Relationship between the peak amplitudes of the linear (2, 2, 0) and the quadratic (2, 2, 0) × (2, 2, 0) QNMs (top panels) as well as the linear (4, 4, 0) QNM (bottom panels), at different model start times u0. Colors show different mass ratios q, and circles and triangles denote systems with remnant dimensionless spin χf ≈ 0.5 and χf ≈ 0.7, respectively. Each blue curve is a pure quadratic fit with start time u0, and the shaded region brackets every one of the individual fits. Credit: Arxiv: DOI: 10.48550/arxiv.2208.07380
When two black holes collide into each other to form a new bigger black hole, they violently roil spacetime around them, sending ripples, called gravitational waves, outward in all directions. Previous studies of black hole collisions modeled the behavior of the gravitational waves using what is known as linear math, which means that the gravitational waves rippling outward did not influence, or interact, with each other. Now, a new analysis has modeled the same collisions in more detail and revealed so-called nonlinear effects.
“Nonlinear effects are what happens when waves on the beach crest and crash,” says Keefe Mitman, a Caltech graduate student who works with Saul Teukolsky (Ph.D. ’74), the Robinson Professor of Theoretical Astrophysics at Caltech with a joint appointment at Cornell University.
“The waves interact and influence each other rather than ride along by themselves. With something as violent as a black hole merger, we expected these effects but had not seen them in our models until now. New methods for extracting the waveforms from our simulations have made it possible to see the nonlinearities.”
The research, accepted for publication in the journal Physical Review Letters, comes from a team of researchers at Caltech, Columbia University, University of Mississippi, Cornell University, and the Max Planck Institute for Gravitational Physics.
In the future, the new model can be used to learn more about the actual black hole collisions that have been routinely observed by LIGO (Laser Interferometer Gravitational-wave Observatory) ever since it made history in 2015 with the first direct detection of gravitational waves from space. LIGO will turn back on later this year after getting a set of upgrades that will make the detectors even more sensitive to gravitational waves. % buffered
Caltech graduate student Keefe Mitman explains a new mathematical model of black hole collisions that contains nonlinear gravitational effects–a phenomenon he compares to what happens when two people jump wildly on a trampoline.
Mitman and his colleagues are part of a team called the Simulating eXtreme Spacetimes collaboration, or SXS. Founded by Teukolsky in collaboration with Nobel Laureate Kip Thorne (BS ’62), Richard P. Feynman Professor of Theoretical Physics, Emeritus, at Caltech, the SXS project uses supercomputers to simulate black hole mergers. The supercomputers model how the black holes evolve as they spiral together and merge using the equations of Albert Einstein’s general theory of relativity. In fact, Teukolsky was the first to understand how to use these relativity equations to model the “ringdown” phase of the black hole collision, which occurs right after the two massive bodies have merged. % buffered
This simulation shows two black holes colliding near the speed of light, revealing the mysterious physics of what one astrophysicist calls “one of the most violent events you can imagine in the universe.” The work is the first detailed look at the aftermath of such a cataclysmic clash, and shows how a remnant black hole would form and send gravitational waves through the cosmos. Credit: Simulation courtesy of Thomas Helfer/Johns Hopkins University
“Supercomputers are needed to carry out an accurate calculation of the entire signal: the inspiral of the two orbiting black holes, their merger, and the settling down to a single quiescent remnant black hole,” Teukolsky says. “The linear treatment of the settling down phase was the subject of my Ph.D. thesis under Kip quite a while ago. The new nonlinear treatment of this phase will allow more accurate modeling of the waves and eventually new tests of whether general relativity is, in fact, the correct theory of gravity for black holes.”
The SXS simulations have proved instrumental in identifying and characterizing the nearly 100 black hole smashups detected by LIGO so far. This new study represents the first time that the team has identified nonlinear effects in simulations of the ringdown phase.
“Imagine there are two people on a trampoline,” Mitman says. “If they jump gently, they shouldn’t influence the other person that much. That’s what happens when we say a theory is linear. But if one person starts bouncing with more energy, then the trampoline will distort, and the other person will start to feel their influence. This is what we mean by nonlinear: the two people on the trampoline experience new oscillations because of the presence and influence of the other person.”
In gravitational terms, this means that the simulations produce new types of waves. “If you dig deeper under the large waves, you will find an additional new wave with a unique frequency,” Mitman says.
In the big picture, these new simulations will help researchers to better characterize future black hole collisions observed by LIGO and to better test Einstein’s general theory of relativity.
Says co-author Macarena Lagos of Columbia University, “This is a big step in preparing us for the next phase of gravitational-wave detection, which will deepen our understanding of gravity in these incredible phenomena taking place in the far reaches of the cosmos.”
It’s fair to say that medicinal mushrooms are finally getting the recognition they deserve as “super shrooms”. But some varieties, like maitake mushroom, are still flying under the radar in spite of their incredible health benefits.
Maitake, sometimes nicknamed “king of mushrooms”, is both delicious and nutritious. It’s filled with powerful nutrients and plant compounds that boost numerous aspects of health and has been celebrated in Japan for many, many years because of these health-boosting properties.
If you haven’t heard about maitake yet or all that it can do, read on to learn more about this mushroom king.
What is Maitake? The Dancing Mushroom
Maitake mushroom (Grifola frondosa) grows natively in certain regions of China, Japan, and North America. It’s usually found growing at the base of maple, oak, and elm trees and has a distinct frilly, almost coral-like appearance.
Over the years, maitake has gained many nicknames. In Japanese, the word maitake means ‘dancing’ and refers, not to dancing mushrooms, but to people dancing with happiness after finding the mushroom in the wild. It’s also called “hen of the woods” because of its resemblance to a fan-like hen tail.
As already mentioned, maitake even has the more impressive nickname of “king of mushrooms”. This could refer to its many health benefits or perhaps to its size, since maitake averages about 10 pounds in weight and can grow to over 100 pounds!
Unlike some other medicinal mushrooms, maitake has a delicious, earthy flavor and delicate texture. This has given it both medicinal and culinary value for centuries.
A Japanese Love for Maitake
Asian cultures have long recognized the outstanding benefits of maitake mushroom. It has a firm place in traditional Chinese medicine, but this shroom has made even more of a mark in Japanese history.
According to lore, it was a group of Buddhist nuns and woodcutters who first discovered maitake in Japan. The mushroom would go on to have a central place in Japanese herbology and cuisine, lasting all the way to modern times.
Some legends state that maitake was worth its weight in silver to anyone fortunate enough to find it growing in the wild (hence why people danced at finding it). It was also given as a gift to Shoguns by local lords to gain favor and rewards.
The popularity of maitake mushroom, particularly among royalty, led to the development of expert Japanese mushroom foragers who still continue their work today. Even though maitake has become largely cultivated, many believe that the wild-grown fungi are superior.
On the medicinal side, maitake mushroom was thought to be a tonic for the immune system, blood pressure, and overall vitality.
Interestingly, all of these medicinal properties have received some kind of confirmation from modern research!
Top Benefits of Maitake Mushroom
Loaded with Nutrients & Antioxidants
Like many other mushroom varieties, maitake is loaded with nutrients, powerful plant compounds, and antioxidants.
Most notably, maitake is a good source of B vitamins (niacin, riboflavin, thiamine, folate), copper, potassium, and phosphorus. The mushrooms also contain smaller amounts of zinc, manganese, selenium, and vitamin B6.
Wild-grown maitake is typically high in vitamin D as well, although the amount will vary based on how much sunlight the mushrooms were exposed to.
In addition to vitamins and minerals, a one cup serving of maitake gives you a decent amount of protein and nearly 2 grams of fiber. You’ll also be consuming highly beneficial polysaccharides known as beta glucans. Beta glucans have documented immune-boosting and antitumor properties— but more on that later.
Finally, no superfood would be complete without the presence of anti-aging antioxidants.
Maitake contains a powerful array, including phenols, flavonoids, vitamin C, and vitamin E. These specific antioxidants can fight many age-related diseases, including cancer and neurodegenerative disorders.
Adaptogenic Properties that Fight Stress
One of the best benefits of maitake mushroom for modern times is its adaptogenic properties.
Adaptogens are herbs and foods that help protect you from the effects of both physical and mental stressors. Essentially, they help your body adapt to stress, reducing its impact. If you’re like most people, you could certainly benefit from this ability!
The term “adaptogen” was first used in the 1940s. It was originally defined as a natural substance or plant extract that had non-specific action to enhance the human body’s resistance to adverse conditions, particularly stress.
Since that time, multiple studies have been conducted on herbal adaptogens with some impressive results.
Overall, adaptogens have shown the ability to decrease fatigue, ease symptoms of anxiety and depression, sharpen mental performance, and even change the chemical stress response within your body. They have also demonstrated nootropic and neuroprotective properties, meaning they help to enhance and protect your brain.
The bottom line is that maitake mushroom can be a huge benefit to your body and mind by combating the negative effects of stress. However, like other adaptogens, it does need to be taken for a period of time (at least 2-3 weeks) before you will notice the full effects.
Unique Cancer-Fighting Potential
The idea of using medicinal mushrooms to fight cancer isn’t a new one. Turkey tail mushroom has potent anticancer potential and is even used as an adjuvant cancer treatment in Japan.
