When Benjamin Franklin asked his contacts in France to send over a mysterious elixir for his gout in the 1760s, he probably did not realise he was ordering a medicine that had already been known, mainly as a poison, for more than a millennium. The concoction, sold as Eau Medicinale by French officer Nicolas Husson, crossed the Atlantic as a fashionable gout cure. What Franklin could not have foreseen is that the same substance would one day appear in the New England Journal of Medicine as a tool for preventing myocardial infarction.

The active ingredient in Husson’s remedy was colchicine, derived from the autumn crocus (Colchicum autumnale). Few medicines in routine UK practice can claim a lineage stretching from ancient Greek botanists to modern cardiology guidelines, but colchicine is one of them.

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From ‘One-Day Killer’ to Medical Curiosity

The earliest descriptions of colchicum-like plants sit deep in classical literature. Theophrastus, writing in the 4th century BC, described a deadly plant known as ephemeron, literally “the one-day killer” (Theophrastus, Historia Plantarum). By the 1st century AD, Dioscorides had formalised the name kolchikon after the Black Sea region of Colchis (Dioscorides, De Materia Medica). His warnings were unambiguous: used unwisely, colchicum “kills by choking”.

For more than 1,500 years, Western physicians largely followed this advice. Medieval herbals listed colchicum among plants to be admired but not consumed. Renaissance herbalist John Gerard summed it up neatly when he wrote that its roots were “very hurtfull to the stomacke” (Gerard, Herball, 1597).

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The 18th Century Breakthrough: Eau Medicinale

Colchicum’s reputation shifted dramatically in the late 1700s when Nicolas Husson marketed Eau Medicinale as a secret gout remedy. It sold at a premium, 22 shillings per tiny bottle, and was widely imitated but poorly understood. European physicians debated its contents, suggesting everything from digitalis to white hellebore.

In 1814, Londoner John Want solved the mystery. Using a mix of literature review, analysis, and possibly a little espionage, Want identified colchicum as the active ingredient. His findings reshaped gout management across Europe almost immediately.

A plant long classified as a poison had become one of medicine’s most reliable abortive treatments for gout flares.

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Why Colchicine Works, and Why It Sometimes Does Not

Colchicine binds to tubulin, preventing microtubule formation. This slows or halts cellular processes that depend on structural scaffolding. For neutrophils, this means impaired migration, reduced endothelial adhesion, and blunted inflammatory signalling. Clinically, this results in anti-inflammatory activity at low doses.

Neutrophils conveniently accumulate colchicine because they express low levels of P-glycoprotein. Other tissues pump it out more effectively, which partly explains why the drug can reduce inflammation without universally causing harm.

However, the mechanism also explains the gastrointestinal side effects familiar to clinicians. Blocking microtubules disrupts cell division in rapidly renewing tissues, particularly the gut and bone marrow. Hence, diarrhoea remains as ancient a side effect as the drug itself.

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Modern Evidence: From FMF to MI Prevention

Familial Mediterranean Fever

Colchicine’s modern renaissance began in the 1970s when researchers discovered that daily colchicine prevents the attacks of Familial Mediterranean Fever and reduces the risk of secondary amyloidosis (Ozen et al., N Engl J Med, 2016). This marked the transition of colchicine from simple gout treatment to targeted anti-inflammatory therapy.

Acute Gout

Surprisingly, despite centuries of use, high-quality evidence arrived only recently. The AGREE trial (Terkeltaub et al., Arthritis Rheum, 2010) showed that a low-dose regimen (1.8 mg over one hour) was nearly as effective as traditional high-dose therapy while causing fewer adverse effects. This finding rapidly changed practice worldwide.

Pericarditis

Cardiology then embraced colchicine. The ICAP trial (NEJM, 2013) demonstrated that combining colchicine with standard therapy halved recurrence rates in acute pericarditis. This led to its incorporation into ESC guidelines and rapid uptake across Europe.

