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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 

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A ‘barbaric’ 24 hours in the ‘horrendous’ Russia-Ukraine war leaves Donald Trump’s peace plan in tatters

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A 'barbaric' 24 hours in the 'horrendous' Russia-Ukraine war leaves Donald Trump's peace plan in tatters

Events in Ukraine over the last 24 hours have been utterly barbaric. Bad even by the standards of this horrendous war.  

Multiple Iranian drones and North Korean missiles laden with explosives brought carnage to swathes of the country, killing yet more civilians.

This was Russia’s answer to President Donald Trump’s peace plan and ultimatum. Normally, strangely reluctant to criticise Russia, even Trump was moved to implore Vladimir Putin to “STOP”.

Ukraine latest – Trump unhappy with Putin

Ukrainian search personnel clear the rubble after a Russian ballistic missile attack in Kyiv, Ukraine, early Thursday, April 24, 2025. (AP Photo/Efrem Lukatsky)
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Ukrainian personnel clear rubble after a Russian ballistic missile attack in Kyiv. Pic: AP

A resident reacts at the site of an apartment building hit by a Russian ballistic missile strike, amid Russia's attack on Ukraine, in Kyiv, Ukraine April 24, 2025. REUTERS/Valentyn Ogirenko TPX IMAGES OF THE DAY
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A woman is helped after an apartment building was hit by a Russian ballistic missile strike. Pic: Reuters

A Ukrainian serviceman carries a dog out of a house damaged by a Russian airstrike in a residential neighborhood in Kyiv, Ukraine, on Thursday, April 24, 2025. (AP Photo/Evgeniy Maloletka)
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A Ukrainian serviceman carries a dog out of a house damaged by a Russian airstrike in Kyiv. Pic: AP

But in truth, throughout Trump’s Ukraine peace process – if it can be called that – most of America’s pressure has been on Ukraine.

The peace plan that has emerged from direct US talks, which were mainly with Russia, is one-sided, and to Ukraine and its European partners, it is a surrender plan which is impossible for Ukraine to accept.

Even Russia’s supporter in this war, China, has problems with it, in particular with America’s proposal that Russia is rewarded for its invasion with sovereignty of Crimea.

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Far from heading towards a peace deal, we are now, it seems, careering towards a crunch point that could see America give up on Ukraine completely, possibly blaming Kyiv for failure and renewing relations with Moscow.

Might will be proven right, and Vladimir Putin will be emboldened to do it all over again in a few years, possibly against other countries too. That is the fear in chancelleries across Europe.

There are two key questions now.

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‘Russia is winning peace talks’

An explosion of a drone is seen in the sky over the city during a Russian drone strike, amid Russia's attack on Ukraine, in Kyiv, Ukraine April 24, 2025. REUTERS/Gleb Garanich
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A drone explosion over Kyiv. Pic: Reuters

Does Trump mean he will walk away from trying to broker peace or supporting Ukraine entirely?

And if he does, can Ukraine carry on without US help?

European nations have said they will carry on supporting Ukraine. They see its survival and victory as essential for their own security.

They already give Ukraine €40bn in financial and military help. Ukraine would need another €20bn or so to fill the US gap – not that tall an order.

Pics from Telegram of Ukraine's capital Kyiv following Russian airstrike. https://t.me/s/dsns_telegram/41679
Russia launched a massive combined strike on Kyiv. According to preliminary data, 9 people have been killed, 63 injured, and 42 hospitalized, including 6 children. Recovery efforts are ongoing in 5 districts
Credit: State Emergency Service of Ukraine
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Destruction in Kyiv following a Russian airstrike. Pic: Telegram

A large-scale Russian missile and drone attack hit Kyiv overnight, killing nine people and injuring another 63, Ukrainian authorities said. Pic: Reuters
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A large-scale Russian missile and drone attack hit Kyiv overnight. Pic: Reuters

And they are beefing up their defence industries to do more to give Ukraine what it needs to fight Russia.

Ukraine’s defence increasingly depends on a homegrown drone industry, which doesn’t rely on American backing.

But Ukraine does need US intelligence, aerial defence support and satellite coverage provided by Starlink.

Were they to lose all that, they could be in trouble.

What exactly Trump does if and, as seems increasingly likely, when his deal fails, he is not making clear.

But what seems certain is America is caring less and less for Ukraine’s plight under this president.

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That poses some urgent and pressing questions for Europe.

Its leaders have always said they will support Ukraine “whatever it takes, as long as it takes”.

Do they have the political will and unity to do that, even without America by their side?

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UK

Mansfield Town footballer Lucas Akins jailed for causing death of cyclist in car crash

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Mansfield Town footballer Lucas Akins jailed for causing death of cyclist in car crash

A professional footballer has been jailed for causing the death of a cyclist in a car crash.

Mansfield Town forward Lucas Akins crashed into Adrian Daniel in his Mercedes G350 in Huddersfield on 17 March 2022, while taking his daughter to a piano lesson.

Leeds Crown Court heard that Mr Daniel, 33, suffered catastrophic head injuries and died 10 days later.