Now, research is showing that there are also potential benefits of maitake mushroom for fighting cancer— some very unique ones.
The main cancer-fighting component of maitake is the polysaccharides it contains (particularly beta glucans). A specific portion of these polysaccharides can be isolated into an extract known as D-Fraction. This unique extract has shown antitumoral and antimetastatic activity AND an ability to inhibit human breast cancer cells.
In a very small human trial with cancer patients, D-Fraction appeared to repress cancer progression primarily by stimulating natural killer cells. It has also been able to enhance the action of a cancer-fighting protein in lab studies.
Other preclinical studies have found that maitake extract can suppress tumor growth, though this has yet to be tested in a human model.
The bottom line is that maitake has shown the potential to fight cancer on its own and enhance other cancer treatments. Hopefully, research will continue to progress and find clinical uses for D-Fraction.
Strengthens Immune Function
One of the ways maitake fights cancer cells is by stimulating the immune system. This enhanced immune response can be beneficial for your body to fend off normal infections as well as cancer.
Yet again, this effect comes from the powerful polysaccharides within maitake, particularly beta glucans. They stimulate natural killer cells, which go after tumor cells and cells infected with a virus, as well as other defensive immune cells.
In one study, an extract from maitake mushroom produced “significant stimulation of defense reaction” in the immune system. Interestingly, the immune-enhancing effects were even stronger when maitake and shiitake extracts were paired together. A good case for consuming a variety of medicinal mushrooms!
One important note to make is that maitake mushroom doesn’t simply stimulate your immune system and leave it “turned up” all the time (which could be harmful).
In fact, a different study discovered that maitake acts more like an immunomodulator than a true immunostimulator, meaning it upregulates or downregulates immune reaction and inflammatory responses as needed.
Good for Digestion & A Healthy Gut
Another of the benefits of consuming maitake mushroom regularly is for your digestion.
Not only do polysaccharides and beta glucans have powerful health properties, they are also forms of soluble fiber. This means they form a thick, gel-like substance in your digestive tract, which helps to “keep you regular”. As a bonus, beta glucan also slows the absorption of sugar and reduces cholesterol absorption in your digestive tract.
Even better is the fact that beta glucans are prebiotic fibers. This means they feed the highly important probiotics living within your gut. Studies have shown that they actually improve the growth and colonization of beneficial microorganisms, which is incredible!
On another note, some preliminary studies have found that maitake extract may be able to alleviate intestinal inflammation. This could be a huge finding for sufferers of IBD and other inflammatory gut disorders, but more research is still needed in this area.
Potential to Support Heart Health
Some early studies have shown that maitake mushroom may be able to help with two specific areas of heart health: cholesterol and blood pressure.
As mentioned in the previous section, the beta glucans in maitake have the ability to reduce cholesterol absorption in your digestive tract. This is likely why maitake mushroom was able to lower cholesterol levels in one study. In theory, this would help to keep arteries open and blood flowing to the heart.
In another study, supplementation with maitake was able to reduce age-related hypertension. These results were confirmed in a separate animal model that found maitake significantly reduced blood pressure over a period of 8 weeks.
Unfortunately, high quality clinical trials on maitake and heart health are still lacking. But given the presence of beta glucans in the mushrooms (also found in heart-healthy oats), it’s safe to conclude that maitake possesses some type of heart-supportive properties.
May Help Balance Blood Sugar Levels
Having consistently high blood sugar levels is a big risk factor for type 2 diabetes. And while a healthy diet is one of the best ways to manage blood sugar, there may be some added benefits of maitake mushroom for blood sugar control.
Once again, we come back to the beta glucans and other polysaccharides found in maitake. By acting as soluble fiber within your digestive tract, they are able to slow the absorption of sugar into your bloodstream. This can help to keep blood sugar more balanced instead of spiking after a snack or meal.
Some preliminary studies have indeed confirmed that maitake has the potential to balance or lower blood sugar.
For example, it was found to improve glucose tolerance and blood glucose levels in one study. A separate animal model also found that a unique maitake preparation was able to improve “diabetes-induced alterations” and positively affected blood glucose levels.
May Promote Fertility
Infertility is a frustrating challenge for many people around the world. There’s no one cause of infertility, so it can be difficult to treat, even using conventional options.
In many traditional medicinal systems, adaptogens are one of the top recommended options for enhancing fertility because they have a balancing and normalizing effect on the body. They also have a balancing effect on hormones (often a factor in infertility) and can even decrease the stress hormone, cortisol.
One study conducted in Japan found that there may be benefits of maitake mushrooms for enhanced fertility, likely due to its adaptogenic effect.
The participants in the study all had polycystic ovarian syndrome (PCOS), a hormonal condition that frequently involves ovarian cysts, decreased or no ovulation, and infertility. By the end of the trial period, over 76% of those taking maitake extract were ovulating again, which is a big step towards fertility.
Of course, this was only one small study, but the results were very promising.
Best Ways to Take Maitake Mushroom
Unless you are a mushroom expert, it is not recommended that you try to forage for maitake in the wild. You don’t want to end up in the hospital as a result of harvesting a poisonous mushroom by mistake!
Fortunately, some specialty grocery stores do now carry fresh maitake mushrooms if you want to try their excellent flavor for yourself (though they can be quite expensive). Always look for organic mushrooms whenever possible to avoid potentially harmful chemical residue.
Another option— and one that is more feasible for most people— is to take maitake mushroom as a supplement.
It can now be found as a powdered or liquid extract, which means you’ll be getting a more concentrated amount of the mushroom than you would eating it fresh. Again, choose your supplements carefully to avoid unwanted chemicals. Ideally, you want one that is third-party tested for contaminants, heavy metals, etc.
The Best Maitake “Super-Shroom” Supplement
There’s no doubt that there are some pretty incredible benefits of maitake mushroom. But why stop at just one medicinal mushroom when you can provide your body with the power of several all at once?
There’s a great argument to be made for consuming a range of mushrooms everyday, and there’s no better option for doing this than Mushroom MindBoost from Purality Health.
This top quality supplement combines the outstanding properties of maitake with four other potent medicinal mushrooms: king trumpet, turkey tail, reishi, and Antrodia camphorata. This powerful combination benefits your entire body but is especially supportive of brain function and mental sharpness.
Mushroom MindBoost is made using micelle liposomal technology, which means your body can absorb the maximum amount of nutrients from it. And as a HUGE bonus, it tastes like chocolate, which makes taking your daily dose incredibly easy.
I had the opportunity to present the results of a randomized phase III study led through the Canadian Clinical Trials Group HE.1. It was a 1:1 randomization to palliative radiotherapy in one fraction versus best supportive care for patients who suffer from pain or discomfort from their primary or metastatic liver cancer.
And the primary objective was to determine the proportion of patients who benefit from the therapy compared to best supportive care. Patients had to have cancers that were unsuitable for standard local or regional or systemic therapies. And their minimal pain score had to be 4 on a scale from 0 to 10, and stable, and bothersome despite attempts at analgesia and steroid and other standard supportive care.
So in this study, there were patients with many different primary cancers who had a very large burden of disease in their liver. No patient was going to be offered any future study — no immunotherapy, targeted therapies. or chemotherapy. And the primary endpoint was in fact 1 month after the simple intervention.
Radiotherapy was given with an antiemetic as though there was a very large volume of the abdomen that was radiated, as many patients had very advanced disease.
So the primary endpoints were met in the study. There was clinically important and statistically significant improvement in pain. So 67% of patients who received the single dose of radiotherapy reported an improvement of pain by 2 or more on their pain scale when asked, “What is your pain at worst in the past 24 hours with radiation?” Whereas with best supportive care alone, only 22% of patients reported an improvement.
The other pain questions were also improved with the use of radiotherapy. And we did a sensitivity analysis where we assumed everyone who did not complete their pain questionnaires at 1 month had worse pain. And with the sensitivity analysis, there remains statistically significant and clinically important improvement in pain.
There was a trend to improved quality of life, and the adverse events were similar. There was some transient grade 2 GI toxicity and fatigue that was reversible. And so overall this intervention was well tolerated.
We also had a secondary endpoint of survival at 3 months. And with radiotherapy, 51% of patients lived at 3 months versus 33% with best supportive care. The P value is 0.07. So it’s hypothesis-generating, but very intriguing, and hopefully will open the door for more palliative radiotherapy studies in the setting of patients who suffer from hepatic pain, whether it be from primary liver cancer or from liver metastases.
Trial results came as a surprise after success in prophylaxis for other groups
Researchers were scratching their heads over findings that doxycycline prophylaxis failed to prevent sexually transmitted infections (STIs) among African cisgender women, unlike its success among men who have sex with men.
In a trial conducted among 449 women in Kenya who were taking daily pre-exposure prophylaxis (PrEP) to prevent HIV infection, 50 of the women randomized to doxycycline around the time of sexual activity became infected with pathogens causing gonorrhoea or chlamydia, as compared with 59 women in the standard-of-care group (RR 0.88, 95% CI 0.60-1.29, P=0.51), reported Jenell Stewart, DO, MPH, of Hennepin Healthcare and the University of Minnesota in Minneapolis.
