Tag: UTIs

Scientists Identify a Type of Brain Cell That is a Master Controller of Urination

Photo by Jan Antonin Kolar on Unsplash

Researchers have identified a subset of brain cells in mice that act as the master regulators of urination.

The research, published as a Reviewed Preprint in eLife, is described by editors as an important study with convincing data showing that oestrogen receptor 1-expressing neurons (ESR1+) in the Barrington’s nucleus of the mouse brain coordinate both bladder contraction and relaxation of the external urethral sphincter.

Urination requires the coordinated function of two units of the lower urinary tract. The detrusor muscle of the bladder wall relaxes to allow the bladder to fill and empty, while the external sphincter opens when it’s appropriate to allow urine to flow out, but otherwise keeps tightly shut.

“Impairment of coordination between the bladder muscle and the sphincter leads to various urinary tract dysfunctions and can significantly degrade a person’s quality of life,” says first author Xing Li, Advanced Institute for Brain and Intelligence, School of Physical Science and Technology, Guangxi University, Nanning, China. “But although we know the individual nerve signalling pathways that control each of these urinary tract components, we don’t know which brain areas ensure they cooperate at the right time.”

To explore this, the authors used state-of-the-art live cell imaging to study the activity of brain cells in anaesthetised and awake mice during urination. They focused on a brain region called the pontine micturition centre (PMC), otherwise known as the Barrington’s nucleus, and compared the activity of different PMC nerve cell subtypes.

In their first experiments, they measured the activity of the cells as the bladder empties by measuring changes in levels of calcium. This revealed that the electrical firing rate of a subset of PMC cells expressing estrogen receptors (PMCESR1+ cells) was tightly linked to bladder emptying. When they combined this with monitoring bladder physiology, they found that it was not only the timing of PMCESR1+ cell activity that correlated with bladder emptying, but the strength of cell electrical activity, too.

Next, they tested what happened to urination if they blocked or triggered the PMCESR1+ cells. They found that when PMCESR1+ cell activity was blocked, the amount of urine the mice passed was significantly reduced and ongoing urination was suspended from the moment the cells were inactive. To understand the mechanism behind this, they measured the activity of the bladder muscle and sphincter. They discovered that both increase of bladder pressure and sphincter muscle bursting activity associated with bladder emptying both stopped when PMCESR1+ cell activity was blocked during an ongoing voiding even. Similarly, when PMCESR1+ cells were artificially activated using light, bladder emptying occurred 100% of the time. This suggests that PMCESR1+ cells work as a reliable master switch that either initiates or suspends bladder emptying.

To test whether PMCESR1+ cells can influence bladder emptying independently of controlling the sphincter, they disconnected either the nerve carrying messages from the brain to the sphincter, or the nerve carrying messages from the brain to the bladder. They found that PMCESR1+ cell control of the bladder was fully operational even when communication to the sphincter was blocked, and vice versa. This showed the cells could control the bladder and sphincter independently of one another, but the question remained: could they coordinate the action of the bladder muscle and sphincter together? That is, operate them in a controlled, perfectly timed manner, to trigger bladder emptying when appropriate?

To explore this, they simultaneously recorded bladder pressure and electromyography measurements of sphincter activity. The timing of bladder pressure changes immediately before sphincter bursting activity was consistent for both spontaneous bladder emptying and emptying caused by activating the PMCESR1+ cells, showing that these cells can coordinate the two steps in a precisely temporal sequence and controlled way.

“Our study shows that a subset of cells in the Barrington’s nucleus of the brain can initiate and suspend bladder emptying with 100% accuracy when needed, for example, to release only a small volume for landmarking by animals, or for a human to urinate into a small sample tube for a health check,” concludes senior author Xiaowei Chen, Third Military Medical University, and Chongqing Institute for Brain and Intelligence, China. “While other cells will no doubt be involved in perfect urination control, our pinpointing of PMCESR1+ cells’ crucial role in bladder–sphincter coordination will aid the development of targeted therapies for treating urination dysfunction caused by brain or spinal cord injury or peripheral nerve damage.”

Source: eLife

Drinking Plenty of Water may Actually be Good for You

Photo by Amanda María on Unsplash

Public health recommendations generally suggest drinking eight cups of water a day. And many people just assume it’s healthy to drink plenty of water.

