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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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Melissa McCarthy responds to Barbra Streisand’s apology after Ozempic comment

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Melissa McCarthy responds to Barbra Streisand's apology after Ozempic comment

Hollywood star Melissa McCarthy has responded by saying, “I win the day”, after Barbra Streisand was criticised for asking her if she had taken a weight-loss drug.

Bridesmaids star McCarthy had posted an image of herself on Instagram at a charity gala alongside US director Adam Shankman on Monday.

Streisand, the legendary singer and actress, replied in a comment below: “Give him my regards, did you take Ozempic?”

The drug can only be prescribed for patients with Type 2 diabetes and is not licensed as a weight-loss treatment in the UK or US.

Streisand posted an apology on X for her original comment which was swiftly deleted after it sparked a backlash online.

In a short video shared on Instagram, hours after the apology, McCarthy said: “The takeaway: Barbra Streisand knows I exist, she reached out to me and she thought I looked good. I win the day.”

McCarthy was holding up a magazine with Streisand on the cover in the video, which was filmed at the premiere of the new Netflix movie Unfrosted, in Los Angeles on Tuesday.

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The 53-year-old will appear in the film alongside Jerry Seinfield and Hugh Grant when it is released this month.

McCarthy was earlier asked by a photographer in Los Angeles what she thought of Streisand’s comments and replied: “I think Barbra is a treasure, and I love her.”

Melissa McCarthy poses at the premiere of the Netflix film 'Unfrosted'. Pic: AP
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Melissa McCarthy poses at the premiere of the Netflix film Unfrosted. Pic: AP

‘I forgot the world is reading’

Streisand, 82, had said in her apology earlier on Tuesday: “I went on Instagram to see the photos we’d posted of the beautiful flowers I’d received for my birthday.

“Below them was a photo of my friend Melissa McCarthy, who I sang with on my Encore album.

“She looked fantastic! I just wanted to pay her a compliment, I forgot the world is reading!”

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File pic: Reuters
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Barba Streisand apologised for the comment. File pic: Reuters

In response to Streisand’s original comment referring to Ozempic, one social media user wrote: “Omg somebody please teach Barbra Streisand how to send a DM.”

Another wrote: “Omg…this comment from Barbra Streisand. Yes, it’s real, but she’s deleted it.”

Ozempic works by suppressing the appetite and lengthens the amount of time food stays in the stomach, leading to weight loss – at least for as long as you carry on taking it.

It has been banned as a treatment for obesity in the UK due to high demand for the drug causing a global shortage.

Numerous Hollywood stars are rumoured to have used Ozempic to lose weight – but just a handful of celebrities have admitted it publicly.

Stephen Fry was prescribed the drug in the US “years ago” and said earlier this year that side effects included vomiting up to five times a day.

Oprah Winfrey has said she has also taken weight-loss drugs, though she’s declined to specify which ones.

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FKA Twigs reveals she has created an AI clone – but condemns unauthorised deepfakes

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FKA Twigs reveals she has created an AI clone - but condemns unauthorised deepfakes

FKA Twigs has revealed she has created an AI version of herself to engage with fans and help with promotion.

The British singer-songwriter and dancer gave details of the project as she addressed a US Senate intellectual property hearing regarding the No Fakes Act, which aims to crack down on unauthorised replicas.

FKA Twigs, whose real name is Tahliah Debrett Barnett, confirmed she had been developing her own AI – but condemned unauthorised deepfakes, saying they leave her feeling “raw and vulnerable”.

The hearing was held in Washington on Tuesday, just hours before the release of a UK report which found that most of the public want regulation to prevent deepfakes of big-name artists such as Dua Lipa and Taylor Swift.

Speaking at the US hearing, FKA Twigs said she had been developing a digital clone of herself over the past year, revealing that it can speak multiple languages.

“I’ve done this to be able to reach more of my fans and to be able to speak to them in the nuance of their language,” she said. “I’ve currently explored French, Korean and Japanese, which is really exciting for me. It means that even with my upcoming album I can really explain in depth what it’s about creatively.”

The 36-year-old said having an AI version of herself also allows her to “spend more time making art”.

She continued: “Often being a music artist, or any artist in this day and age, requires a lot of press and a lot of promo, a lot of one-liners.

“So it means if it’s something simple that doesn’t really require my heart, I can do a one-liner and give it to people to promote a piece of work and, you know, it’s harmless but ultimately I can spend more time making something that’s really meaningful for my fans.”

‘I am a human being, and we have to protect that’

Addressing unauthorised deepfakes, she told the hearing about songs and collaborations with other artists that exist online, which she had nothing to do with.

