By Vijay Kumar Malesu Mar 7 2024 Reviewed by Lily Ramsey, LLM
In a recent study published in Science Immunology, a group of researchers investigated how sensory nerve sprouting and mast cell activity, driven by nerve growth factor (NGF), contribute to persistent bladder pain and dysfunction in recurrent urinary tract infection (rUTI) cases.
Study: Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity . Image Credit: Rabizo Anatolii/Shutterstock.com Background
Urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), lead to numerous clinical visits annually due to their high recurrence rate, especially in women.
Recurrences are often attributed to UPEC persisting within the urinary tract's epithelial cells, causing rUTIs even in individuals with intact immune systems.
Standard UTI treatment involves a short course of antibiotics, with longer prophylactic use in cases of frequent recurrences.
rUTI patients frequently experience symptoms like pelvic pain and increased urination frequency, often treated with antibiotics despite negative urine cultures.
Further research is needed to develop targeted therapies that address the underlying neuro-immunological mechanisms contributing to chronic pelvic pain and bladder dysfunction in rUTI patients. About the study
In the present study, researchers employed a rUTI mouse model to mimic symptoms and phenotypes observed in human clinical settings.
They evaluated voiding behavior, pain-like responses, and nerve anatomy through various techniques such as cystometry, histology, and three-dimensional (3D) model reconstruction.
Additionally, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were utilized to identify proteins and cell types relevant to rUTI pathology.
To validate their findings, the team implemented multiple targeting strategies, including receptor antagonists and neutralizing antibodies against NGF, as well as genetically modified mice lacking specific immune cell receptors or cells. Related StoriesCellectricons expertise in pain research recognized by second EU research grantLow back pain? Theres good and bad newsNew drug targets key mechanism in ALS, protects motor neurons
To further establish the connection between their observations in mice and human patients, the researchers administered NGF, histamine, and bradykinin to naive mice.
This replicated the primary observations from the rUTI model, suggesting a possible translational significance of their findings.
Human bladder biopsies and urine samples were collected from control individuals and rUTI patients experiencing pain to confirm the animal model data with human clinical observations.
These human samples underwent similar analysis protocols to those applied in animal studies, ensuring that the insights gained from the research were grounded in both preclinical and clinical realities.
The study explored nerve growth in rUTI through various methods. Researchers collected dorsal root ganglia (DRGs) from mice, treated them with enzymes for dissociation, and then cultured the cells on coated coverslips. Adding NGF or its antagonist revealed NGF's role in neurite outgrowth.
This was paralleled by in vivo experiments where NGF was instilled into mouse bladders to induce nerve sprouting, contrasting with treatments that neutralized NGF or blocked its receptor, which prevented such growth.
Additionally, monocytes and mast cells were cultured with neurons to demonstrate further NGF's influence on nerve development.
Various techniques were employed to assess pelvic sensitivity and bladder innervation effects, underscoring NGF's central role in sensory nerve sprouting associated with rUTI symptoms. Study results
Patients experiencing rUTI often report persistent symptoms such as pelvic sensitivity and urinary frequency, even after bacterial cultures show no signs of infection. This observation led researchers to investigate the role of bladder sensory nerves and their connection to rUTI symptoms.
Upon examining bladder biopsies from rUTI patients, an increase in Substance P (SP+), a marker for nociceptive sensory nerves, was observed, suggesting alterations in nociceptive activity.
A mouse model of rUTI was employed to explore these clinical findings further, revealing similar symptoms of increased pelvic sensitivity and urinary frequency alongside significant sensory nerve sprouting in the lamina propria.
The investigation into the underlying mechanisms of these observations pointed towards the role of NGF, a key mediator in nerve sprouting and sensitization. Elevated levels of NGF, but not brain-derived neurotrophic factor (BDNF), were identified in the bladders of rUTI mice.
Targeting NGF signaling through the administration of native NGF to naive mice or utilizing NGF-neutralizing strategies replicated the rUTI phenotype or alleviated symptoms, respectively, confirming NGF's pivotal role.
The cellular source of NGF was traced back to recruited monocytes and bladder-resident mast cells, which were identified as primary contributors to the elevated NGF levels during rUTI.
These findings were further confirmed by in vitro experiments showing that monocytes and mast cells induced nerve growth. This process could be blocked by Tropomyosin receptor kinase A (TrkA) antagonism, indicating the specificity of NGF from these immune cells in inducing sensory nerve sprouting.
Exploring the link between sensory nerve sprouting, sensitization, and the observed rUTI symptoms, researchers discovered that the sustained release of NGF-sensitized nociceptors leads to pain-like responses and urinary frequency.
This process involved the activation of Transient Receptor Potential Vanilloid 1 Positive (TRPV1+) nerves, with mast cell products such as histamine and bradykinin playing significant roles in mediating these symptoms.