Now researchers at UC San Francisco have taken a systematic look at the available evidence, analysed 18 randomised controlled trials. In their review, published in JAMA Network Open, they concluded that drinking enough water can help with weight loss and prevent kidney stones, as well as migraines, urinary tract infections and low blood pressure.

“For such a ubiquitous and simple intervention, the evidence hasn’t been clear, and the benefits were not well established, so we wanted to take a closer look,” said Benjamin Breyer, MD, MAS, professor and chair of the UCSF Department of Urology.

“The amount of rigorous research turned out to be limited, but in some specific areas, there was a statistically significant benefit,” said Breyer, the senior author of the study. “To our knowledge, this is the first study assessing the benefits of water consumption on clinical outcomes broadly.”

Strong evidence suggested that drinking eight cups of water a day significantly decreased the likelihood of getting another kidney stone. Several studies found that drinking about six cups of water a day helped adults lose weight. But a study that included adolescents found that drinking a little more than eight cups of water a day had no effect.

Still, the authors said that encouraging people to drink water before meals would be a simple and cheap intervention that could have huge benefits, given the increased prevalence of obesity.

Other studies indicated that water can help prevent migraines, control diabetes and low blood pressure, and prevent urinary tract infections. Adults with recurrent headaches felt better after three months of drinking more water. Drinking about four more cups of water a day helped diabetic patients whose blood glucose levels were elevated.

Drinking an additional six cups a day of water also helped women with recurrent urinary tract infections. It reduced the number of infections and increased the amount of time between them. Drinking more water also helped young adults with low blood pressure.

“We know that dehydration is detrimental, particularly in someone with a history of kidney stones or urinary infections,” Breyer said. “On the other hand, someone who suffers from frequent urination at times may benefit from drinking less. There isn’t a one size fits all approach for water consumption.”

Source: University of California – San Francisco

Cranberry Products for UTI Prevention Really Do Work

A global study looking at the benefits of cranberry products has determined that cranberry juice, and its supplements, reduce the risk of repeat symptomatic UTIs in women by more than a quarter. The study researchers, from Flinders University and The Children’s Hospital at Westmead, also found that was reduced in children by more than half, and in people susceptible to UTI following medical interventions by about 53%.

Cranberry juice and healthcare supplements that commonly include the fruit, such as capsules and tablets, have long been promoted as a readily available solution to ward off the infection but the most recent review in 2012, with evidence from 24 trials, showed no benefit from the products.

The medical scientists behind this updated review published in Cochrane Reviews aimed to update these findings, as by looking at 50 more recent trials that included almost 9000 participants.

“This incredible result didn’t really surprise us, as we’re taught that when there’s more and better evidence, the truth will ultimately come out. UTIs are horrible and very common; about a third of women will experience one, as will many elderly people and also people with bladder issues from spinal cord injury or other conditions,” says the study lead author Dr Gabrielle Williams.

“Even back in 1973, my mum was told to try cranberry juice to prevent her horrible and frequent UTIs, and for her it’s been a saviour. Despite me niggling in her ear about evidence, she’s continued to take it daily, first as the nasty sour juice and in recent years, the easy to swallow capsules. As soon as she stops, wham the symptoms are back. As usual, it turns out that mum was right! Cranberry products can help some women prevent UTIs.”

Flinders University epidemiologist Dr Jacqueline Stephens, a co-author of the study, says if the UTI persists untreated it can move to the kidneys and cause pain and more complications, including sepsis in very severe cases, so prevention is the most effective way to reduce risks.

“Most UTIs are effectively, and pretty quickly, treated with antibiotics, sometimes as little as one dose can cure the problem. Unfortunately, in some people UTIs keep coming back. Without being sure if or how it works, some healthcare providers began suggesting it to their patients. It was a harmless, easy option at the time. Even centuries ago, Native Americans reportedly ate cranberries for bladder problems, leading somewhat more recently, to laboratory scientists exploring what it was in cranberries that helped and how it might work.”