“None of the women in the study contracted HIV, so we assume they were adherent in taking their PrEP, so we keep asking ourselves, ‘Why was doxycycline not effective in preventing other sexual transmitted diseases, such as chlamydia and gonorrhea?'” Stewart told MedPage Today at the annual Conference on Retroviruses and Opportunistic Infectionsopens in a new tab or window.
So what went wrong? Stewart suggested that it might be anatomy: Endocervical tissue may differ from urethral, rectal, and pharyngeal tissues. She also hypothesized that there could be resistance pathogens that muted the effectiveness of doxycycline in the groups tested. And, Stewart noted, doxycycline might have been taken by women in the standard-of-care contingent through clinics outside the study, which would have skewed results.
She also suggested that adherence to doxycycline might have been imperfect.
“We were trying to reduce the use of antibiotics in this study so the cisgender women were taking doxycycline when they were having sexual contact, whereas the PrEP for HIV was daily,” she said. “It is pretty clear that doxycycline is not the answer for preventing sexually transmitted infections among this population of cisgender women in Africa.”
In the study, Stewart and colleagues randomly assigned 225 non-pregnant women to standard of care (quarterly STI testing and treatment) and another 224 women to 200-mg doxycycline within 72 hours of sexual activity. Women were followed for 12 months during 2020-2022. If a woman became pregnant during the trial, doxycycline therapy was discontinued.
At baseline, the median age of the women was 24 years, and the median duration of HIV PrEP was about 7 months. Two-thirds of the women were single, 69% had prior pregnancies, 61% were using hormonal contraception, and 37% reported transactional sex. About 18% of the women had a sexually transmitted disease at the start of the trial, mostly chlamydia. Quarterly visits were completed by 95% of the women in the prophylaxis cohort and by 98% of the women receiving standard of care.
About 78% of the women said they had used doxycycline in weekly surveys, indicating a sexually active group. There were 80 pregnancies in the study, 44 among women in the doxycycline group and 36 in the standard-of-care group.
No severe adverse reactions were reported by the women taking doxycycline, although four women in the group reported having experienced social harms related to taking the drug.
Overall, STIs were detected in 109 women during the study, including 85 cases of chlamydia, 31 cases of gonorrhoea, and one case of syphilis (eight women had both a chlamydia and gonorrhoea infection). Chlamydia occurred in 35 women in the doxycycline group and 50 women in the standard-of-care group (RR 0.73, 95% CI 0.47-1.13). Gonorrhoea occurred in 19 and 12 women, respectively (RR 1.64, 95% CI 0.78-3.47).
“The burden of sexually transmitted infections on cisgender women is large and growing,” Stewart said. “Sexually transmitted infection prevention interventions remain needed.”
In commenting on the study, press conference moderator Landon Myer, MD, of the University of Cape Town, South Africa, called it a “hugely important study in an area that requires greater interest.”
However, “I don’t think the problem is the drug,” he told MedPage Today. “I think the reason the trial failed to show a significant difference is probably due to drug resistance or to adherence. We have more work to do to find the answer.”
Seismic waves travel differently through innermost core than through outer section.
Seismic waves have helped researchers to learn about the layers that comprise Earth’s solid centre.
The reverberations from earthquakes as they bounce back and forth through the centre of Earth have revealed new details about the structure of the planet’s inner core, according to a study published in Nature Communications this week1.
For several decades, evidence has been mounting to suggest that the planet’s solid inner core is made up of distinct layers2,3 but their properties have remained mysterious.
To better understand the inner core’s structure, researchers used multiple seismometers to examine how seismic waves are distorted as they pass through the solid ball of iron nickel at Earth’s heart. “Earth oscillates like a bell after a large earthquake, and not just for hours, but days,” says co-author Hrvoje Tkalčić, a geophysicist at the Australian National University in Canberra, Australia.
To detect these oscillations, researchers recorded the waveforms at close to the original site of the earthquake and at the antipode —the direct opposite position on the surface of Earth. This enabled them to look at the multiple journeys through Earth’s centre. “It’s like a ping-pong ball that’s bouncing back and forth,” says co-author Thanh-Son Pham, a postdoctoral fellow at the Australian National University. Each reverberation takes around twenty minutes to cross from one side of the planet to the other, and the seismometers recorded up to five bounces from a single event.
Stacked measurements
The original earthquakes each reached a magnitude of greater than six, but the waves got progressively weaker as they passed through Earth’s core. The researchers used a technique called ‘stacking’, in which they combined the waveforms from a single event to build a more detailed picture of the distortion from the innermost core.
They found that the waves travelled differently through the innermost inner core — which they estimate to be around 650 kilometres thick — than through the outer part. Waves passing through the innermost part of the core slowed down in one direction, whereas waves passing through the outer layer slowed down in another direction. “It simply means that the iron crystals — iron, which is dominant in the inner core — is probably organized in a different way than in the outer shell of the inner core,” Tkalčić says.
Geophysicist Vernon Cormier at the University of Connecticut in Storrs says that the study is important because it offers a measurement of Earth’s innermost section that was very difficult to achieve. “It requires finding seismic waves recorded at very long distance and that are fairly weak in amplitude, and then enhancing the amplitude so that you could measure the wave speed in the very deep interior of the Earth,” says Cormier.
Although the technique is routinely used for minerals exploration, it is not commonly used in geophysics.
The latest finding will help in understanding how Earth’s solid inner core formed — a process that is thought to have started somewhere between 600 million and 1.5 billion years ago — and what role that might have had in shaping the magnetic field.
It was suspected that a 75-year-old woman had advanced infiltrative gastric cancer. However, endoscopic forceps biopsy specimens did not reveal adenocarcinoma.
She was referred to our institute for further examination and treatment. To obtain sufficient submucosal specimens, underwater EMR was performed. Histological examination of 3 of the 6 specimens revealed a poorly differentiated adenocarcinoma in the deep lamina propria and submucosa. Laparoscopy histologically confirmed peritoneal dissemination, and chemotherapy was performed.
The underwater EMR technique enables resection of sufficient deep submucosal tissue, yielding a high en bloc resection rate for colorectal polyps. EUS-guided FNA is often performed to acquire deep submucosal tissue for diagnosis when neoplastic tissues exist beyond the mucosa, and pathological diagnosis using endoscopic forceps biopsy is difficult.
With the use of EUS-guided FNA for both the gastric wall and lymph nodes, overall diagnostic yield could reach 87.5% to 93.7%, but EUS-guided FNA poses a certain risk of seeding. In this case, no enlarged lymph nodes were detected on a CT scan. Thus, we performed underwater EMR instead of EUS-guided FNA.
Conventional EMR has reportedly been shown to be useful for diagnosing infiltrative gastric cancer. However, needle injection for a lift into the hard tumor tissue is often difficult, and inappropriate injection makes subsequent snaring of the tissue challenging. Using underwater EMR, adequate submucosal tissue could be obtained without needle injection, providing an accurate pathological diagnosis.
This video will help readers understand the usefulness of underwater EMR for infiltrative gastric cancer.
Abnormally thickened folds with poor extension of the gastric body.
cute kidney injury (AKI) is a common condition in patients with cirrhosis. It occurs in up to 50% of hospitalized patients with cirrhosis and in 58% of such patients in the intensive care unit (ICU).1-5 AKI is associated with high morbidity and mortality and an increased incidence of chronic kidney disease (CKD) after liver transplantation.1-3,5,6 Progression to advanced stages of AKI (Table 1) portends an even worse prognosis.1,2,5
In general, the three main causes of AKI11 are renal hypoperfusion (also referred to as prerenal AKI), which in most cases is due to hypovolemia; intrinsic, structural kidney injury; and postrenal injury due to urinary obstruction. A unique cause of AKI due to renal hypoperfusion in patients with cirrhosis is the hepatorenal syndrome (HRS), which is the result of renal vasoconstriction. Hypoperfusion from hypovolemia accounts for approximately half the cases of AKI in patients with cirrhosis, intrinsic causes (e.g., acute tubular necrosis) account for approximately 30% of cases, and HRS accounts for approximately 15 to 20%, with less than 1% of cases attributable to postrenal obstruction.3
Definition of AKI and HRS
Before 2012, criteria defining AKI in cirrhosis were absent, but HRS was defined as a syndrome that occurred in patients with cirrhosis and portal hypertension and was characterized by impaired kidney function (defined as a serum creatinine level of >1.5 mg per deciliter [132.6 μmol per liter]) in the absence of underlying kidney disease.7 Clinically, HRS was divided into type 1 (HRS-1), characterized by a rapid reduction in kidney function, with an increase in serum creatinine to a level exceeding 2.5 mg per deciliter [221.0 μmol per liter] in less than 2 weeks, and type 2 (HRS-2), a more chronic deterioration in kidney function.