Coronary Disease

The LoDoCo2 (NEJM, 2020) and COLCOT (NEJM, 2019) trials further broadened interest. Daily low-dose colchicine (0.5 mg) reduced cardiovascular events, including myocardial infarction and stroke, by roughly 23 to 30 percent. These results positioned colchicine as a serious contender in long-term cardiovascular risk reduction.

A once-feared botanical toxin had become a frontline anti-inflammatory drug across multiple specialties.

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Regulatory Plot Twist: When Safety Creates a Monopoly

For decades, colchicine in the United States existed in a regulatory grey zone. It was widely manufactured, rarely questioned, and astonishingly cheap.

The FDA’s 2006 Unapproved Drugs Initiative changed that. The programme encouraged companies to fund modern studies in exchange for temporary market exclusivity. URL Pharma undertook the necessary research, including pharmacokinetic studies and the AGREE trial, and gained approval for Colcrys in 2009.

Once approved, the FDA ordered all other unapproved colchicine products off the market. Overnight, a ten-cent pill became a five-dollar pill.

The backlash was swift. US senators accused URL Pharma of exploiting regulation to create a monopoly. Analysts estimated that if all gout patients required daily colchicine at the new price, annual costs could exceed 11 billion dollars.

Generics eventually returned after exclusivity expired, but prices have never returned to the pre-2009 level. The episode became a case study in how well-intended policy can distort markets.

In 2020, partly because of such cases, the programme was formally discontinued.

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The Road Ahead

Colchicine’s journey mirrors the evolution of medicine itself. It has travelled from ancient herbal lore to modern pharmacology, from empirical remedies to targeted anti-inflammatory therapy. Its expanding role in cardiovascular medicine continues to attract attention, and further repurposing trials are underway.

Yet the Colcrys episode remains a lasting reminder that the scientific merit of a drug can be overshadowed by regulatory and economic forces. Poorly designed incentives can restrict patient access to medicines that humanity has relied on for centuries.

For UK doctors, colchicine’s story is more than an interesting historical footnote. It is a window into how policy, economics, and pharmacology intersect, and how even the most familiar medicines can have dramatic backstories.

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Selected References

• Theophrastus. Historia Plantarum, 4th century BC

• Dioscorides. De Materia Medica, 1st century AD

• Gerard J. The Herball, 1597

• Terkeltaub R et al. AGREE Trial. Arthritis Rheum. 2010

• Ozen S et al. FMF Review. N Engl J Med. 2016

• Imazio M et al. ICAP Trial. N Engl J Med. 2013

• Nidorf SM et al. LoDoCo2 Trial. N Engl J Med. 2020

• Tardif J et al. COLCOT Trial. N Engl J Med. 2019

• FDA Unapproved Drugs Initiative, US HHS, 2006 to 2020

Heart disease remains the leading cause of death globally. Despite advancements in understanding risk factors like high cholesterol and blood pressure, a groundbreaking discovery from Spanish researchers at the National Center for Cardiovascular Research (CNIC) in Madrid has unveiled an unexpected villain: your gut bacteria.

Fifteen years ago, researchers set out to study thousands of Banco Santander employees, hoping to unlock the mysteries behind cardiovascular disease. The results, recently published in the prestigious scientific journal Nature, uncovered a startling link. Scientists found that certain gut bacteria produce a molecule called imidazole propionate (C₆H₈N₂O₂), which directly causes atherosclerosis—the dangerous buildup of fat and cholesterol in arteries that leads to heart attacks and strokes.

A Silent Threat: Widespread Hidden Disease

The comprehensive study involved detailed medical imaging (using CAT and PET scans) of apparently healthy volunteers aged between 40 and 55. Shockingly, 63% showed signs of early-stage atherosclerosis. The culprit behind these hidden dangers turned out to be imidazole propionate, a molecule released by certain gut microbes, including strains from Escherichia, Shigella, and Eubacterium.

