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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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Hamas confirms direct peace talks with US – as it calls on Trump to ‘pressure’ Israel

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Hamas confirms direct peace talks with US - as it calls on Trump to 'pressure' Israel

A senior Hamas official has confirmed the militant group is in direct talks with the United States over peace in Gaza, adding that it believes Donald Trump can help broker a deal.

Speaking to Sky News’ lead world news presenter Yalda Hakim, Dr Basem Naim said Hamas has shared its proposed agreement both through mediators and “directly with some persons in the US administration”.

They are calling for “a prisoner exchange, total withdrawal of Israeli forces, allowing all the aid to get into Gaza and rebuilding of [the] Gaza Strip without forceful immigration,” he said.

Basem Naim being interviewed by Yalda Hakim
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Basem Naim

Dr Naim also addressed whether Hamas – which has been in power since it won the 2006 Palestinian election – could step down from government in order to secure peace.

“We have also told the Americans, we are ready to, again, to hand over the government immediately if we reach an end of this war,” he said.

Donald Trump at an air base in Qatar
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Trump, seen here at a US airbase in Qatar, is on the final day of a Middle East tour

Dr Naim added Hamas has “accepted” an Egyptian peace proposal which “is talking about forming a Palestinian, independent, politically unaffiliated body to run the Gaza Strip”.

“Before that, as long as we are still occupied people, we have all the right to continue defending our people and resisting the occupation with all means including under resistance,” he said.

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Turning his attention directly to the US president, the senior Hamas official said he thinks Mr Trump “has the capability and the will to reach this peaceful situation”.

He said: “Gaza and Gazans are deserving, like all other people everywhere, to live in peace and dignity.

“And I think President Trump can do it if he exercises enough pressure on the Israelis to end this war immediately. And we are ready to cooperate with him to achieve this goal of a more peaceful region.”

Responding to the interview with Hamas, White House National Security Council spokesman James Hewitt told Sky News that Hamas “has not demonstrated they are serious about peace” and that Mr Trump “has been clear Hamas must lay down their arms”.

“Hamas continues to wrongfully hold hostages, including American bodies, in the dungeons of Gaza who could easily be freed and have shown no changes in behaviour to indicate they will cease to attack civilians,” he added.

Hamas has set out ceasefire conditions – but Trump remains as stern as ever


 Yalda Hakim joined Sky News at the end of last year

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Donald Trump’s Middle East tour has been full of surprises.

But the revelation that officials in his administration are speaking directly to Hamas is one of the most significant.

As the US president addressed troops at the Al Udeid airbase in Qatar – the largest in the region – I sat down with a senior Hamas official who confirmed direct talks were ongoing.

In an exclusive interview, Dr Bassem Naim praised Trump and talked up chances of finding a peaceful resolution.

It’s a remarkable statement from a senior figure within the group, which is considered by the US and UK to be a terrorist organisation.

Much has been made of Trump’s ‘transactional’ approach here in the region.

His commitment to the ‘art of the deal’ can often achieve unexpected results but also anger his allies – which is almost certainly the case with Israel’s embattled Prime Minister Benjamin Netanyahu.

When I asked Dr Naim about the demands from Israel and the United States for Hamas to disarm and accept that it can no longer be the governing force in Gaza, he set out conditions that Hamas says would have to be met.

However, President Trump’s public stance on Hamas remains as stern as ever.

The group “needed to be dealt with” he said earlier, adding he has “concepts for Gaza,” and that the US should “take it” and turn it into a “freedom zone”.

Israel’s war in Gaza has now entered its 20th month with more than 53,000 people believed to be dead, according to Gaza’s Hamas-run health ministry.

Some 15,000 of them are children, according to UNICEF.

There are still more than 50 Israeli hostages held by Hamas in the Strip.

In a statement released on Thursday, Hamas highlighted the fact it recently released hostage Edan Alexander, an Israeli soldier with American citizenship.

It continued: “We expect, based on the understandings reached with the American side, and with the knowledge of the mediators, that humanitarian aid should have entered the Gaza Strip immediately, a call been made for a permanent ceasefire, and that comprehensive negotiations would have been held on all issues to achieve security and stability in the region, a goal we aspire to achieve.

“However, failure to achieve these steps, especially the entry of humanitarian aid to our people, will cast a negative effect over any efforts to complete negotiations on the prisoner exchange process.”

Read more:
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Analysis: Israel’s escalation in Gaza

The US president has previously shared plans of his own for Gaza and in February, he posted a bizarre AI video showing the region transformed into a paradise complete with its own Trump tower and exotic beaches.

The States could “own that piece of land” and develop it, he said – but the idea was swiftly condemned as the effective “ethnic cleansing” of Palestinians from Gaza.

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Moment of Israeli strike on house

Mr Trump is currently on a visit to the Middle East, which has included stops in the United Arab Emirates, Qatar and Saudi Arabia – but not Israel.

There had been hopes his trip could lead to a ceasefire deal, but Israeli Prime Minister Benjamin Netanyahu has pushed ahead with an escalation of force on the Gaza Strip.

Israel has this week launched airstrikes on two consecutive nights while continuing to block aid for the region, worsening the humanitarian crisis.