Over the past decade, the definitions of AKI and HRS in patients with cirrhosis have been revised (Table 1).8-10 The new definition of AKI was harmonized with the Kidney Disease: Improving Global Outcomes definition as an increase in the serum creatinine level of 0.3 mg per deciliter (26.5 μmol per liter) or higher within 48 hours or as an increase in the serum creatinine level that is at least 1.5 times the baseline level and that is known or presumed to have occurred within the previous 7 days.8-10,12 The new definition of HRS eliminated the threshold value for the serum creatinine level (1.5 mg per deciliter), allowing for earlier diagnosis and treatment in patients with normal serum creatinine levels but reduced kidney function, such as women, older patients, or those with sarcopenia. The acute form of HRS, HRS-1, was also renamed HRS-AKI to distinguish it from the more chronic type, HRS-2, now renamed HRS-CKD.10 Changes in urinary output should be considered in the definition of AKI, particularly in critically ill patients with cirrhosis in whom changes in urinary output have been shown to be a sensitive, early marker of AKI and are associated with worse outcomes (Table 1).5,10,13 One of the major limitations of the definition of HRS is the exclusion of underlying parenchymal kidney disease. In an era marked by an increasing incidence of nonalcoholic steatohepatitis, the presence of underlying CKD due to diabetes mellitus, hypertension, or both is also increasing. In patients with preexisting CKD, the prognostic and therapeutic implications of HRS-AKI have yet to be determined, and these implications will probably differ from those in patients with HRS-AKI that progresses to HRS-CKD.8,10
Pathophysiology
Figure 1. Pathophysiology of the Hepatorenal Syndrome and Acute Kidney Injury (HRS-AKI) in Patients with Cirrhosis.
Patients with cirrhosis, particularly those with ascites, have an increased susceptibility to AKI because of the hemodynamic alterations that result from portal hypertension (Figure 1).14,15 The initial mechanism in the pathogenesis of portal hypertension is increased intrahepatic resistance due to distortion of the liver architecture (fibrosis and nodules) and an increase in intrahepatic vascular tone. Subsequent activation of vasodilators in the splanchnic circulation (the most important being nitric oxide) leads to progressive splanchnic and systemic vasodilatation. Increased translocation of bacteria and bacterial products due to intestinal dysbiosis, bacterial overgrowth, and altered tight-junction proteins contributes further to vasodilatation, resulting in a reduction in the effective arterial blood volume that will activate the neurohumoral systems (the renin–angiotensin–aldosterone, sympathetic, and arginine–vasopressin systems) leading to sodium and water retention and ascites formation.16,17 In advanced stages of cirrhosis, progressive vasodilatation leads to more avid retention of sodium and water, resulting in refractory ascites and dilutional hyponatremia, respectively (Figure 1).
With progressive vasodilatation, vasoconstrictive systems (mainly renin and angiotensin) are activated, resulting in renal vasoconstriction and decreased renal blood flow. In addition, a relative decrease in cardiac output in this high-output state of cardiac failure (so-called cirrhotic cardiomyopathy) may further contribute to decreased renal perfusion.18-20 The reduced renal blood flow results in a decrease in the glomerular filtration rate (GFR) and a prerenal type of kidney injury that does not respond to volume expansion — that is, HRS-AKI. Renal vasoconstriction in patients with cirrhosis is not countered by the release of vasodilatory substances (e.g., prostaglandins) because of a decrease in their production and local release of vasoconstrictors such as endothelin.
The pathogenesis of renal vasoconstriction and decreased renal blood flow in cirrhosis (“hepatorenal physiology”) represents a continuum of the mechanisms that initially lead to ascites. Thus, patients with cirrhosis who have ascites, particularly those with refractory ascites, are at the highest risk not only for the development of AKI but also for its most severe clinical form, HRS-AKI (Figure 1). Although HRS-AKI can occur in the absence of a precipitating factor, it is more commonly precipitated by factors that cause a decrease in effective arterial blood volume. These factors include rapid fluid loss (e.g., excessive diuresis or gastrointestinal bleeding), worsening vasodilatation induced by drugs (e.g., angiotensin-converting–enzyme inhibitors), and a systemic inflammatory response (e.g., infection) (Figure 1). Not all cases of AKI in patients with cirrhosis result from renal hypoperfusion; some cases may result from structural kidney injury. However, renal hypoperfusion may lead to structural kidney injury when prolonged or when coupled with a “second hit,” such as exposure to nephrotoxic medications, resulting in a delay in renal recovery.
Assessment of Kidney Function
Evaluation of kidney function in patients with cirrhosis remains critically important and a challenging problem. The serum creatinine level, which is the most practical and commonly used marker of kidney function and the measure used in the Model for End-Stage Liver Disease (MELD) score to prioritize candidates for liver transplantation, overestimates the GFR in patients with cirrhosis because of a combination of decreased creatinine production due to liver disease, protein calorie malnutrition, and muscle wasting. In addition, in patients with AKI and fluid overload, an increase in the serum creatinine level can lag by several hours to days, despite a decrease in the GFR.21,22 Exogenous clearance markers such as inulin and iothalamate are not readily available and are confounded by changes in the volume of distribution due to ascites and extracellular volume expansion. Measurements of creatinine clearance with the use of timed urinary collection (typically over 24 hours) are subject to inaccuracy because of errors in urinary collection (i.e., incomplete collection or overcollection) or increased tubular secretion of creatinine as the GFR declines.
Estimated GFR (eGFR) equations based on serum creatinine, cystatin C, or both are a simple method of determining kidney function in the general population of persons with stable serum creatinine levels. In patients with cirrhosis, however, eGFR equations tend to overestimate the true GFR by 10 to 20 ml per minute per 1.73 m2 of body-surface area, especially in patients with a GFR of less than 40 ml per minute per 1.73 m2, ascites, or both and should be used with caution.23-25 The accuracy of eGFR measurements is particularly important in patients with cirrhosis because eGFR is one of the factors used to determine candidacy for simultaneous liver and kidney transplantation. The removal of race from all eGFR equations was recently recommended as an important step in efforts to eliminate disparities in the care of patients with kidney disease,26 and this removal has been adopted within the transplantation community; however, the effect of this change in eGFR equations on candidacy for simultaneous liver and kidney transplantation remains to be adequately studied.27
Diagnostic Workup and Management of AKI
Figure 2. Workup and Management of AKI in a Patient with Cirrhosis.
Once AKI is diagnosed, it is important to discontinue any medications that could have a role in precipitating or worsening AKI — specifically, diuretics, vasodilators, nonselective beta-blockers, nonsteroidal antiinflammatory drugs — and to rule out infection, particularly spontaneous bacterial peritonitis, which is frequently a precipitant of AKI and HRS-AKI (Figure 2). At the same time, a diagnostic workup for AKI is essential for treating early AKI and for preventing progression, which is associated with increased mortality.1,2,5 The cause of AKI is determined on the basis of the patient’s history and physical examination, urinary tests, the response to diuretic withdrawal, and a volume challenge when clinically indicated (Figure 2). Microscopical examination of urinary sediment is important to rule out intrinsic causes of AKI.
Measurements of fractional excretion of sodium and urea have been used by clinicians to confirm hypovolemia and HRS-AKI and to rule out acute tubular necrosis. However, patients with cirrhosis and ascites already have avid sodium retention, and fractional excretion of sodium of less than 1.0% is common in such patients, even in the absence of AKI.28 Differentiating between HRS-AKI and acute tubular necrosis is therefore often challenging. In general, cutoff values of less than 0.1% for fractional excretion of sodium, less than 21% for fractional excretion of urea, and less than 44 mg per deciliter for urinary albumin may help to confirm HRS-AKI and rule out acute tubular necrosis.28-30 These cutoff values should be interpreted cautiously, however, and always in the context of the patient’s clinical presentation, since they are not very sensitive or specific and have not been correlated with histologic findings. Urinary neutrophil gelatinase–associated lipocalin, a marker of tubular injury, has been shown to differentiate between HRS-AKI and acute tubular necrosis. However, its use in clinical practice has been limited because of lack of standardization, uncertainty regarding the cutoff value, and the unavailability of the biomarker in many countries.28,31-34 Kidney biopsy should be considered only if the results might change management (e.g., treatment of glomerular diseases), since biopsy is an invasive procedure and may be associated with bleeding complications.
Volume expansion is central in reversing AKI due to volume depletion, and the response to volume expansion will help to determine the cause of AKI (Figure 2). The type of resuscitation fluid (crystalloids vs. albumin) and the amount should be individualized according to the cause of AKI and the patient’s volume status (Figure 2). Volume resuscitation is recommended for a trial period of 24 to 48 hours in patients who are clinically hypovolemic or euvolemic. However, it is important to exercise caution in administering fluids in patients with AKI in order to avoid fluid overload and pulmonary edema. Assessment of intravascular volume and volume responsiveness is desirable but has been challenging, since many of the hemodynamic tools have not been studied in patients with cirrhosis and may be misleading because of increased intraabdominal pressures due to ascites.13 In a small, single-center, retrospective study that assessed volume status with the use of point-of-care ultrasonography in patients with a diagnosis of HRS-AKI who were considered to have adequate volume repletion, 21% of the patients had intravascular fluid overload, and 28% continued to have intravascular volume depletion.35 A combination of assessments, including a careful history taking and physical examination, point-of-care ultrasonography, and static and dynamic measurements, when available, should be used to evaluate volume status and fluid responsiveness.
There is insufficient evidence supporting the use of paracentesis to improve intraabdominal pressure (and theoretically, kidney function) in patients with cirrhosis and AKI. Partial ascites removal is recommended for comfort in patients with tense ascites and should be accompanied by intravenous administration of albumin to prevent circulatory dysfunction, a vasodilatory state that follows large-volume paracentesis (removal of >5 liters) and can lead to worsening kidney function.36-38
Treatment of HRS-AKI
In patients with cirrhosis, HRS-AKI should be treated only after other causes of AKI have been investigated and excluded (Figure 2).