This molecule, researchers found, doesn’t just correlate with heart disease—it actively triggers it. Imidazole propionate enters the bloodstream, stimulates inflammation in arteries, and initiates the formation of fatty plaques.

From Molecule to Disease: Confirming the Link

Lead scientist David Sancho explains, “Imidazole propionate induces atherosclerosis on its own. There’s a causal relationship.” Experiments in mice confirmed the findings: animals exposed to the molecule rapidly developed artery-clogging plaques. Crucially, these effects occurred even in mice without elevated cholesterol levels, highlighting a previously unknown inflammatory and autoimmune component of heart disease.

Moreover, approximately one in five human volunteers with active, dangerous forms of atherosclerosis showed elevated levels of imidazole propionate, strengthening the real-world relevance of these findings.

Prevention and New Treatment Possibilities

Thankfully, the discovery isn’t all bad news. Scientists also identified how imidazole propionate interacts with our cells, paving the way for potential treatments. By blocking the molecule’s receptor with an experimental drug, researchers completely prevented disease progression in mice—even on a high-cholesterol diet.

This promising development offers hope for preventing heart disease in humans by targeting gut bacteria directly. Dietary changes also appear beneficial: individuals consuming diets rich in vegetables, fruits, whole grains, fish, and low-fat dairy showed lower imidazole propionate levels.

Broader Implications: Beyond Cholesterol

Swedish biologist Fredrik Bäckhed previously linked high imidazole propionate levels with type 2 diabetes, reinforcing the broader health impact of gut microbes. Independent research from Ruhr University Bochum recently validated these cardiovascular findings, further underscoring their significance.

The research suggests that heart disease isn’t solely driven by traditional factors like cholesterol. Instead, our gut bacteria might silently orchestrate damage even in those who appear healthy.

Future Steps and Continued Research

While the current findings are groundbreaking, further research is essential to pinpoint specific bacterial strains responsible for producing imidazole propionate. Still, scientists are optimistic about the potential to revolutionize heart disease prevention, diagnosis, and treatment.

This groundbreaking study, made possible by thousands of volunteers and significant funding from institutions like the “la Caixa” Foundation and the European Research Council, marks a pivotal moment in cardiovascular medicine. Understanding and managing our gut microbiome could soon become as routine as checking cholesterol levels.

Your gut health might just hold the key to a healthier heart.

References

Sancho, D., Mastrangelo, A., Robles, I., Fuster, V., et al. (2025). Gut microbiota–derived imidazole propionate drives atherosclerosis. Nature. https://www.nature.com/articles/s41586-025-09263-w

Breaking the Cycle of Recurrent UTIs: An Innovative Non-Antibiotic Approach

Recurrent urinary tract infections (rUTIs) are among the most common and frustrating clinical conditions faced by healthcare professionals. Not only do they impair patients’ quality of life, but they also significantly contribute to antibiotic resistance—a growing global health crisis. A recent groundbreaking study published in Probiotics and Antimicrobial Proteins offers promising evidence that a carefully designed non-antibiotic “bundle” treatment can effectively manage rUTIs, drastically reducing antibiotic use while improving patient outcomes.

Tackling the rUTI Challenge

Women suffering from rUTIs often find themselves in a relentless cycle of infections, symptoms, and antibiotics. The overuse of antibiotics is especially concerning due to the rising prevalence of multidrug-resistant organisms. Recognizing this, researchers from the ASFO Santa Maria degli Angeli Hospital in Pordenone, Italy, investigated a multimodal non-antibiotic strategy, targeting both infection prevention and overall patient wellness.

The Non-Antibiotic Bundle: A Holistic Intervention

The study enrolled 47 women experiencing recurrent UTIs, testing a comprehensive six-month intervention that combined:

• Behavioral Changes: Enhanced hydration (minimum 2 liters daily), improved bowel management, and optimized intimate hygiene practices.
• Phytotherapy: Regular consumption of cranberry extract and D-mannose, both known to inhibit bacterial adhesion to urothelial surfaces.
• Probiotics: A combination of oral and vaginal probiotics containing strains such as Lactobacillus, Bifidobacterium, and Saccharomyces boulardii, aimed at restoring healthy vaginal and intestinal microbiota.