Interestingly, the administration of histamine or bradykinin directly into the bladder of naive mice induced similar symptoms to those observed in rUTI, suggesting a role for these mast cell products in the pathological process. Journal reference:
Byron W. Hayes et al. Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity. Sci. Immunol. (2024). doi:10.1126/sciimmunol.adi5578. https://www.science.org/doi/10.1126/sciimmunol.adi5578
Lucy Powell has accused Bridget Phillipson’s team of “throwing mud” and briefing against her in the Labour deputy leadership race in a special episode of Sky’s Electoral Dysfunction podcast.
With just days to go until the race is decided, Sky News’ political editor Beth Rigby spoke to the two leadership rivals about allegations of leaks, questions of party unity and their political vision.
Ms Powell told Electoral Dysfunction that through the course of the contest, she had “never leaked or briefed”.
But she said of negative stories about her in the media: “I think some of these things have also come from my opponent’s team as well. And I think they need calling out.
“We are two strong women standing in this contest. We’ve both got different things to bring to the job. I’m not going to get into the business of smearing and briefing against Bridget.
“Having us airing our dirty washing, throwing mud – both in this campaign or indeed after this if I get elected as deputy leader – that is not the game that I’m in.”
Ms Powell was responding to a “Labour source” who told the New Statesman last week:“Lucy was sacked from cabinet because she couldn’t be trusted not to brief or leak.”
Ms Powell said she had spoken directly to Ms Phillipson about allegations of briefings “a little bit”.
Image: Bridget Phillipson (l) and Lucy Powell (r) spoke to Sky News’ Beth Rigby in a special Electoral Dysfunction double-header. Pics: Reuters
Phillipson denies leaks
But asked separately if her team had briefed against Ms Powell, Ms Phillipson told Rigby: “Not to my knowledge.”
And Ms Phillipson said she had not spoken “directly” to her opponent about the claims of negative briefings, despite Ms Powell saying the pair had talked about it.
“I don’t know if there’s been any discussion between the teams,” she added.
On the race itself, the education secretary said it would be “destabilising” if Ms Powell is elected, as she is no longer in the cabinet.
“I think there is a risk that comes of airing too much disagreement in public at a time when we need to focus on taking the fight to our opponents.
“I know Lucy would reject that, but I think that is for me a key choice that members are facing.”
She added: “It’s about the principle of having that rule outside of government that risks being the problem. I think I’ll be able to get more done in government.”
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But Ms Powell, who was recently sacked by Sir Keir Starmer as leader of the Commons, said she could “provide a stronger, more independent voice”.
“The party is withering on the vine at the same time, and people have got big jobs in government to do.
“Politics is moving really, really fast. Government is very, very slow. And I think having a full-time political deputy leader right now is the political injection we need.”
The result of the contest will be announced on Saturday 25 October.
The deputy leader has the potential to be a powerful and influential figure as the link between members and the parliamentary Labour Party, and will have a key role in election campaigns. They can’t be sacked by Sir Keir as they have their own mandate.
The contest was triggered by the resignation of Angela Rayner following a row over her tax affairs. She was also the deputy prime minister but this position was filled by David Lammy in a wider cabinet reshuffle.
The family of Virginia Giuffre has said Prince Andrew’s decision to give up his titles, including the Duke of York, is “vindication for our sister and survivors everywhere”.
“This is not just a victory for her, but for every single survivor of the horrific crimes perpetrated by [Jeffrey] Epsteinand his co-conspirators,” they said in a statement.
Andrewwill no longer be known as the Duke of York, in a move which finally completes his banishment from royal life. However, he will remain a prince, as the son of Queen Elizabeth II.
His former wife, Sarah Ferguson, will also no longer use her title of The Duchess of York, it is understood.
In a statement, Prince Andrew said: “In discussion with The King, and my immediate and wider family, we have concluded the continued accusations about me distract from the work of His Majesty and the Royal Family.
“I have decided, as I always have, to put my duty to my family and country first. I stand by my decision five years ago to stand back from public life.
“With His Majesty’s agreement, we feel I must now go a step further. I will therefore no longer use my title or the honours which have been conferred upon me.
“As I have said previously, I vigorously deny the accusations against me.”
Image: Prince Andrew leaves Westminster Abbey following the Coronation of the King in 2023
Why is this happening now?
The decision comes following increased pressure on Prince Andrew after continuing reports of his relationship with paedophile financier Jeffrey Epstein, and his relationship with an alleged Chinese spy.
The posthumous memoir of Virginia Giuffre, who died in April, is due to be released on Tuesday. She had accused Andrew of sexual assault, and sued him in August 2021.
The book will go on sale a week after an email emerged showing Andrew told Epstein “we are in this together”, three months after he said he had stopped contact with the convicted sex offender.
Image: Flight logs released by a US committee from Epstein’s estate name Prince Andrew. Pic: House Committee on Oversight and Government
On Friday evening, the US House Oversight Committee also released documents from Epstein’s estate showing “Prince Andrew” listed as a passenger on the financier’s private jet – the so-called Lolita Express – from Luton to Edinburgh in 2006, alongside Ghislaine Maxwell.
He was also listed on another flight to West Palm Beach, Florida, in 2000.
The flight logs have been reported on for years but the release may have added to pressure.
“The situation has become untenable and intolerable, and this week in particular, the tipping point had been reached,” said Sky News royal correspondent Laura Bundock.