Pharmacologic Therapy
Figure 3. Management Algorithm for Suspected HRS-AKI.
The mainstay of pharmacologic management of HRS-AKI is the use of vasoconstrictors combined with intravenous albumin (Figure 3).39,40 As proof of concept, changes in the serum creatinine level correlate inversely with changes in mean arterial pressure induced by vasoconstrictors.41 Vasoconstrictors have not been shown to improve survival, so their use should be considered a bridge to transplantation rather than a cure for HRS-AKI.
Terlipressin, a vasopressin analogue, is the most common vasoconstrictor used worldwide, and both U.S.37 and European38 guidelines recommend it as a first-line agent for HRS-AKI. Terlipressin can be administered intravenously as a bolus or as a continuous infusion, with similar efficacy. However, the cumulative daily dose and the incidence of adverse events are lower with a continuous infusion.42 The initial dose can be increased, maintained, or discontinued, according to the response (changes in the serum creatinine level) (Figure 3). In a large randomized, controlled trial showing the efficacy of terlipressin in patients with HRS-AKI, which led to its approval in the United States, the agent was associated with an increased incidence of respiratory failure due to pulmonary edema.43 Therefore, it is essential to withhold terlipressin and albumin if there is clinical evidence of intravascular volume overload (i.e., anasarca, jugular venous distention, hypoxemia, pulmonary congestion on a chest radiography, or elevated right ventricular systolic pressure on an echocardiography).
Small single-center studies have shown that the responses to norepinephrine, an alternative vasopressor, are similar to those to terlipressin. However, norepinephrine requires continuous infusion in an ICU.39,40 The combination of octreotide and midodrine has weak vasoconstrictive activity, and a randomized, controlled trial showed that the combined treatment was inferior to terlipressin in reversing HRS-AKI.44 Therefore, octreotide and midodrine should be used only temporarily, for 24 to 48 hours, and only if terlipressin is unavailable or contraindicated.
Transjugular Intrahepatic Portosystemic Shunt
An important therapeutic option in patients with portal hypertension is the placement of a transjugular intrahepatic portosystemic shunt (TIPS) that may improve kidney function by redistributing blood volume and reducing portal pressure.45-48 A meta-analysis of nine small studies suggested that treatment with TIPS led to a significant improvement in kidney function, with a pooled response of 93% among patients with HRS-AKI.49 However, there is currently insufficient evidence to recommend TIPS for HRS-AKI.
Renal-Replacement Therapy
Renal-replacement therapy (also known as kidney-replacement therapy) has been viewed as a bridge to liver transplantation, but renal-replacement therapy for patients with HRS-AKI who are not candidates for liver transplantation has been controversial because of high mortality.50 However, because mortality associated with renal-replacement therapy has been shown to be similar among patients with HRS-AKI and those with cirrhosis and acute tubular necrosis,51 a trial of renal-replacement therapy in selected patients with HRS-AKI could be considered.13,37 There is no consensus on when renal-replacement therapy should be initiated in patients with cirrhosis and AKI. Although several randomized, controlled trials have not shown a benefit of early initiation of renal-replacement therapy in the general population of critically ill patients in the ICU, patients with cirrhosis were excluded or were largely underrepresented in those studies.52-55 Therefore, in patients with cirrhosis, the decision about when to initiate renal-replacement therapy should be individualized on the basis of life-threatening indications that are refractory to medical treatment (e.g., hyperkalemia, acidosis, or fluid overload), uremic complications, the trajectory of kidney function, or the overall prognosis.13,37,56,57
Liver Transplantation
Liver transplantation is the treatment of choice in patients with HRS-AKI. Simultaneous liver and kidney transplantation is a potential therapeutic option for patients with prolonged kidney dysfunction before liver transplantation, since recovery of kidney function is less likely in these patients than in those with a shorter duration of kidney dysfunction. However, predicting the severity and duration of kidney dysfunction that make recovery unlikely remains challenging.6,58 In 2017, the Organ Procurement and Transplantation Network set forth criteria for simultaneous liver and kidney transplantation on the basis of previous national guidelines. These criteria included factors such as prolonged duration of AKI and dialysis and the presence of CKD. The organization also implemented a safety-net policy that gave priority to patients with persistent, severe kidney dysfunction after liver transplantation to receive a kidney transplant within the first year.59,60 Kidney biopsy may assist in establishing the diagnosis and determining the reversibility of kidney dysfunction and the need for simultaneous liver and kidney transplantation.61 Predictors of reversibility of AKI after transplantation, such as biomarkers, are needed to guide the allocation of kidney grafts.62,63
Prevention of AKI
The development of AKI is a common, yet severe complication in patients with cirrhosis. Therefore, it is imperative to recognize and manage events that may result in AKI, particularly in patients with ascites (Figure 1).64 Volume depletion should be prevented through the careful use of diuretics (with a goal of <1 lb [0.45 kg] of body-weight loss per day), careful use of lactulose (with dose adjustment to yield two or three formed bowel movements a day), and prevention of variceal hemorrhage.65 Intravenous albumin infusions at a dose of 4 to 6 g per liter of ascites removed have been shown to ameliorate circulatory dysfunction and prevent AKI after large-volume paracentesis (removal of >5 liters).66 Albumin infusions have also been shown to reduce the incidence of AKI and to decrease mortality among patients with spontaneous bacterial peritonitis.67 However, in a study involving patients with infections other than spontaneous bacterial peritonitis, intravenous albumin did not prevent AKI and was actually associated with an increased incidence of pulmonary edema.68 The long-term use of intravenous albumin infusions (weekly or every 2 weeks) in the outpatient setting has led to controversial results. An open-label, randomized, controlled trial showed that this approach was associated with a reduced incidence of complications of ascites (including AKI) and death,69 whereas a randomized, placebo-controlled trial showed no significant reductions in the incidence of AKI or death with long-term albumin infusions.70 In a randomized, controlled trial involving hospitalized patients, an intravenous albumin infusion targeted at maintaining serum albumin levels at approximately 3 g per deciliter did not improve outcomes (one of which was the development of AKI) and was associated with an increased incidence of pulmonary edema.71 Therefore, long-term use of albumin in the outpatient or inpatient setting is currently not recommended.
Various medications such as nonsteroidal antiinflammatory drugs and renin–angiotensin–aldosterone system blockers have direct nephrotoxic effects by impairing intrarenal blood flow. Some agents (e.g., radiocontrast dye, aminoglycosides, vancomycin, and amphotericin B) have direct renal tubule toxicity, and some (e.g., beta-lactam antibiotics and proton-pump inhibitors) cause allergic interstitial injury. Thus, kidney function should be closely monitored in patients with cirrhosis and ascites while they are receiving these medications. Data on the use of intravenous contrast material in these patients are lacking. Cautious use of intravenous contrast material is recommended, especially in patients with an eGFR of less than 45 ml per minute per 1.73 m2.72
Conclusions
Advances over the past decade in the classification, pathophysiological understanding, diagnosis, and management of AKI in patients with cirrhosis will allow for earlier diagnosis and treatment of HRS-AKI. Since previous studies of the treatment of HRS-AKI used the old criterion of a serum creatinine level exceeding 2.5 mg per deciliter, it is possible that with the new definition, reversal of HRS-AKI with terlipressin and albumin may occur more frequently and with lower doses or for a shorter duration than reported in recent randomized trials. However, the extent to which the presence of systemic inflammation or underlying kidney parenchymal damage limits the efficacy of treatment in patients with HRS-AKI remains unknown. Further development of urinary biomarkers and their inclusion in the diagnostic or treatment algorithm could potentially improve the differential diagnosis of AKI, guide vasoconstrictor therapy for HRS-AKI, and assist in predicting the reversibility of AKI after liver transplantation. Additional investigations are needed to determine the amount of albumin necessary for the prevention and treatment of AKI and HRS-AKI and to support wider use of point-of-care ultrasonography to guide fluid repletion.
A 72-year-old woman with a history of spinal cord injury and resultant quadriplegia from a motor vehicle accident many years earlier presents to the emergency department with fevers, abdominal pain, and increased urinary frequency. She has a neurogenic bladder for which intermittent straight catheterization is performed at home. Over the past 2 years, she has been admitted to the hospital several times for recurrent urinary tract infections (UTIs), for which she has received intravenous antibiotic therapy. Her most recent admission, 3 months ago, was complicated by a diagnosis of nonsevere Clostridioides difficile infection, which was treated with fidaxomicin.
In the emergency department, she is febrile (temperature, 38.4°C) and her condition is hemodynamically stable. Examination reveals a tired-appearing woman with suprapubic tenderness and dry mucous membranes. She reports no diarrhea, nausea, or vomiting. Laboratory studies show a neutrophilic-predominant leukocytosis and mildly elevated creatinine level, and a straight-catheter urinalysis is consistent with infection. Urine culture is pending. As the admitting general medicine provider, you review her previous microbial data and note that cultures have never grown a multidrug-resistant organism. You decide to initiate intravenous ceftriaxone for treatment of her UTI, but you must also consider whether oral vancomycin should be administered prophylactically to reduce her risk of recurrent C. difficile infection.