Akins, 36, played in Mansfield’s 0-0 draw with Wigan on 4 March, hours after pleading guilty at Leeds Crown Court to death by careless or inconsiderate driving.

The footballer has continued to play for Mansfield since the incident.

Judge Alex Menary said on Thursday that he had considered imposing a suspended sentence, but had concluded that only an immediate sentence of 14 months’ imprisonment was appropriate.

Lucas Akins of Mansfield Town.
Pic:  George Wass/PPAUK/Shutterstock
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Mansfield Town’s Akins. Pic: George Wass/PPAUK/Shutterstock

A spokesperson for Mansfield Town FC said it “acknowledges” the court’s decision and offered the club’s “sincere and deepest condolences to the family of Adrian Daniel at this difficult time”.

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“The club is considering its position with regards to Lucas and will be making no further comment at this stage,” the spokesperson added.

‘Like hell’

Prosecuting, Carmel Pearson said it was a “difficult junction to emerge from” but that the defendant “did not stop at the give-way sign”.

Savanna Daniel, Mr Daniel’s wife, told the court it had been “like hell and a nightmare [she is] not waking up from”.

“There was no reason for Adrian to be killed that way,” she said, adding it was “too simple a collision to have taken a life”.

Adrian Daniel. Pic: West Yorkshire Police/PA
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Adrian Daniel. Pic: West Yorkshire Police/PA

Mrs Daniel said she did not want Akins’s children growing up without their father as she did not want “any more lives to be destroyed from this”, but she criticised the defendant for failing to plead guilty at an earlier stage.

Tim Pole, representing Akins, said he was “fundamentally a decent, honest and hard-working individual”.

“I want to publicly apologise on his behalf,” he said.

Mr Pole added that Akins understood Mrs Daniel’s “frustration and anger” over the time it took him to plead guilty.

Handing down his sentence, the judge accepted that Akins’s remorse was genuine but by not admitting to the offence at an earlier stage, he had prolonged Mrs Daniel’s “heartache and grief”.

After the sentencing, Mrs Daniel said “three years of hell” had come to a close, in a statement via West Yorkshire Police.

She said Akins had made a “farce” of the justice system and that his failure to plead guilty sooner “makes a mockery of any remorse that Akins offers for his actions”.

Akins, who has played for Mansfield Town since 2022 and was previously with clubs including Huddersfield Town, Tranmere Rovers and Burton Albion, was also suspended from driving for 12 months.

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UK weather: Large parts of country set to be warm and sunny early next week

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UK weather: Large parts of country set to be warm and sunny early next week

Much of the UK will bask in warm, sunny conditions at the start of next week, with inland temperatures up to 10C higher than average, but it’s a mixed picture before then.

The first half of spring brought warmth and sunshine for many, but the last 10 days have been more changeable.

Some areas of Ireland, Northern Ireland, southwest Wales, and southwest England have seen much-needed rainfall, whereas parts of northern Britain have observed very little.

See the latest weather forecast where you are

Cherry blossom in full bloom at The Stray in Harrogate, Yorkshire. Picture date: Thursday April 24, 2025.
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Warm, sunny conditions, such as those in Harrogate on Thursday, are expected at the start of next week. Pic: PA

Tyne and Wear in northeast England has recorded just 7% of its average April rainfall, whereas Cornwall in the southwest of the country has already seen 156%.

And the Milford Haven rain gauge in Wales has seen over twice its average April rainfall.

There’ll be more rain over the next few days, mainly in the West, but it looks like high pressure will settle things down from Sunday.

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Temperatures will rise too, becoming widely above average on Monday and Tuesday.

Highs of 22C (72F) to 24C (75F) can be expected.

The highest temperature of the year so far is 24C (75F), seen at Northolt in northwest London on Saturday 12 April.

The settled conditions will bring plenty of sunshine, with UV levels expected to be around moderate.

Tree pollen levels will be high in the South, low to moderate in the North.

What happens from next Wednesday onwards is unclear.

A thundery breakdown is possible from the South, or wet and windy conditions may move in from the North West.

Other computer models suggest high pressure will hold on, with the fine weather continuing and potentially higher temperatures.

The last time that 25C (77C) was reached in April was during the COVID-19 lockdown in 2020.

The highest temperature ever recorded in April was 29.4C (85F), seen at Camden Square in London on 16 April 1949.

All this means that it will be quite warm for the London Marathon, which will take place this Sunday.

Temperatures will be around 11-12C (52-54F) at the start, potentially peaking at a warm 22C (70F).

That’s a little off the highest temperature ever recorded for the race, which stands at 24.2C (76F) seen at St James’s Park in 2018.

But it will be a lot higher than the 12.6C (55F) seen last year.

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It’ll be dry for runners and spectators, with sunny spells and light winds.

Competitors in the Manchester Marathon on Sunday will face similar conditions to London’s runners; it should be dry with sunny spells. The temperature first thing will be around 9C (48F), but it’ll warm up with a high of about 19C (66F).

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