Watch the full interview with Dr Basem Naim from 9pm this evening on The World With Yalda Hakim on Sky News

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Ben & Jerry’s co-founder arrested after US Capitol Gaza protest

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Ben & Jerry's co-founder arrested after US Capitol Gaza protest

The co-founder of Ben & Jerry’s has been arrested after disrupting a Senate hearing with a pro-Gaza protest.

Ben Cohen, Ben of the famous ice cream company Ben & Jerry’s, was one of seven people arrested at a Senate Health, Education, Labor and Pensions Committee hearing on Wednesday, Sky News’ US partner NBC News reported.

Robert F Kennedy Jr was speaking to the committee when the protests started with someone shouting: “RFK kills people with AIDs!”

“When Bobby lies, children die,” is also heard, as well as: “Anti-vax, anti-science, anti-America” in reference to Mr Kennedy’s vaccine views.

Police quickly flooded into the room and began dragging out protesters.

Moments after, Mr Cohen got to his feet and accused the US government of playing a role in the deaths of children in Gaza.

The ice cream boss can be seen in footage of the incident on his feet, gesturing as he shouted at the US health secretary.

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“You’re killing poor kids in Gaza and paying for it by cutting Medicaid for kids here,” shouted Mr Cohen.

He is one of the last protesters hauled out of the room.

But even as he’s removed, he can still be heard shouting.

“Congress and the senators need to ease the siege. They need to let food into Gaza. They need to let food to starving kids,” he said.

Mr Cohen was dragged out along with a number of other protesters.
Pic: Reuters
Image:
Mr Cohen was dragged out along with a number of other protesters.
Pic: Reuters

The other six protesters were charged with resisting arrest and assault on an officer, NBC News said.

Earlier on Wednesday, Mr Cohen had attended a pro-Palestine event with Democratic Representative Rashida Tlaib.

Afterwards, Mr Cohen tweeted out a video of the incident, saying: “I told Congress they’re killing poor kids in Gaza by buying bombs, and they’re paying for it by kicking poor kids off Medicaid in the US.

“This was the authorities’ response.”

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Mr Cohen is no stranger to protests or getting arrested.

In July 2023, he was arrested after protesting about the US prosecution of Julian Assange.

‘Poor kids in Gaza’

Israel has killed around 53,000 Palestinians during its war with Hamas, many of them women and children, according to the Hamas-run health ministry.

The Gaza health ministry does not distinguish between civilians and combatants in its count, but said that more than half of the fatalities are women and children.

It is said the real death toll in Gaza is higher because thousands of bodies remain buried under the rubble or in areas that medics cannot access.

Ben Cohen, of Ben & Jerry's.
File pic: AP
Image:
Ben Cohen, of Ben & Jerry’s.
File pic: AP

The fighting began after the militant group led an attack across the border in October 2023, killing 1,200 people and taking around 250 hostage.

Since Israel broke a ceasefire on 18 March, almost 3,000 people have been killed, the ministry said.

The Israeli military has claimed, without evidence, to have killed 17,000 militants.

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Three climbers dead after 200ft fall – while one ‘miraculously’ survives

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Three climbers dead after 200ft fall - while one 'miraculously' survives

Three climbers have died after they fell hundreds of feet on to jagged rock, while the survival of one man in the group is being called “miraculous”.

Vishnu Irigireddy, 48, Tim Nguyen, 63, Oleksander Martynenko, 36, died while climbing down a steep gully on the 7,800ft Early Winters Spire peaks in Washington state on Sunday.

Their fall was likely caused by a “weathered” piton, which is a metal spike serving as an anchor used to slow the descent down a steep mountainside, tearing from the rock, the Okanogan County Sheriff’s Office said.

The fourth climber, Anton Tselykh, 38, from Seattle, miraculously survived, despite also plummeting 200ft on to jagged rock and tumbling another 200ft before coming to rest in a tangle of ropes and climbing equipment.

The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
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Rescuers near where the climbers were found. Pic: Okanogan County Sheriff’s Office/AP)

He suffered internal bleeding and severe head trauma, which caused him to pass out until around 10pm, hours after the estimated time of the fall, police said.

He managed to untangle himself before “crawling and feeling around in nearly pitch darkness” to find his way back to his car, Okanogan County Undersheriff David Yarnell told Sky News’ US partner NBC News.

Mr Tselykh drove west over the mountain range and collided with a guardrail on the way, falling unconscious, before finally reaching a pay phone to call for help.

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His survival “is miraculous to say the least,” Mr Yarnell said.

Mr Tselykh is being treated in a Seattle hospital and is in “satisfactory condition”, according to a hospital spokesperson.

The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
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The bodies of the three climbers have been recovered. Pic: Okanogan County Sheriff’s Office/AP

The bodies of the three climbers have since been recovered, locating them via a GPS device in their kit.

Police said the three men had suffered massive leg and cranial traumas.

Authorities believe the group had been ascending the north Early Winters Spire peak when they decided to reverse course due to an approaching storm.

Read more from Sky News:
Ben & Jerry’s co-founder dragged out of Senate
Menendez brothers’ murder sentences reduced

The Early Winters Spires in the Northern Cascades consist of two 7,800ft peaks, which are popular with climbers.

The route the group was taking was of moderate difficulty and sees climbers moving between ice, snow and rock, according to a local guide, who cautioned that conditions can change rapidly depending on the weather.

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