Treatment Options
Which one of the following approaches would you take for this patient? Base your choice on the published literature, your own experience, published guidelines, and other information sources.
Recommend prophylactic oral vancomycin.
Do not recommend prophylactic oral vancomycin.
To aid in your decision making, we asked two experts in the field to summarize the evidence in favor of approaches assigned by the editors. Given your knowledge of the patient and the points made by the experts, which approach would you choose?
Option 1: Recommend Prophylactic Oral Vancomycin
Option 2: Do Not Recommend Prophylactic Oral Vancomycin.
Do Not Recommend Prophylactic Oral Vancomycin
Andrew M. Skinner, M.D., Erik R. Dubberke, M.D., M.S.P.H.
C. difficile is the most common cause of health care–associated infections in the United States, and clinicians and hospitals continually seek strategies to prevent it.6 One such strategy has been the use of oral vancomycin as secondary prophylaxis when patients receive systemic antibiotics.5 Oral vancomycin is effective at treating C. difficile infection, but owing to a paucity of evidence surrounding the use of oral vancomycin as secondary prophylaxis, the 2017 Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA–SHEA) clinical practice guidelines for C. difficile infection provide no definitive recommendations.6 Concerns regarding oral vancomycin as secondary prophylaxis are the disruptive effect of oral vancomycin on the gut microbiome, which may increase the risk of future C. difficile infection, and the lack of high-quality data supporting the approach.
Oral vancomycin is highly disruptive to the gut microbiome.7,8 Oral vancomycin causes greater depletion of the microbiome Firmicute population than third-generation cephalosporins.8 Firmicutes have been hypothesized to play a critical role in prevention of C. difficile infection.6,7 A study in humans has shown that oral vancomycin, when administered with other antibiotics, causes disruption to the gut microbiome beyond that caused by the other antibiotics, which further contributes to delayed microbiome recovery and greater shedding of antibiotic-resistant organisms after antibiotics are discontinued.7 This additional disruption to the gut microbiome may actually increase the risk of C. difficile infection once oral vancomycin prophylaxis is discontinued and may explain the high incidence of recurrence when oral vancomycin is used to treat C. difficile infection. As such, careful monitoring of patients after discontinuation of secondary prophylaxis with oral vancomycin is essential to understand its true risk–benefit profile.
In addition, there are currently no robust randomized, controlled trial data to support the use of oral vancomycin as secondary prophylaxis.6 Existing literature on this treatment is fraught with biases.6 Many but not all studies suggest that secondary prophylaxis with oral vancomycin may reduce the risk of C. difficile infection during therapy. However, these studies frequently fail to adequately follow patients beyond discontinuation of oral vancomycin. Without such data, the studies lack a critical time frame during which patients would be at increased risk for C. difficile infection.6
Important features to keep in mind when considering the risk–benefit balance of secondary prophylaxis with oral vancomycin in the vignette include the patient’s 2-year history of recurrent UTIs but only one episode of C. difficile infection and the fact that the patient completed fidaxomicin treatment for that episode 3 months earlier. Microbiome recovery starts soon after antibiotics are stopped. Considering that the patient completed treatment with fidaxomicin, an agent that is more sparing of the gut microbiome than oral vancomycin, 3 months ago,9 her risk of C. difficile infection with this course of ceftriaxone should be no higher than it would be if she had never had C. difficile infection previously. We believe that the risk of additional microbiome disruption caused by prophylaxis and the risk of C. difficile infection after discontinuation of the regimen outweigh the potential benefit of preventing infection during treatment for the UTI.
Prevention of C. difficile infection remains a critical issue. Oral vancomycin is highly disruptive to the gut microbiome, more so than cephalosporins alone, which theoretically makes the risk of C. difficile infection once vancomycin is stopped higher than if it had never been administered.7,8 Even tapering vancomycin may not provide benefit to prevent C. difficile infection after secondary prophylaxis with oral vancomycin.9 Given these factors, while we wait for results from randomized, well-controlled trials (e.g., ClinicalTrials.gov number, NCT03462459. opens in new tab), we would recommend against the use of oral vancomycin as secondary prophylaxis for this patient.
Recommend Prophylactic Oral Vancomycin
Jessica Allegretti, M.D., M.P.H.
Recurrent C. difficile infection occurs in about 20% of patients after an initial episode and can be a very challenging condition to treat. Preventive strategies are needed in high-risk patients in whom a recurrent episode could lead to serious complications. In the recently updated American College of Gastroenterology guidelines,1 oral vancomycin was conditionally recommended as prophylaxis for C. difficile infection during subsequent systemic antibiotic courses in patients with a history of C. difficile infection who are at high risk for recurrence. Given the risk factors noted in the vignette, this woman would benefit from oral vancomycin prophylaxis.
The data to support this recommendation include several retrospective cohort studies in which oral vancomycin prophylaxis was used concurrently with systemic antibiotics to reduce the risk of relapse in patients with a history of C. difficile infection.2 The largest of these studies evaluated 557 patients who had received systemic antibiotics within 30 days after diagnosis of a primary or recurrent episode of C. difficile infection.3 Various doses of oral vancomycin prophylaxis were provided to 227 patients for a mean duration of 7 days. In this study, oral vancomycin prophylaxis was found to be effective at preventing another C. difficile infection in patients with a history of recurrent infection (number needed to treat to prevent one infection, 7; P<0.001).3 Another retrospective study showed decreased recurrence of C. difficile infection in the oral vancomycin prophylaxis group as compared with the control group in patients who had had one previous episode.4 Finally, a meta-analysis of nine studies examining oral vancomycin prophylaxis for primary or secondary prevention showed that overall recurrence of C. difficile infection was less likely in patients who received oral vancomycin prophylaxis than in controls (odds ratio, 0.24; 95% confidence interval [CI], 0.13 to 0.48).5 The small sample sizes, varied doses and durations of oral vancomycin prophylaxis, and retrospective design are major limitations to these studies; however, given the overall safety profile of oral vancomycin, the benefits of prophylaxis can, in the right patient, outweigh the risks. Oral vancomycin prophylaxis should be considered in high-risk patients who have been recently treated for C. difficile infection and need subsequent treatment with systemic antibiotics. These high-risk patients include those 65 years of age or older, those with significant immunocompromise, and those hospitalized for severe C. difficile infection within the previous 3 months.
With regard to the patient in the vignette, I would proceed with oral vancomycin prophylaxis given her risk factors. She is a 72-year-old woman with a history of spinal cord injury and resultant neurogenic bladder who has presented with a recurrent UTI. She is likely to continue to need systemic antibiotics, given the need for intermittent straight catheterization and has several risk factors for recurrent C. difficile infection, including her age and her recent C. difficile infection diagnosis. Taken together, I believe the benefits for this patient outweigh the risks, and I would proceed with oral vancomycin prophylaxis.
Melatonin is a natural hormone made by the brain that helps people fall asleep at night. It is also available as a dietary supplement that may help people with sleep disorders such as jet lag and insomnia. Melatonin supplements may work best when taken a few hours before an individual wishes to fall asleep.
People who struggle to doze off are often curious about options to help them sleep. In fact, nearly one in ten U.S. adults Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source take medicine to help them sleep at least four days a week. The number of people in the U.S. that use melatonin supplements has markedly risen over the last 20 years.
Several factors can affect how melatonin supplements work and the best time to take them, including an individual’s health, lifestyle, and other medications they are taking. People considering taking melatonin supplements should be aware of these factors, the various forms of melatonin available, and potential safety concerns related to using this common supplement.
How Melatonin Affects Sleep
Melatonin makes a person feel sleepy through its effect on circadian rhythms, which are the near 24-hour cycles that affect every cell in the human body. One important circadian rhythm is the sleep-wake cycle, which affects when people fall asleep and when they wake up.
While the human brain naturally makes melatonin, supplements are also available in the U.S. over-the-counter. In some countries, melatonin supplements are only available with a prescription.
Naturally-Occurring Melatonin
When it is dark, messages from the eyes send signals to the brain to produce melatonin. After melatonin is released into the bloodstream, it binds to proteins in the brain to make people feel tired. Melatonin also turns off other signals that promote alertness.
Although melatonin is best known for its effects on sleep, it has several other functions in the body. According to current research, melatonin may also:
Support healthy bones
Prevent or reduce damage to cells
Reduce inflammation
Lower blood pressure
Calm anxiety
Block or reduce pain
Affect the reproductive system
Fight tumor development
Melatonin Supplements
Melatonin supplements have a variety of potential uses. Melatonin may help people who have low levels of natural melatonin and difficulty sleeping. When taken a few hours before their bedtime, melatonin helps to reinforce their circadian rhythm. For this reason, melatonin supplements may help some people whose sleep schedules differ from their circadian rhythms.
Melatonin supplements may help reduce symptoms of jet lag. Studies have found that melatonin improves the length and quality of sleep after eastward air travel. People who take melatonin for jet lag after air travel also adjust to new time zones more quickly than people who do not take melatonin.
Melatonin may also help people who constantly fall asleep and wake up later than they want or need to sleep. While some people may stay up late for work, school, or social reasons, some people have a sleep disorder involving markedly delayed circadian rhythms even when they could go to sleep on time. Studies have found that melatonin helped people with this condition Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source fall asleep faster and sleep longer.