Remarkable Results: Reduced Antibiotic Use and Improved Quality of Life

After six months, the results were impressive:

• 76% reduction in urinary tract infections compared to the previous six months.
• Over 90% decrease in antibiotic exposure, significantly minimizing the risk of antimicrobial resistance.
• Significant improvement in chronic symptoms like abdominal discomfort, urinary urgency, and suprapubic pain.
• Enhanced quality of life reported by over 80% of participants.

Clinical Implications: A Paradigm Shift in UTI Management

The findings suggest that a holistic, multimodal strategy can profoundly change the standard approach to managing rUTIs. By focusing on patient education, lifestyle adjustments, and microbiota health rather than solely relying on antibiotics, clinicians have a powerful new tool to combat recurrent infections.

Moving Forward

Although this initial study had a modest sample size, the outcomes strongly support further large-scale trials. By reducing antibiotic dependence, healthcare providers can not only manage rUTIs more effectively but also contribute to global antibiotic stewardship efforts.

This study represents an important step toward a future where non-antibiotic solutions play a central role in infectious disease management. It’s time to shift our clinical focus towards strategies that not only address symptoms but also promote long-term health and resilience against infections.

Reference:
Venturini, S., Reffo, I., Avolio, M. et al. (2024). The Management of Recurrent Urinary Tract Infection: Non-Antibiotic Bundle Treatment. Probiotics & Antimicro. Prot., 16, 1857–1865. https://doi.org/10.1007/s12602-023-10141-y

A Fresh Look at an Old Ally:

Mirtazapine for Insomnia in the Older Adult
(7.5mg superior than 15mg)

https://doi.org/10.1093/ageing/afaf050

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1. Why This Conversation Won’t Go Away

Anyone running a geriatric clinic knows the nightly battle cry: “Doctor, I just can’t sleep.” Benzodiazepines and so-called “Z-drugs” remain common fixes, yet both families bring cognitive haze, falls, and dependency. For years clinicians have quietly pivoted to low-dose mirtazapine—an antidepressant whose antihistaminic and serotonergic blockade leaves most patients yawning within the hour. Until now, hard data were scarce. The MIRAGE trial, published 26 March 2025, finally puts numbers behind this off-label ritual.

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2. Trial in One Breath

Design: single-centre, double-blind, randomized, placebo-controlled
Population: 60 community-dwelling adults ≥ 65 y with chronic insomnia (per ICSD-3)
Intervention: mirtazapine 7.5 mg nightly vs identical placebo for 28 days
Primary endpoint: change in Insomnia Severity Index (ISI) from baseline to day 28
Key safety endpoints: any adverse event (AE) and AEs causing discontinuation

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3. Efficacy: More than a Sedative Fog

After four weeks, ISI scores fell by a mean 6.5 points in the mirtazapine arm versus 2.9 with placebo (p = 0.003). In practical terms, roughly half the treated patients slid from the “clinical insomnia” range into the “sub-threshold” zone. Subjective reports mirrored the index: wake-after-sleep-onset shortened, total sleep time lengthened, and sleep efficiency nudged upward.
Take-home: At 7.5 mg, mirtazapine delivers a clinically meaningful, moderate-to-large improvement—something cognitive behavioural therapy matches but few pills can boast in this age group.

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4. Safety: The Price of a Quiet Night

No severe AEs surfaced, but tolerability was not trivial. Six of thirty mirtazapine recipients (20 %) quit early because of side-effects—primarily morning grogginess, dizziness, and next-day confusion—versus one in the placebo cohort. Nobody fell or fractured, yet the signal reminds us: histamine blockade plus age-related pharmacokinetics equals prolonged hangover.