“The studies we looked at included a range of methods to determine the benefits of cranberry products. The vast majority compared cranberry products with a placebo or no treatment for UTI and determined drinking cranberries as a juice or taking capsules reduced the number of UTIs in women with recurrent cases, in children and in people susceptible to UTi’s following medical interventions such as bladder radiotherapy.”

“It’s also important to consider that few people reported any side effects with the most common being tummy pain based on the results. We also did not find enough information to determine if cranberry products are more or less effective compared with antibiotics or probiotics in preventing further UTIs.”

The data also doesn’t show any benefit for elderly people, pregnant women or in people with bladder emptying problems.

The study’s senior author, Professor Jonathan Craig, says the real benefits of cranberry products became clear when the researchers expanded the scope of the review to include the most recently available clinical data.

“This is a review of the totality of the evidence and as new evidence emerges, new findings might occur. In this case, the new evidence shows a very positive finding that cranberry juice can prevent UTI in susceptible people,” says Professor Craig.

“We have shown the efficacy of cranberry products for the treatment of UTIs using all the evidence published on this topic since the mid-nineties. The earlier versions of this review didn’t have enough evidence to determine efficacy and subsequent clinical trials showed varied results, but in this updated review the volume of data has shown this new finding.”

The study authors conclude that while cranberry products do help prevent UTIs in women with frequent recurrence, more studies are needed to further clarify who with UTI would benefit most from cranberry products.

Source: Flinders University

Oestrogen may Protect against Delirium in Older Women with UTIs

Photo by Karolina Grabowska

Delirium is common among women with urinary tract infections (UTIs) – especially those who have experienced menopause. In mouse models, researchers have been able to prevent symptoms of the condition by administering oestrogen. Their study was published in the peer-reviewed journal Scientific Reports.

“There has been a resurgence of interest in hormone replacement therapy, and this study, which builds on our previous work, shows that it may be a tool to mitigate delirium,” said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai and senior author of the study. “I think it is a major step toward a clinical trial of oestrogen in human patients with UTIs.”

Lahiri said that delirium is a common problem in older women with UTIs.

“Even as a medical student, you know that if an older woman comes to the hospital and she’s confused, one of the first things you check is whether the patient has a UTI,” Lahiri said.

In previous studies, Lahiri’s team found a connection between delirium and an immune-regulating protein called interleukin 6 (IL-6). Events such as lung injury or UTI cause IL-6 to travel through the blood to the brain, causing symptoms such as disorientation and confusion. Oestrogen is a known suppressor of IL-6, so the investigators designed experiments to test its effects on UTI-induced delirium.

The researchers compared pre- and postmenopausal mice with UTIs and observed their behaviour in several types of specialised environments. They found that the mice in which menopause had been induced exhibited symptoms of delirium, such as anxiousness and confusion, while the others did not.

When they treated the mice with oestrogen, levels of IL-6 in the blood and delirium-like behaviour were greatly reduced. The behavioural differences were not related to UTI severity, as bacterial levels in the urine weren’t markedly different between the two groups, Lahiri said.

The investigators also looked at the direct effects of oestrogen on neurons, using what Lahiri called a “UTI in a dish.”

“We exposed individual neurons to an IL-6 inflammation cocktail to create UTI-like injury,” Lahiri said. “But when we added oestrogen to the cocktail, it mitigated the injury. So, we showed that there are at least two ways that oestrogen helps reduce symptoms of delirium. It reduces IL-6 levels in the blood and protects the neurons directly.”

Just how oestrogen acts to protect neurons is still unexplained. And before conducting a clinical trial, researchers need to identify which patients with UTIs are most likely to experience delirium and at what point oestrogen treatment might be most effective.

“Currently, it is common practice to treat UTI-induced delirium using antibiotics, even though there are no clinical trials that indicate this practice is effective and it is not supported by clinical practice guidelines,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This work is an important step in determining whether modulating immune response via oestrogen replacement or other means is a more effective treatment.”

The team is also working to understand the different effects of delirium on females versus males, which was not a topic of this study. Effective treatment of delirium could be of long-term importance, Lahiri said, because it is a known risk factor for long-term cognitive impairments, such as Alzheimer’s disease and related dementia.