What is Prince Andrew giving up?
Prince Andrew is giving up his Duke of York title
His knighthood as a Knight Grand Cross of the Royal Victorian Order (GCVO)
His Garter role as a Royal Knight Companion of the Most Noble Order of the Garter
Christmas with the Royal Family at Sandringham
He had already stopped using his HRH title and and was stripped of military patronages by the Queen in 2022
He will retain his dukedom, which can only be removed by an Act of Parliament, but will not use it
He will also remain a prince as he was born the son of Elizabeth II
It is understood the changes will take effect immediately, with the Giuffre family calling for the King to go further and “remove the title of Prince”.
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9:31
‘Extreme pressure’ on Prince Andrew
King ‘glad’ of the outcome
The King is glad of the outcome, it is understood, and the decision was taken in close consultation with His Majesty and other members of the Royal Family.
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1:02
Pressure ‘piled on’ Prince Andrew
Jack Royston, chief royal correspondent at Newsweek, told Sky News: “This does not go far enough.”
There should be an acknowledgement from the Royal Family, he said, “irrespective of whether Prince Andrew denies the substantive allegations against him [that] it was morally wrong for him to grovel to Jeffrey Epstein”.
The Guardian’s former royal correspondent Stephen Bates also told Sky News: “He’s shown no sign of any sort of contrition. He continues to deny all the allegations against him. And he speaks of his duty to the family. Well, it’s a bit late to be thinking about that.”
What is Prince Andrew accused of?
Prince Andrew has denied allegations made by Ms Giuffre – one of Epstein’s victims – of sexual assault.
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1:11
‘Next step might be to squeeze Andrew out of royal lodge’
She had filed a civil lawsuit against him, accusing him of sexually assaulting her on three occasions after she was introduced to him by Epstein.
In a 2019 interview with BBC Newsnight, Andrew said he had no knowledge of ever meeting Ms Giuffre, claiming a well-known image of them together had been doctored.
Image: The 2001 photo of Prince Andrew and Virginia Roberts which the royal claimed had been doctored. Pic: Shutterstock
The case was settled outside court for a sum believed to have been around £12m.
Following Ms Giuffre’s death in April, aged 41, her family said she “lost her life to suicide” at her farm in Western Australia.
Giuffre’s family: ‘Victory for Virginia’
In a statement, the family of Ms Giuffre said they supported Andrew’s decision but repeated accusations that he had made misleading statements. Andrew has repeatedly denied any wrongdoing.
Analysis: Prince Andrew giving up titles was clearly not entirely his decision
It is extraordinary that it has come to this but the distraction had to stop.
The statement comes straight from Prince Andrew, the tone of it very personal as he says he is putting his “duty to my family and country first”.
But this was clearly not entirely his decision.
From the first sentence, where he says “in discussion with the King”, we’re left in no doubt that his brother must have said enough was enough.
“We, the family of Virginia Roberts Giuffre, believe that Prince Andrew’s decision to give up his titles is vindication for our sister and survivors everywhere.
“This decisive action is a powerful step forward in our fight to bring Jeffrey Epstein and Ghislaine Maxwell’s child sex-trafficking network to justice.
“This moment serves as victory for Virginia, who consistently maintained, ‘He knows what happened, I know what happened, and there’s only one of us telling the truth, and I know that’s me.’
“This is not just a victory for her, but for every single survivor of the horrific crimes perpetrated by Epstein and his co-conspirators.”
Anyone feeling emotionally distressed or suicidal can call Samaritans for help on 116 123 or email jo@samaritans.org in the UK. In the US, call the Samaritans branch in your area or 1 (800) 273-TALK.
It is extraordinary that it has come to this but the distraction had to stop.
The statement comes straight from Prince Andrew, the tone of it very personal as he says he is putting his “duty to my family and country first”.
But this was clearly not entirely his decision.
From the first sentence, where he says “in discussion with the King”, we’re left in no doubt his brother must have said enough was enough.
The fact we’re being guided that the King is glad of this outcome says it all; for the monarch and the wider family, the questions of what they were going to do about Andrew had to stop.
Image: Andrew at Charles’s coronation in 2023 Pic: PA
After years of upset caused by his association with convicted paedophile Jeffrey Epstein, he has done the family one favour by personally announcing that he will no longer use his titles.
For the King to forcibly remove them would have taken up precious parliamentary time and weeks of column inches.
More on Prince Andrew
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Image: The King is said to be ‘glad’ of the decision
To be clear, his titles aren’t removed, they remain extant but inactive like his HRH title.
But Andrew won’t use them any more, and that will be humiliation enough for a man who has already been stripped of his military affiliations, his charity patronages and his ability to have any kind of public profile.
This ends the questions on what more the monarch could do to show how the family felt about the accusations, the upset and the embarrassment caused.
Will it stop the stories, the allegations and the interest in Prince Andrew? That is far less certain.
But in what is his first public statement since that ill-fated Newsnight interview in 2019, it is striking that he signs it off by saying: “I vigorously deny the accusations against me.”