic foci that were not punctate and were posterior to microcytic areas of the nodule.

Characteristics of concern

The generally accepted sonographic characteristics of thyroid nodules that are concerning for malignancy include solid composition, hypoechogenicity, intranodular vascular flow, micro- and macro-calcification, blurred margins, capsular invasion and hypermetabolic rate on F-18 fluorodeoxyglucose (FDG) PET scan.

The shape of a nodule is also independently associated with the risk for thyroid cancer. Cappelli and colleagues found that an A/T ratio >1 was associated with thyroid cancer with a sensitivity of 84% and a specificity of 82%. The taller-than-wide (A/T >1) shape plus two additional worrisome sonographic features (hypoechoic, micro-calcifications, blurred margins and increased intranodular vascular flow) will detect thyroid cancer with a sensitivity of 99% but a specificity of 57%. This group has suggested that biopsy should be performed when a nodule is found with this characteristic on ultrasound. For our patients, the older woman had a <1 cm nodule with a blurred margin and A/T >1 but no other risk factors such as radiation, adenopathy or family history of thyroid cancer. It was elected to watch.

Patient follow-up

After 18 months, the nodule grew in largest dimension to 1.4 cm and developed micro-calcifications. The nodule was biopsied with ultrasound guidance and found to be a papillary thyroid carcinoma. After thyroidectomy, she was found with a unifocal 1.2-cm papillary thyroid carcinoma with classical papillary histology, no invasion, no nodes and BRAF mutation negative. She was not treated with radioactive iodine. She is disease-free after 3 years.

The younger patient had an ultrasound-guided biopsy at the time of the initial visit and was found to have a papillary thyroid carcinoma. After thyroidectomy, she was found to have a unifocal 2.5-cm papillary thyroid carcinoma with classic histology, minimal capsular invasion, two metastatic perithyroidal nodes and BRAF mutation positive. She received 50 mCi radioactive iodine remnant ablation with a post-therapy whole-body scan showing only a small thyroid remnant. She is disease-free after 2 years.

Ultrasound characteristics of these two cases emphasize that thyroid malignancy occurs in nodules that do not have the usual worrisome characteristics of hypoechogenicity, vigorous intranodular vascularity or calcification. Both of these nodules were isoechoic to hyperechoic but had the characteristic of being taller than wide. It is important that clinicians include this characteristic of A/T ratio >1 in the transverse view when describing the ultrasound appearance of a nodule and use it in the decision to biopsy that nodule, regardless of the lack of other sonographic features of malignancy.

References:
  • Cappelli C. Clin Endocrinol. 2005;63:689-693.
  • Cappelli C. Eur J Endocrinol. 2006;155:27-31.
  • Kim EK. AJR Am J Roentgenol. 2002;178:687-691.

·         Source: Endocrine Today.

Researchers assess 48-hour effects of cinacalcet in patients with secondary hyperparathyroidism.


 

The association between patients on hemodialysis with elevated parathyroid hormone, serum calcium, phosphorus levels, and the development of vascular calcifications has been established. However, in this patient population with secondary hyperparathyroidism controlled by cinacalcet (Sensipar, Amgen), researchers have found a transient reduction in parathyroid hormone and phosphorus, and an increase in calcitonin following each dose, further suggesting that the discontinuation of cinacalcet induces a significant increase of parathyroid hormone.

Researchers from the Hospital Perpetuo Socorro in Alicante, Spain, conducted a phase 4, open-label, single arm, single dose, clinical trial. Ten patients on cinacalcet for 6 months or longer with intact parathyroid hormone (PTH) levels of 100 pg/mL to 400 pg/mL were administered 30 mg (n=6), 60 mg (n=3) or 90 mg (n=1) of the drug.

According to data, patients displayed a significant reduction in intact PTH between 1 and 6 hours, and values returned to baseline at 24 hours (maximum mean percentage change from baseline: –50%; 95% CI, –34% to –66% at 3 hours). Researchers also observed a transient increase in calcitonin and a decrease in phosphorus, with no changes to calcium levels, they wrote.

Additionally, researchers reported a significant increase in intact PTH (51%; 95% CI, 26-76) and phosphorus at 48 hours. They determined that changes to PTH were similar with the three determination methods (intact PTH, Scantibodies Laboratory; iPTH, Roche Diagnostics; PTH 1-84, Scantibodies Laboratory).

These findings suggest that blood samples taken at 12 and 24 hours after the last dose of cinacalcet provide reliable information on the overall degree of PTH control over the 24-hour dosing period. Furthermore, the assay used to measure PTH does not influence relative changes induced by cinacalcet, the researchers wrote.

Source: Endocrine Today.

Papillary thyroid carcinoma linked to Hashimoto’s thyroiditis.


 

Data from a recent meta-analysis demonstrate that papillary thyroid cancer is significantly associated with pathologically confirmed Hashimoto’s thyroiditis, despite decades of controversy.

Researchers from Korea University Ansan Hospital used citation databases to search the literature for relevant studies; they found 38 eligible studies that included 10,648 patients with papillary thyroid carcinoma (PTC). Of those, 23.2% had histologically proven Hashimoto’s thyroiditis.