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5. Clinical Pearl—Dose Matters More Than You Think

Why 7.5 mg? At this level, α2-adrenergic auto-receptors are only partially blocked, while H1 and 5-HT2A/C antagonism dominates—key for sleep promotion. Climbing to 15 mg or 30 mg may paradoxically lift noradrenergic tone and lighten sedation, but also raises metabolic baggage (weight gain, lipids). For insomnia, start low, stay low.

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6. Where Does MIRAGE Fit into the Landscape?

Factor	Mirtazapine 7.5 mg	Z-Drugs	Low-dose Doxepin
Evidence in ≥ 65 y	Now RCT-supported	Sparse, mostly extrapolated	One pivotal RCT
Cognitive impact	Mild, transient	Moderate	Minimal
Fall risk	Possible (orthostasis)	Documented	Minimal
Typical half-life	20–40 h	1–7 h	15 h
Insurance coverage (UK)*	Generic	Generic	Branded (high-cost)

*Formulary differences apply; check local guidance.

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7. Limitations Worth a Minute of Skepticism

• Single centre – practice patterns and patient profiles may differ outside an academic geriatric clinic.
• Short intervention – 28 days answers “can it work?”, not “does it keep working?”.
• Subjective sleep metrics – polysomnography was not employed; misperception of sleep may inflate gains.
• Modest N – the confidence interval, though statistically tight, still leaves room for over- or under-estimation.

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8. Putting It into Practice—A Mini Algorithm

1. First-line remains CBT-I. Refer whenever feasible.
2. Rule out mimics. Pain, nocturia, REM behaviour disorder, OSA.
3. If pharmacotherapy is unavoidable:
   • Start mirtazapine 7.5 mg HS.
   • Reassess after two weeks (ISI ≥ 6-point drop is a “response”).
   • At four weeks, taper off if ineffective; continue up to three months if benefit outweighs sedation.
4. Monitor weight, orthostatic BP, and cognition at each visit.
5. Document taper plan to minimise long-term, off-label drift.

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9. Future Directions—Beyond the Mirage

• Long-range outcomes: Does the ISI advantage persist at six or twelve months?
• Objective sleep metrics: Actigraphy or at-home EEG could clarify true sleep architecture effects.
• Frailty-stratified safety: Are discontinuation rates higher in prefrail or sarcopenic elders?
• Comparative head-to-head: How does mirtazapine fare against low-dose doxepin or lemborexant in this cohort?

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10. Bottom Line for the 17:00 Ward Round

For older adults wrestling with chronic insomnia, low-dose mirtazapine now carries randomized evidence of benefit, shaving roughly 6–7 ISI points over four weeks. Yet one in five may abandon therapy owing to next-day somnolence or dizziness. Use it prudently, monitor closely, and remember: sedative is not synonymous with benign.

ClinicalTrials.gov Identifier NCT05247697 — Published 26 March 2025.

 

 

 

A substantial cohort study suggests that for adults who cannot or do not prefer regular exercise, engaging in short bursts of vigorous activity, as simple as climbing a flight of stairs, may still significantly reduce their risk of cancer. The study, led by Dr. Emmanuel Stamatakis and his team from the University of Sydney in Australia, found that even as little as 1 minute of vigorous intermittent lifestyle physical activity (VILPA) per day, totaling 4.5 minutes weekly, was associated with a 20% decrease in the overall risk of cancer.

The researchers also observed a 31% reduction in the risk of physical activity-related cancer, which includes cancer types known to be possibly linked to low levels of physical activity. These findings were published in JAMA Oncology.

The potential impact of VILPA on cancer prevention is promising, particularly for individuals who cannot or lack motivation to exercise during leisure time. The study’s authors advocate for further exploration through long-term trials with cancer-related biomarkers and well-designed cohort studies using wearable devices to better understand VILPA’s potential as a cancer prevention intervention for non-exercisers and those who find traditional exercise unappealing.