“The fact that somebody could take my voice, change lyrics, change messaging, maybe work with an artist that I didn’t want to work with, or maybe work with an artist that I wanted to work with and now the surprise is ruined, it really leaves me very raw and very vulnerable,” she said.

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The star called for legislation to protect artists and added: “My spirit, my artist and my brand is my brand, and I’ve spent years developing it.

“And it’s mine, it doesn’t belong to anybody else to be used in a commercial sense, or cultural sense, or even just for a laugh. I am me, I am a human being, and we have to protect that.”

Unacknowledged AI music: Is it theft?

Meanwhile, a poll by the All-Party Parliamentary Group (APPG) on Music has found that 83% of UK adults agree that a music artist’s creative “personality” should be protected in law against AI copies.

The research involving more than 2,000 adults also found that 83% agree with the statement that if AI has been used to generate a song it must be clearly labelled, and 77% believe it amounts to theft when generated music fails to acknowledge the creator of the original.

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APPG recommendations include the government introducing a UK AI Act, generated music being clearly labelled, the creation of a personality right to protect creators and artists from deepfakes, misappropriation and false endorsement, and setting up an international taskforce.

A government spokesperson said: “We are committed to helping artists and the creative industries work with the AI sector to harness the opportunities this technology provides, and ensure our music can continue to be enjoyed around the world.”

In April, more than 200 artists signed an open letter objecting to the “predatory” use of AI to “steal professional artists’ voices and likenesses”.

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Ex-politician seen beating his wife to death in CCTV footage – sparking outrage in Kazakhstan

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Ex-politician seen beating his wife to death in CCTV footage - sparking outrage in Kazakhstan

The murder trial of a former senior politician in Kazakhstan who has been accused of beating his wife to death has attracted the attention of the nation, sparking calls for new legislation tackling domestic violence. 

Shocking footage showing businessman Kuandyk Bishimbayev, Kazakhstan’s former economy minister, beating his wife at a family restaurant has been streamed online from the court.

The case has touched a nerve among the public as tens of thousands of people have signed petitions calling for new laws to hold those guilty of abuse to account.

Disturbing CCTV footage shows the former senior politician hitting his wife.
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Disturbing CCTV footage shows the former senior politician hitting his wife

Why is the case so high profile?

The trial of Bishimbayev, 44, is the first in the country to ever be streamed online – making it readily accessible to the 19 million people in Kazakhstan.

The former politician was already well known, having been jailed for bribery in 2018. He spent less than two years of his 10-year sentence in prison before he was pardoned.

Bishimbayev is on trial for killing his wife, Mrs Nukenova, and the case has touched a nerve in the Central Asian country. Pic: Kazakhstan Supreme Court Press Office/Telegram/AP
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Bishimbayev admitted last month in court that he had beaten his wife. Pic: Kazakhstan Supreme Court Press Office/Telegram/AP

Bishimbayev was charged with torturing and killing his wife after her death last November. For weeks, he maintained his innocence but admitted last month in court that he had beaten her and “unintentionally” caused her death.

Saltanat Nukenova, 31, was found dead in November in a restaurant owned by one of her husband’s relatives.

Disturbing CCTV footage shows the defendant, a father of four, dragging his wife by her hair, and then punching and kicking her.

Hours after it was recorded, she died of brain trauma.

Businessman Kuandyk Bishimbayev, the country's former economy minister, sits in a defendants’ cage in court in Kazakhstan. Pic: Kazakhstan Supreme Court Press Office/Telegram/AP
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Bishimbayev was jailed for bribery in 2018. Pic: Kazakhstan Supreme Court Press Office/Telegram/AP

Bishimbayev’s lawyers initially disputed medical evidence indicating Ms Nukenova died from repeated blows to the head.

They also portrayed her as prone to jealousy and violence, although no video from the restaurant’s security cameras that was played in court has shown her attacking Bishimbayev.

According to a 2018 study backed by UN Women, about 400 women die as a result of domestic violence in Kazakhstan every year, although many go unreported.

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What reaction has the trial caused?

Tens of thousands of people in the country have signed a petition calling for harsher measures against perpetrators of domestic violence in the wake of Ms Nukenova’s tragic death.

The signatures resulted in senators approving a bill which toughens spousal abuse laws last month – dubbed “Saltanat’s Law”.

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Aitbek Amangeldy, Ms Nukenova’s brother and a key prosecution witness, told the Associated Press he had no doubt his sister’s tragic fate has shifted attitudes about domestic violence.

“It changes people’s minds when they see directly what it looks like when a person is tortured.”

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