According to the analysis, Compared with benign thyroid diseases and other carcinomas, Hashimoto’s thyroiditis was more commonly seen in PTC (OR=2.4 vs. 2.8; P<.001).

Additionally, cases of PTC with existing Hashimoto’s thyroiditis were significantly linked to female patients (OR=2.7; P<.001); multifocal involvement (OR=1.5; P=.010); no extrathyroidal extension (OR=1.3; P=.002); and no lymph node metastasis (OR=1.3; P=.041), the researchers wrote. The long recurrence-free survival among patients with both PTC and Hashimoto’s thyroiditis also was significant (HR=0.6; P=.001).

“Our meta-analysis showed that PTC is significantly associated with pathologically confirmed [Hashimoto’s thyroiditis]. PTC patients with [Hashimoto’s thyroiditis] have favorable clinicopathologic characteristics compared with PTCs without [Hashimoto’s thyroiditis]. However, patients with [Hashimoto’s thyroiditis] need to be carefully monitored for the development of PTC,” they wrote.

Source: Endocrine Today.

Study reveals how inherited risk factors in ‘junk DNA’ affect breast cancer predisposition.


 

Novel method provides insights in biology of breast cancer

In light of recent large population studies, it’s known that some people carry inherited DNA changes that increase their lifetime risk of diseases, including breast and prostate cancer. To the surprise of scientists, scores of these “risk alleles” have been found in vast regions of the genome – sometimes called “junk DNA” or “dark matter” – that don’t carry the genetic code for proteins, so how they influence an individual’s cancer risk isn’t known.

In a new study, scientists at Dana-Farber Cancer Institute have shown that several such alleles affect DNA segments known as “enhancers” and turn on or off genes involved in breast cancer. Interestingly, four of the genes the research team pinpointed hadn’t previously been implicated in breast cancer. The scientists, led by Matthew Freedman, MD, PhD, reported their findings in the Jan. 31 issue of Cell.

“We can use this tool to show that the DNA variation that influences risk controls the expression of a nearby gene involved in cancer,” said Freedman, of Dana-Farber’s Center for Cancer Genome Discovery and Center Functional Cancer Epigenetics and the Broad Institute. Freedman explained that knowing this link gives scientists new insights into the biology of breast cancer. “If you can identify which pathway or gene is involved in the risk of developing cancer, primary cancer prevention efforts can be more rationally designed.”

In the past several years, investigations called genome-wide association studies (GWAS) have helped define the genetic root causes of many diseases, including cancer. These studies have identified large numbers of relatively common polymorphisms, or places in the human genome where the genetic code differs among individuals, that are associated with inherited, increased risks of cancer.

About 70 such variants – also known as single-nucleotide polymorphisms, or SNPs – have been identified in prostate cancer and an equal number in breast cancer. Although these risk alleles are common in the population, each one increases cancer risk by only a modest amount, according to Freedman. Some individuals may inherit enough risk variants, however, to make a significant difference that someday might prompt physicians to recommend preventive measures.

Freedman said that because the segments of DNA containing the variants lie in uncharted regions of the genome, “it has been a challenge to connect these variants to genes that influence cancer risk.” Clues to their function came in 2012, when reports based on a public database called ENCODE suggested that many of these SNPs are located within regions that regulate the activity of genes.

The Dana-Farber scientists tapped this information and another large publicly funded database, The Cancer Genome Atlas, which contains thoroughly analyzed samples of tumors and the corresponding normal tissue from cancer patients. They studied data on increased gene activity in tumor samples from 407 breast cancer patients. At the same time, they examined data on normal blood samples from those same patients, which revealed the number of breast cancer risk alleles the patients had been born with.

Sophisticated computational methods then linked the risk alleles’ promoter functions to six overactive genes within the breast cancers: two of the genes had already been implicated in breast cancer, but four were identified for the first time, the scientists reported. “Our data showed that the expression of these genes was under genetic control [of the DNA variants],” Freedman said.

He said that this study, the largest of its kind, “is just the beginning” of further work to understand how these variants affect the biology of breast cancer development.

First author of the report is Qiyuan Li, PhD, a postdoctoral fellow in the Freedman lab.

The research was supported in part by grants from the National Institutes of Health (U19CA148537 and R01 CA131341), the Mayer Foundation, the H.L. Snyder Medical Foundation, the Kohlberg Foundation, and the A. David Mazzone Awards Program.

At Dana-Farber/Brigham and Women’s Cancer Center, breast cancer is treated through the Susan F. Smith Center for Women’s Cancers Breast Oncology Program.

Source: Dana-Farber Cancer Institute.

 

How to Eat Better and Fight Cancer with Your Fork.


 

Good nutrition is essential for maintaining a healthy weight and lifestyle and, according to Dana-Farber Nutritionist Stacy Kennedy, MPH, RD, CSO, LDN, it can also help in the battle against cancer.

“Good nutrition is really important for supporting a healthy immune system, which helps the healing process, and healthy eating can even help to alleviate side effects or symptoms related to cancer and treatment, such as fatigue, constipation, nausea, and mouth sores,” Kennedy says.