Interestingly, the researchers found that even a “minimal dose” of VILPA, equivalent to 3.4 minutes of vigorous activity per day, was associated with a 17% reduced risk of total cancer incidence. Likewise, 3.7 minutes of daily vigorous activity was linked to a 28% decreased risk of physical activity-related cancer incidence.

An editorial accompanying the study emphasizes that physical activity can have additional benefits, such as improving physical fitness, muscle strength, fatigue related to cancer, and overall quality of life for cancer survivors. However, more research is needed to determine if the results can be applied to cancer patients specifically.

The study involved 22,398 adults from the U.K. Biobank accelerometry subsample, with participants who reported no leisure time exercise and engaged in one or fewer recreational walks per week. Vigorous intermittent lifestyle physical activity was defined as short bursts of intense physical activity, like fast walking or stair climbing, and was measured using wearable trackers, such as wrist-worn accelerometers.

The participants were followed for an average of 6.7 years, during which 2,356 new cancer events were reported, including 1,084 cases related to physical activity. The analyses were adjusted for various factors such as age, sex, body mass index, education level, smoking status, alcohol consumption, sleep duration, fruit and vegetable consumption, medications, parental cancer history, cardiovascular disease, daily durations of light- and moderate-intensity physical activity, and daily duration of longer vigorous exercise bouts.

The study highlights the importance of incorporating even sporadic episodes of brief, vigorous physical activity into daily life as it positively impacts health and helps reduce the risk of disease. Ultimately, any form of physical activity is beneficial, and the key is to establish exercise as a regular habit for overall well-being.

 

The Competition and Markets Authority (CMA) has called for an indepth inquiry into the EMIS Health PLC acquistion by United Health Group (UNH) Inc.

The reasons cited are:

• The combined market share of UNH and EMIS in the supply of healthcare IT systems to GPs in the UK.
• The potential for the merger to lead to higher prices or reduced innovation in the market.
• The potential for the merger to make it more difficult for new entrants to compete in the market.

These are valid concerns and we agree with them.

However, there is an unmitigated disaster looming on the horizon if the acquisition goes ahead for all individuals who have their data stored with EMIS health.

To say it in simple terms it is that the largest health insurance provider on the planet will have potential access to all EMIS patient data.

What can they do with that data, and why does it matter? Currently, for the most part the NHS is the provider for health services in the UK, in the future this might change-, with the government and bureaucracy intending to follow the Australian mode of health insurance.

This is then where things become ugly, and several conflicts of interest arise: (UNH means UnitedHealth Group or its subsidiaries)

 

1. Access to Sensitive Information: UNH may have access to detailed medical records of patients, which could potentially influence their decisions regarding coverage, claims, or treatment options. This raises concerns about the privacy and security of patients’ personal health information.
2. Denial of Claims: UNH may have a financial incentive to deny or restrict coverage based on the information obtained from EMIS. They could use this information to argue that certain medical conditions were pre-existing or that specific treatments are not medically necessary.
3. Premium Setting: The ownership of EMIS could provide UNH with insights into patients’ health profiles. This information could potentially be used to set premiums or adjust coverage options based on individuals’ health risks, which may not align with fair and equitable pricing practices.
4. Provider Selection Bias: UNH might be inclined to steer patients toward healthcare providers or facilities associated with EMIS or UNH, even if there are better options available elsewhere. This could limit patients’ choices and potentially compromise the quality of care.
5. Data Monopolization: If UNH has exclusive ownership or control over EMIS, it could create a monopoly or dominant position in the market. This can hinder competition and limit patients’ access to alternative healthcare data management services.
6. Ethical Dilemmas: UNH might face ethical challenges when it comes to managing and safeguarding patients’ data. Conflicting interests could arise between prioritizing profit margins and ensuring the privacy, security, and appropriate use of medical records.
7. Patient Consent and Control: Patients may have concerns about who has access to their medical records, how the data is used, and whether they have given informed consent for their records to be shared between UNH and EMIS. Lack of transparency or control over their own data can erode patient trust.