Source: Cedars-Sinai Medical Center

New Drug Combination More Effective in Treating Urinary Tract Infections

E. Coli bacteria. Image by CDC
E. Coli bacteria. Image by CDC

An international study published in JAMA comparing new and older treatments against complicated urinary tract infections has found that a new drug combination of cefepime and enmetazobactam to be more effective, especially against drug-resistant strains.

Researchers in the ALLIUM Phase 3 clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections (UTIs) and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than the standard combination of piperacillin and tazobactam. UTIs are considered complicated when they are associated with risk factors such as fevers, sepsis, urinary obstruction or catheters, that increase the danger of failing antibiotic therapy.

“This new antibiotic was superior to the standard-of-care therapy,” said Professor Keith Kaye at Rutgers Robert Wood Johnson Medical School, the study’s lead author. “It represents an exciting option for treatment.”

Prof Kaye added this drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme the bacteria produce. ESBL-producing bacteria can’t be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.

“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Prof Kaye said.

The trial was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. More than 1000 patients participated in the study. Some 79% of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9% of those receiving the conventional treatment of piperacillin and tazobactam.

Of the 20% of patients from the overall group belonging to the subset of those with ESBL infections, 73% receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51% on the standard therapy.

The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been fast-tracked for approval by the U.S. Food and Drug Administration (FDA).

Source: Rutger University

New Study Explains Diabetes and UTI Link

Huge clumps of E. coli (red) infecting diabetic mouse bladder. Photo: Soumitra Mohanty

Lower immunity and recurring infections are common in type 1 and type 2 diabetes. Research has shown that the immune system of people with diabetes has lower levels of the antimicrobial peptide psoriasin, which compromises the urinary bladder’s cell barrier, increasing the risk of urinary tract infection. The study is published in Nature Communications.

One effect of diabetes is that it compromises the innate immune system, leaving many people with increased susceptibility to regular infections, such as urinary tract infections (UTI)s caused by E. coli bacteria. In people with diabetes, these are more likely to lead to general blood poisoning, sepsis, originating in the urinary tract.

An endogenous antibiotic

Karolinska Institutet researchers investigated whether glucose levels in people with diabetes (type 1, type 2, or prediabetes) are linked with psoriasin, an endogenous antibiotic which is a part of the innate immune system.

Using samples of urine, bladder cells and blood serum from patients, the researchers analysed levels of psoriasin and other peptides necessary for ensuring that the bladder mucosa remains intact and protects against infection. The findings were then verified in mice and urinary bladder cells with and without infection.

“We found that high glucose concentrations reduce the levels of the antimicrobial peptide psoriasin, while insulin has no effect,” said Professor Annelie Brauner, who led the study. “People with diabetes have lower levels of psoriasin, which weakens the cells’ protective barrier function and increases the risk of bladder infection.”

Oestrogen therapy reduced bacterial population

Professor Brauner’s research group has previously shown that oestrogen restores the protective function of bladder cells in humans and mice and thereby help to regulate the immune response to a UTI. The researchers therefore tested how oestrogen treatment affects infected cells exposed to high glucose concentrations. They found that the treatment boosted levels of psoriasin and reduced bacterial populations, indicating that the treatment may have an effect also among patients with diabetes.

“We now plan to probe deeper into the underlying mechanisms of infections in individuals with diabetes,” said lead author Soumitra Mohanty. “The ultimate goal is to reduce the risk of infection in this growing patient group.”

Source: Karolinska Institutet

Community-acquired Antimicrobial Resistant UTIs can be More Deadly

Pseudomonas
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr.

A study from Australia’s scientific organisation CSIRO has revealed that antimicrobial resistant (AMR) bacteria in urinary tract infections are more lethal, especially Enterobacteriaceae. The findings are published online in Open Forum Infectious Diseases.

Antimicrobial resistance (AMR) bacteria can be passed between humans: through hospital transmission and community transmission. While hospital acquired resistance is well researched, there are few studies focusing on the burden of community transmission.