Melatonin may also help people who work night shifts to sleep longer and better during the daytime. However, more research is needed to better understand how melatonin works, when night workers should take it, and what dosage works best for this purpose.
Experts have mixed opinions on whether melatonin helps people with insomnia to sleep. Melatonin may help people with insomnia to fall asleep faster, but only by a few minutes.
Supplemental melatonin does not appear to keep people from waking up during the night.
How Fast Does Supplemental Melatonin Work?
The brain ordinarily makes more melatonin about one to two hours before bedtime and most people start to feel sleepy Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source about two hours after melatonin levels rise. Similarly, most people will feel the effects of supplemental melatonin about two hours after taking it. Most research has studied melatonin given one to two hours before bedtime.
Supplemental melatonin comes in many different forms. The way that a supplement or medicine is made affects how quickly it works Trusted Source Merck Manual First published in 1899 as a small reference book for physicians and pharmacists, the Manual grew in size and scope to become one of the most widely used comprehensive medical resources for professionals and consumers. View Source . Therefore, different types of melatonin supplements may work more quickly or slowly. People considering taking melatonin supplements should talk to their doctors about what form of melatonin may work best for them.
Extended-Release Melatonin
Some pills have a special coating or additive to slow the release of the active ingredient. These kinds of medications and supplements are sometimes called extended-release, controlled-release, sustained-release or modified-release. Extended-release pills take effect more slowly and work longer than regular pills. Extended-release pills should never be crushed, cut, or chewed as doing so could be dangerous.
Some melatonin supplements are extended-release pills. While data is limited on how quickly extended release melatonin takes effect, extended release melatonin pills may reach peak levels Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source in the bloodstream later than fast-release melatonin. Experts believe that extended-release melatonin may be better at reducing the number of times people wake up after falling asleep.
Melatonin Patches
The effect of a supplement or medication can also be slowed by releasing it through a patch on the skin. Melatonin patches release melatonin into the bloodstream more slowly than melatonin pills. Studies have also found that melatonin patches reduce time awake after falling asleep and increase time spent sleeping.
Melatonin Melts
Drug makers may also adjust a supplement or medication to make it act more quickly. Some melatonin supplements are available as fast-acting melts that dissolve under the tongue or between the gums and the cheek. Medications and supplements taken in this way are absorbed more quickly than gummy vitamins were.
People should take supplements and medications only as instructed by their doctor or as indicated on the label. Pills that are designed to be swallowed whole may not work well if taken differently than directed.
Melatonin Gummies
Melatonin supplements are widely available as gummies. Researchers have not yet discovered how quickly melatonin gummies take effect. However, studies of gummy vitamins may shed some light on how melatonin gummies compare to melatonin pills.
To date, research findings on how gummy vitamins compare to vitamin pills have been conflicting. While some studies have found that gummy vitamins are better absorbed Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source than pills, others found that gummy vitamins were similar to vitamin pills Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. View Source .
Parents and guardians should take care to keep melatonin gummies out of children’s reach. Children may confuse Trusted Source Centers for Disease Control and Prevention (CDC) Blog As the nation’s health protection agency, CDC saves lives and protects people from health threats. View Source gummy supplements with candy and gummies may be a choking hazard for young children.
How to Take Melatonin
Melatonin is usually taken one to two hours before bedtime. Travelers taking melatonin to prevent jet lag can time their dosage on their day of arrival based on the desired bedtime at their destination. To reduce the symptoms of jet lag, melatonin can continue to be taken for up to five days after arrival.
Sleep experts have not agreed upon a standard dosage of melatonin Trusted Source Merck Manual First published in 1899 as a small reference book for physicians and pharmacists, the Manual grew in size and scope to become one of the most widely used comprehensive medical resources for professionals and consumers. View Source . The adult dosage of melatonin is usually between 1 to 5 milligrams. For children, experts recommend lower doses of melatonin Trusted Source UpToDate More than 2 million healthcare providers around the world choose UpToDate to help make appropriate care decisions and drive better health outcomes. UpToDate delivers evidence-based clinical decision support that is clear, actionable, and rich with real-world insights. View Source than for adults. Parents and guardians should speak with their child’s doctor before giving melatonin to children, and should follow their doctor’s advice on the dosage.
Some medications, herbs, and beverages can increase natural melatonin levels and may magnify the supplement’s effect. People who take melatonin along with any of the following should talk to their doctors about the appropriate dosage:
Higher doses of melatonin do not appear to be more effective than lower doses, but may have higher risks of side effects. For that reason, people taking melatonin supplements should start at a lower dose. If they decide to try a higher dose, then they should increase the dose slowly until they find a dose that works for them. People should talk to their doctor if sleeping problems do not improve after taking melatonin.
Are There Side Effects to Melatonin?
The side effects of melatonin have not been studied in-depth. However, health experts believe that melatonin is probably safe for most healthy adults. The most common side effects reported by people taking melatonin are:
Feeling sleepy during the day
Headache
Dizziness
Upset stomach
Irritability
Strong nightmares
Temporary depression
People should not drive or operate heavy machinery within four to five hours after taking melatonin. Melatonin supplements should never be taken with alcohol or other sleeping pills as the combined effects may cause breathing problems or make people too sleepy.
Melatonin supplements may be unsafe for people who are trying to get pregnant. Health experts do not yet know whether melatonin is safe to take during pregnancy or while breastfeeding. People who are pregnant, trying to get pregnant or breastfeeding should speak to their doctors before starting melatonin supplements.
Melatonin supplements interact with many medications, including birth control pills, blood pressure medicine, antiseizure medicine, medicine to weaken the immune system, and blood thinners. People who take any of these medicines should speak to their doctor before trying melatonin supplements.
Melatonin is not regulated by the U.S. Food and Drug Administration (FDA). Research has found that the levels of melatonin in over-the-counter supplements may be different from the dosage listed on the labels. People who use melatonin can find reputable sleep supplements by talking to a doctor, pharmacist, or selecting products that undergo third-party testing.
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis. GMB are highly recurrent mainly because of radio- and chemoresistance. Radiotherapy with Temozolomide (TMZ) is until today the golden standard adjuvant therapy, however, the optimal treatment of recurrent glioblastoma remains controversial. Ouabain belongs to the Cardiotonic Steroids (CTS) the natural ligands of the Na/K-ATPase (NKA). It is established that the NKA represents a signal transducer with either stimulating or inhibiting cell growth, apoptosis, migration and angiogenesis. Over the last decade evidence grew that CTS have anti-tumor properties especially in GBM.
Discussion
The results show that with regard to cell migration as well as plasma cell membrane depolarization Ouabain indeed has different effects on the two GBM cell lines, the TMZ-sensitive LN229 and the TMZ-resistant T98G cell line, similar to the results found by the group of Chen and coworkers with respect to apoptosis [46]. The authors showed that in T98G cells apoptosis was induced at significantly lower Ouabain concentrations (0.1 μM) as compared to LN229 cells (> 1 µM). However, in our setting, LN229 cells did not show any reaction to Ouabain neither in the migration assay nor in the cell membrane potential assay, even at higher concentrations (> 10 µM). For this discrepancy we do not have a plausible explanation and further studies are needed.
In contrast, the TMZ-resistant cell line T98G showed a marked inhibition of migration at rather low doses of Ouabain (0.01–0.1 µM), which correlated significantly with an increase in cell membrane depolarization (p = 0.002). A similar opposite reaction pattern to Ouabain was observed in the LN229 and T98G cells in the Bcl-2 analysis i.e., only in the T98G cell line we saw a down-regulation whereas LN229 did not show any reaction. The fact, that the Bcl-2 down-regulation was detected only at very low Ouabain concentrations (0.01 nM) must be interpreted with caution, we will discuss this issue further down. In summary, while the TMZ-resistant T98G cell line is sensitive to Ouabain, the TMZ-sensitive LNN29 cell line seems to be resistant to Ouabain.
Interestingly, migrating GBM cells are per se resistant to apoptosis. Joy and coworkers revealed an activation of the phosphoinositide 3-kinase (PI3-K) survival pathway by migrating glioma cells, which renders them resistant to apoptosis [68]. Applying a specific inhibitor of PI3-K (LY294002) to migrating cells the phosphorylation of Akt was inhibited and consequently, an increased rate of apoptosis was seen. Yang and coworkers could demonstrate that Ouabain is able to prevent phosphorylation of Akt and mTOR, inhibiting cell migration and enhancing apoptosis [47]. Lefranc and coworkers also stressed the importance of an inverse relationship between migration and apoptosis in GBM and the key role of the PI3-K/Akt pathway [69].
The fact that the T98G cells reacted to the cell migration assay as well as to the plasma cell membrane potential assay at similar Ouabain concentrations strongly indicates a causal relationship between migration inhibition, depolarization of the cell membrane, and consequent induction of apoptosis.