 

It is important that the inquiry is widened to incorporate these concerns and in our opinion the acquisition should be blocked.

The CMA has proven that it is an independent body relying on evidence and working for the public good cf. Activision and Microsoft merger was blocked.

 

References:

1. UnitedHealth Group / EMIS merger inquiry – GOV.UK: https://www.gov.uk/cma-cases/unitedhealth-group-slash-emis-merger-inquiry
2. CMA provisionally finds UnitedHealth Emis tie-up could reduce competition – Digital Health: https://www.digitalhealth.net/2023/03/cma-provisionally-finds-unitedhealth-emis-tie-up-could-reduce-competition/
3. UnitedHealth Deal Questioned by DOJ on Risk of Data Misuse: https://www.bloomberg.com/news/articles/2022-08-10/unitedhealth-internal-audit-shows-data-misuse-risks-doj-says

A common characteristic of neurodegenerative diseases such as Huntington’s disease and various forms of dementia is the build-up in the brain of clusters—known as aggregates—of misfolded proteins, such as huntingtin and tau. These aggregates lead to the degradation and eventual death of brain cells and the onset of symptoms.

One method that our bodies use to rid themselves of toxic materials is autophagy, or ‘self-eating,” a process whereby cells ‘eat’ the unwanted material, break it down and discard it. But this mechanism does not work properly in neurodegenerative diseases, meaning that the body is no longer able to get rid of the misfolded proteins.

In a study published today in Neuron, a team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the University of Cambridge has identified a process that causes autophagy not to work properly in the brains of mouse models of Huntington’s disease and a form of dementia—and importantly, has identified a drug that helps restore this vital function.

The team carried out their research using mice that had been genetically-altered to develop forms of Huntington’s disease or a type of dementia characterized by the build-up of the tau protein.

Using mice, the team showed that in neurodegenerative diseases, microglia release a suite of molecules which in turn activate a switch on the surface of cells. When activated, this switch—called CCR5—impairs autophagy, and hence the ability of the brain to rid itself of the toxic proteins. These proteins then aggregate and begin to cause irreversible damage to the brain—and in fact, the toxic proteins also create a feedback loop, leading to increased activity of CCR5, enabling even faster build-up of the aggregates.

When the researchers used mice bred to ‘knock out’ the action of CCR5, they found that these mice were protected against the build-up of misfolded huntingtin and tau, leading to fewer of the toxic aggregates in the brain when compared to control mice.

This discovery has led to clues to how this build-up could in future be slowed or prevented in humans. The CCR5 switch is not just exploited by neurodegenerative diseases—it is also used by HIV as a ‘doorway’ into our cells.

The team used maraviroc to treat the Huntington’s disease mice, administering the drug for four weeks when the mice were two months old. When the researchers looked at the mice’s brains, they found a significant reduction in the number of huntingtin aggregates when compared to untreated mice.

The same effect was observed in the dementia mice. In these mice, not only did the drug reduce the amount of tau aggregates compared to untreated mice, but it also slowed down the loss of brain cells. The treated mice performed better than untreated mice at an object recognition test, suggesting that the drug slowed down memory loss.

Professor Rubinsztein added: “We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted, potentially even with an existing, safe treatment.”

“Maraviroc may not itself turn out to be the magic bullet, but it shows a possible way forward. During the development of this drug as a HIV treatment, there were a number of other candidates that failed along the way because they were not effective against HIV. We may find that one of these works effectively in humans to prevent neurodegenerative diseases.”

Reference: Mitchell CA, Verovskaya EV, Calero-Nieto FJ, et al. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing. Nat Cell Biol. 2023;25(1):30-41.
https://www.nature.com/articles/s41556-022-01053-0.epdf