To address this, the study analysed data from 21 268 patients across 134 Queensland hospitals who acquired their infections in the community. The researchers found that patients were almost two and a half (2.43) times more likely to die from community acquired drug-resistant UTIs caused by Pseudomonas aeruginosa and more than three (3.28) times more likely to die from community acquired drug-resistant blood stream infections caused by Enterobacteriaceae than those with drug-sensitive infections. The high prevalence of UTIs make them a major contributor to antibiotic use, said CSIRO research scientist, Dr Teresa Wozniak.

“Our study found patients who contracted drug-resistant UTIs in the community were more than twice as likely to die from the infection in hospital than those without resistant bacteria,” Dr Wozniak said. “Without effective antibiotics, many standard medical procedures and life-saving surgeries will becoming increasingly life-threatening. “Tracking the burden of drug-resistant infections in the community is critical to understanding how far antimicrobial resistance is spreading and how best to mitigate it.”

The study’s findings will provide further guidance for managing AMR in the community, such as developing AMR stewardship programs that draw on data from the population being treated.

CEO of CSIRO’s Australian e-Health Research Centre, Dr David Hansen, said the magnitude of the AMR problem needs to be understood to mitigate it. “Tracking community resistance is difficult because it involves not just one pathogen or disease but multiple strains of bacteria,” Dr Hansen said. “Until now we haven’t been using the best data to support decision making in our fight against AMR. Data on community acquired resistance is an important contribution to solving the puzzle. “Digital health has an important role in using big data sets to describe patterns of disease and drive important population health outcomes.”

Source: CSIRO

Treatment for Women with Frequent UTIs Found Wanting

Photo by Sora Shimazaki from Pexels

Women with frequent urinary tract infections report being unhappy at perceived overuse of antibiotics by their doctors and with the limited treatment options available to them, according to a new study.

The study highlights the need to get to the cause of women’s recurrent UTIs, to come up with prevention and to avoid unnecessary antibiotics use, which can eventually lead to resistance.

“Since there’s already a common treatment for UTIs – antibiotics – many doctors don’t see a need to do anything differently,” said senior author Dr Ja-Hong Kim, an associate professor at UCLA Health. “This study really gave us insight into the patient perspective and showed us those with recurrent UTIs are dissatisfied with the current management of the condition. Continued episodes can have a major impact on their quality of life.”

More than half of women will develop a UTI at some point, and roughly 1 in 4 will have repeat infections that can last for years. Many with recurrent infections will be prescribed antibiotics frequently over their lifetime.

The researchers conducted focus groups with 29 women with recurrent UTIs, which were defined as two infections in six months or three in a year. Participants were asked about their knowledge of UTIs and prevention strategies and about treatment impact on their quality of life. Two common themes were revealed: fear and frustration.

Participants were concerned foremost about antibiotic use, with a fear of unnecessary antibiotic prescriptions and developing resistance. Some also reported antibiotic treatment for symptoms which may have signified other genitourinary conditions, like an overactive bladder.

“Other bladder diseases can cause symptoms similar to recurrent UTIs, such as urination frequency and urgency, pain with urination and blood in the urine,” Dr Kim said. “These could be signs of an overactive bladder, interstitial cystitis, kidney or bladder stones, or something more serious, like bladder cancer. As physicians, we really need to be careful about not just giving patients with these symptoms antibiotics without verifying a UTI through a positive urine culture.”

SInce diagnoses take 48 hours, women can wait days for the correct prescription. This shows the need for better diagnostic tools, Dr Kim said.

Frustration and resentment toward their medical providers for “throwing antibiotics” at them without presenting alternative options for treatment and prevention, and for not understanding their experience with UTIs. In addition, many said their physicians did not properly educate them on the potential negative impacts of antibiotics; the women instead had to rely on information from the internet, magazines and TV.

Beyond improved diagnostics, treatment approaches and guidelines, better patient education is key, Dr Kim said. “We need to do a better job of letting patients know when antibiotics are necessary and when to consider alternative therapy for bladder conditions other than UTIs.”

Dr Kim and her colleagues are currently working to improve UTI diagnosis and management, including developing comprehensive patient-care pathways through which primary care physicians and general gynecologists and urologists will provide initial UTI patient education and management. They are also pursuing studies examining the relationship of the vaginal microbiome to lower urinary tract symptoms and are working to incorporate novel diagnostic methods to allow for point-of-care treatment for UTIs.

Source: UCLA