Many authors described a correlation between plasma cell membrane (PCM) depolarization and early apoptosis, but it is not fully clear whether it constitutes a causal relationship or a mere epiphenomenon. There is evidence that PCM depolarization is a prerequisite for apoptosis. Suzuki-Karasaki and coworkers described the disruption of intracellular K + and Na + concentrations as a basic important event leading to depolarization, cell shrinkage, and hence apoptosis [70]. Bortner and coworkers reported in Jurkat T-cells a PCM depolarization immediately after application of diverse apoptotic stimuli (anti-Fas antibody, thapsigargin and the calcium ionophore A23187) followed by cell shrinkage [71]. Moreover, an early increase in intracellular Na + as well as inhibition of K + uptake was observed in response to anti-Fas, indicating an inactivation of the Na + /K + -ATPase. Interestingly, Ouabain enhanced anti-Fas-induced apoptosis. Finally, applying an anti-apoptotic signal, i.e., protein kinase C, did not only inhibit apoptosis but also prevent cell membrane depolarization in response to anti-Fas. Thus, the authors concluded that cell membrane depolarization per se is a crucial early step in anti-Fas-induced apoptosis [71].
Interestingly, the PCM depolarization was not a short-lasting phenomenon, as known from electrically excitable cells, but rather was sustained. We also saw in the T98G cell line over time (up to 6 h) a sustained PCM depolarization. This sustained PCM depolarization is an indication that upon apoptotic stimulation, the cells lose their ability to repolarize.
At this point it is important to mention the role of Bcl-2, the classic anti-apoptotic protein of the Bcl-2 family [72]. Usually, they are localized at the outer mitochondrial membrane, but recent studies discovered intracellular truncated forms in the neighborhood of the plasma cell membrane [73]. The most known function of Bcl-2 is exerted by inhibiting the oligomerization of Bcl-2-associated X protein (BAX) and Bcl-2-associated agonist of cell death protein (BAD) hereby preventing their pro-apoptotic effect.
But already decades ago the importance of Bcl-2 in modulating the plasma cell membrane has been stressed. We mentioned above the works of Gilbert and coworkers who observed that overexpression of the anti-apoptotic Bcl-2 gene is associated with membrane hyperpolarization rendering cells more resistant to radiation-induced apoptosis [61]. Further studies revealed that Bcl-2 itself has pore-forming domains similar to that of bacteria toxins and that the activation of K + channels by the myeloid leukemia cell differentiation protein (Mcl-1), a member of the Bcl-2 family, results in plasma cell membrane hyperpolarization [59, 74]. Finally, Lauf and coworkers could demonstrate a direct co-localization of Bcl-2 specifically with the NKA in the cell membrane providing the missing link to the hypothesized interaction between Bcl-2 and NKA [63].
The numerous functions of Ouabain on intracellular pathways are well described; one of them is the down-regulation of Bcl-2/Mcl-1 by accelerating its proteasomal degradation via reactive oxygen species (ROS) generation [75].
So, it seems, that Ouabain can not only depolarize the plasma cell membrane directly by inhibiting the NKA but additionally by down-regulating Bcl-2. We saw only in the TMZ-resistant T98G cell line a Bcl-2 down-regulation after treatment with Ouabain for 24 h at very low concentrations (0.01 nM) which unfortunately did not correlate with the concentrations, at which we observed PCM depolarization and cell migration inhibition. Consequently, in our study we could not confirm that Bcl-2 down-regulation contributes to PCM depolarization.
But with caution, we may interpret the down-regulation of Bcl-2 as a kind of sensitizing effect to facilitate e.g., apoptosis. Only recently, a Bcl-2 effect on cell migration was discovered [76,77,78]. In Fig. 1b we see a slight inhibitory effect of Ouabain on cell migration at very low (≤ 0.01 nM) concentrations which correlates exactly with those of Bcl-2 down-regulation (Fig. 5). As we outlined above, inhibition of cell migration is a prerequisite to apoptosis. Additional studies in future are needed and may focus not only on Bcl-2 but also on Mcl-1 expression [61, 63]. Interestingly, Wang and coworkers demonstrated that Mcl-1 causes a hyperpolarization of the PCMP through activation of K + channel activity [59] hereby preventing apoptosis.
At this point it should be stressed that Ouabain is known to have significant effects at nanomolar concentrations [56], e.g., at 0.1 to 10 nM the NKA is stimulated in non-malignant (cardiac and neuronal) cells, interestingly, via the high glycoside affinity α3 isoform [79].
As outlined above the PI3-K/Akt pathway is one important modulator of cell migration. We revealed in T98G cells an increase in p-Akt after 24 h treatment with 0.1 µM Ouabain. In contrast, LN229 cells did not show any change in p-Akt. It contradicts the anti-migratory effect of Ouabain which we revealed at 0.1 µM in T98G cells. In fact, we expected a p-Akt down-regulation, at least after prolonged 24 h treatment similar to Chen and coworkers, who observed a p-Akt down-regulation at 2.5 µM Ouabain in U-87 GBM cells [46].
The significant decreased level of pan-Akt after 24 h Ouabain treatment at 1 µM hints to a different mechanism by which Ouabain exerts its antitumor effects. You and coworkers were concerned about the short-lasting effects of phosphorylation inhibitors and developed a pan-AKT degrader by conjugating the Akt-phosphorylation inhibitor GDC-0068 to Lenalidomide. He showed that this compound (INY-03–041) induced significant degradation of all Akt isoforms at 24 h and, interestingly, improved the anti-proliferative effects compared to GDC-0068 alone [80].
Ouabain is known to contribute to degradation of several compounds in the signalosome by internalization and disturbed intracellular trafficking [81, 82]. With specific respect to the epidermal growth factor receptor (EGFR) Hafner and coworkers described in lung cancer A549 cells a specific phenomenon called endosomal arrest. After treatment with Ouabain, Digoxin, or Acovenoside they revealed persistent granules with internalized EGF-receptor without further degradation [83].
This endosomal arrest may be considered as a crucial checkpoint in cell biology [84] by diverting growth factors either to the recycling or the degradation pathway. In case of prolonged endosomal arrest, however, they are simply “stuck there”, losing any biological function.
We assume that pan-Akt like other compounds of the signalosome is endocytosed upon prolonged Ouabain stimulation and undergoes an endosomal arrest together with NKA α-subunits and EGFR. Indeed, it was shown that endosomal Akt is associated with the intracellular trafficking of growth factor receptor complexes and thus modifying their activity in a time and location dependent manner [85].
The peak in Akt activation (p-Akt Ser473) at prolonged lower doses of Ouabain might serve as a stimulus for inducing its degradation. Kometiani and coworkers stressed the time factor in intracellular activation processes i.e., while short term activation of ERK1/2 induced cell proliferation, sustained ERK1/2 activation resulted in increased expression of the cyclin-dependent kinase inhibitor 1 (p21Cip1) resulting in growth arrest [86]. Hence, this could be the main mechanism by which e.g., pan-Akt is down-regulated resulting in inhibition of migration and induction of apoptosis. Further studies certainly are here needed.
The reciprocal response of LN229 and T98G cells to Ouabain resp. Temozolomide is striking and may have significant clinical consequences. The underlying mechanisms are not yet known. There is evidence that Ouabain induces different endocytotic trafficking and signaling pathways according to the EGFR mutation status, the NKA isoforms [56, 87] and other not yet fully analyzed factors. Many authors described the interaction between NKA and EGFR e.g., Liu and Shapiro analyzed in the renal cell line LLC-PK1 the role of the signalosome in the process of endocytosis and demonstrated that Ouabain-stimulated endocytosis of the NKA is dependent on Caveolin-1 and Clathrin as well as the activation of c-Src, transactivation of EGFR and activation of phosphoinositide 3-kinase (PI3K). They showed that c-Src, EGFR, and the extracellular signal-regulated kinases 1 and 2 (ERK1/2) all were endocytosed along with the plasmalemmal NKA [81].
We did not analyze the NKA isoforms in our GBM cell lines but as shown by Chen and coworkers the T98G cell line is characterized by a high NKA α3/ α1 isoform ratio. He stressed that the high expression of the α3 isoform in the T98G cell line was correlating with a higher sensitivity to the apoptosis inducing effect of Ouabain [46]. Xiao and coworkers proved that the knockdown of the α3 isoform with siRNA impaired the anti-proliferative effect of Ouabain, indicating that Ouabain preferentially binds to the NKA α3 isoform [88]. Future studies are warranted to analyze the exact role of EGFR- and NKA isoform expression at the cell surface in directing ouabain-induced signaling either towards enhanced or reduced cell proliferation and migration.
Last, but not least, we could demonstrate for the first time an anti-angiogenic effect of Ouabain at low concentrations (0.01 µM) which correlated significantly with the inhibitory effect on cell migration (Fig. 7). Angiogenesis is considered as prerequisite for migration and invasion of tumor cells [89,90,91] and as such it constitutes an important target for cancer therapy, especially the hypervascularized gliomas. Bevacizumab a humanized monoclonal antibody against VEGF was approved in the treatment of recurrent GBM but, at least as monotherapy, it prolonged only the progression-free survival, but not the overall survival [92, 93]. The effect of Ouabain on angiogenesis resp. endothelial cells is rarely investigated [94, 95]. Trenti and coworkers revealed that Digitoxin in therapeutic range (1–25 nM) inhibited effectively angiogenesis via focal adhesion kinase (FAK) inhibition (51). At the same time Digitoxin as well as Ouabain protected HUVEC cells from apoptosis induced by growth factor deprivation (51). Dual actions of all CTS—dependent on cell types and dose regimen—remain a scientific and therapeutic challenge we have to accept and address in future studies.
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