 

So where should the nutrition novice begin? The produce section. “Maintaining a healthy diet that is rich in plant-based foods is one way to not only promote survivorship, but also help to prevent cancer – it really is an excellent choice for everyone,” Kennedy says. She offers up these tips.

  1. Reach for bright colors. Look for brightly colored, in-season, preferably local, fruits and vegetables. What gives a fruit or vegetable its bright color, are specific phytonutrients, which are extremely beneficial for our immune systems.
  2. Be mindful of meat. A healthy diet can include protein-rich foods, like meat or fish. Just be mindful of the quality, type, and portion size.  Don’t forget to reach for protein-rich plants too, like lentils, beans, nuts, seeds, whole grains, and dark green, leafy vegetables.
  3. Keep certain foods off your plate. Reduce and limit your intake of sugary or processed foods, artificial ingredients (sweeteners, colors, preservatives, etc.), and fatty red meat; grass fed beef is healthy in moderation.
  4. Start small. If you are not ready to overhaul your diet, start with little steps. If you are eating a sandwich, add a tomato, avocado, or cucumber. Or grab an apple as a snack instead of a bag of chips. Even a slight increase in your fruit and vegetable intake can have lasting benefits.
  5. Ask an Expert. There’s often conflicting information in the media about nutrition and its role in treatment. Work with someone who can help you take in all of the information and create a plan that is right for you.
  • professional nutrition experts

 “I do love this app,” says Susan Gimilaro, a Dana-Farber patient who was diagnosed with multiple myeloma in March 2011. “First, the recipes are delicious.  And I like the shopping list; just click on a recipe, press the shopping list, and voila – I’ve got a grocery list!  The steps, nutrition info, and tips included in each recipe leave me without questions.”

But when Gimilaro does have questions, she knows where to turn. I was looking for information about chia seeds.  I found a variety of information on the Internet, but could I trust these sources?  I wasn’t sure,” Gimilaro says. “However, in this app, under the Ask the Nutritionists feature, there was information on chia seeds – from a source I can trust.”

“I feel that I am eating healthier because the app is so readily available and offers delicious recipes,” Gimilaro says. “It is just easy to use – there is really no learning curve.”

Source: Dana-Farber Cancer Institute.

 

Ultrasound predicted biologic behavior of papillary thyroid cancer.


Ultrasound criteria have been used to differentiate benign from malignant thyroid lesions. However, researchers in Korea now suggest that ultrasound features at the time of a papillary thyroid cancer diagnosis can be a predictive tool for the biological behavior of the disease.

“Although papillary thyroid carcinomas usually carry a favorable prognosis, some tumors are progressive and become life-threatening for patients. It is useful to identify patients with poor prognosis using easily accessible parameters,” Sang Yu Nam, MD, of the department of radiology in Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, Korea, and colleagues wrote.

They retrospectively reviewed the clinical records, histological data and ultrasound findings of index tumors among 488 patients who underwent surgery there for papillary thyroid carcinoma (PTC).

According to data, benign-looking PTCs justified 74 (15.2%) of 488 PTCs. Although the mean tumor size was not considered significantly different between the groups (1.1 cm for malignant-looking PTCs; 1.11 cm for benign-looking PTCs; P=.947), univariate and multivariate analyses demonstrated that malignant-looking PTCs displayed lymph node metastasis, extrathyroidal extension, and a higher stage more frequently compared with benign-looking PTCs (all P<.05). The researchers also reported significant size in tumors 1 cm or larger, but not in tumors smaller than 1 cm.

Additionally, the risk for recurrence was independently associated with lymph node metastasis (OR=4.362; 95% CI, 1.226-15.521) and larger tumor size (OR=1.769; 95% CI, 1.175-2.665), they wrote.

The researchers determined there was a greater chance for advanced age (P=.028), multifocality (P=.002), extrathyroidal extension (P<.001), lymph node metastasis (P=.007), a higher stage (P<.001), and receiving radioiodine therapy (P<.007) when the number of malignant ultrasound features increased.

Therefore, findings indicate ultrasound features could serve as an important differentiating factor in the diagnosis of PTC. Furthermore, ultrasound features have the potential to predict clinical outcomes or appropriate management of patients with PTC.

Disclosure: The researchers report no relevant financial disclosures.

Perspective

Iain J. Nixon

  • This report is not surprising. Ultrasound has a long history of being predictive of malignancy, and I see no reason for surprise that worrying appearance on ultrasound translates to worrying appearance on pathology.

    It should be remembered that, after 5 years, the difference in recurrence rate, although significant (P<.05), was only 3%, so clinical significance is unclear.

    Perhaps the findings of ultrasound could be used to select the lowest-risk patients for less aggressive therapy (no radioactive iodine and lobectomy, rather than total thyroidectomy). Those with aggressive features were more likely to have nodal disease and extra thyroid extension, which would mandate total thyroidectomy and probable radioactive iodine.

    • Iain J. Nixon, MBCHB
    • Clinical fellow in the head and neck surgery department
      Memorial Sloan-Kettering Cancer Center, New York

Source: Endocrine Today.