One sleepless night can rapidly reverse depression for several days

 Most people who have pulled an all-nighter are all too familiar with that "tired and wired" feeling. Although the body is physically exhausted, the brain feels slap-happy, loopy and almost giddy.

Now, Northwestern University neurobiologists are the first to uncover what produces this punch-drunk effect. In a new study, researchers induced mild, acute sleep deprivation in mice and then examined their behaviors and brain activity. Not only did dopamine release increase during the acute sleep loss period, synaptic plasticity also was enhanced—literally rewiring the brain to maintain the bubbly mood for the next few days.

These new findings could help researchers better understand how mood states transition naturally. It also could lead to a more complete understanding of how fast-acting antidepressants (like ketamine) work and help researchers identify previously unknown targets for new antidepressant medications.

The research was published online on Thursday (Nov. 2) in the journal NeuronThe study is titled "Dopamine pathways mediating affective state transitions after sleep loss." Northwestern postdoctoral fellow Mingzheng Wu is the paper's first author, and Professor Yevgenia Kozorovitskiy is the corresponding author.

"Chronic sleep loss is well studied, and it's uniformly detrimental effects are widely documented," Kozorovitskiy said. "But brief sleep loss—like the equivalent of a student pulling an all-nighter before an exam—is less understood. We found that sleep loss induces a potent antidepressant effect and rewires the brain. This is an important reminder of how our casual activities, such as a sleepless night, can fundamentally alter the brain in as little as a few hours."

An expert in neuroplasticity, Kozorovitskiy is an associate professor of neurobiology and the Irving M. Klotz Professor at Northwestern's Weinberg College of Arts and Sciences.

Signs of sleep loss

Scientists long have known that acute perturbations in sleep are associated with altered mental states and behaviors. Alterations of sleep and circadian rhythms in patients, for example, can trigger mania or occasionally reverse depressive episodes.

"Interestingly, changes in mood state after acute sleep loss feel so real, even in healthy subjects, as experienced by myself and many others," Wu said. "But the exact mechanisms in the brain that lead to these effects have remained poorly understood."

To explore these mechanisms, Kozorovitskiy and her team developed a new experiment to induce acute sleep loss in mice that did not have genetic predispositions related to human mood disorders. The experimental setup needed to be gentle enough to avoid causing substantial stress for the animals but just uncomfortable enough to prevent the animals from falling asleep.

After a sleepless night, the animals' behavior shifted to become more aggressive, hyperactive and hypersexual, compared to controls that experienced a typical night's sleep.

Using optical and genetically encoded tools, the researchers measured the activity of dopamine neurons, which are responsible for the brain's reward response. And they found activity was higher in animals during the brief sleep loss period.

"We were curious which specific regions of the brain were responsible for the behavioral changes," Kozorovitskiy said. "We wanted to know if it was a large, broadcast signal that affected the entire brain or if it was something more specialized."

Specialized signal

Kozorovitskiy and her team examined four regions of the brain responsible for dopamine release: the prefrontal cortex, nucleus accumbens, hypothalamus and dorsal striatum. After monitoring these areas for dopamine release following acute sleep loss, the researchers discovered that three of the four areas (the prefrontal cortex, nucleus accumbens and hypothalamus) were involved.

But the team wanted to narrow down the results even further, so they systematically silenced the dopamine reactions. The antidepressant effect disappeared only when researchers silenced the dopamine response in the medial prefrontal cortex. By contrast, the nucleus accumbens and hypothalamus appeared to be most involved in the hyperactivity behaviors but were less connected to the antidepressant effect.

"The antidepressant effect persisted except when we silenced dopamine inputs in the prefrontal cortex," Kozorovitskiy said. "That means the prefrontal cortex is a clinically relevant area when searching for therapeutic targets. But it also reinforces the idea that has been building in the field recently: Dopamine neurons play very important but very different roles in the brain. They are not just this monolithic population that simply predicts rewards."

Heightened neuroplasticity

While most of the behaviors (such as hyperactivity and increased sexuality) disappeared within a few hours following acute sleep loss, the antidepressant effect lingered for a few days. This suggested that synaptic plasticity in the prefrontal cortex might be enhanced.

When Kozorovitskiy and her team examined individual neurons, they discovered just that. The neurons in the prefrontal cortex formed tiny protrusions called dendritic spines, highly plastic features that change in response to brain activity. When the researchers used a genetically encoded tool to disassemble the synapses, it reversed the antidepressant effect.

Evolving to avoid predators?

While researchers do not fully understand why sleep loss causes this effect in the brain, Kozorovitskiy suspects evolution is at play.

"It's clear that acute sleep deprivation is somehow activating to an organism," Kozorovitskiy said. "You can imagine certain situations where there is a predator or some sort of danger where you need a combination of relatively high function with an ability to delay sleep. I think this could be something that we're seeing here. If you are losing sleep routinely, then different chronic effects set in that will be uniformly detrimental. But in a transient way, you can imagine situations where it's beneficial to be intensely alert for a period of time."

Kozorovitskiy also cautions people not to start pulling all-nighters in order to brighten a blue mood.

"The antidepressant effect is transient, and we know the importance of a good night's sleep," she said. "I would say you are better off hitting the gym or going for a nice walk. This new knowledge is more important when it comes to matching a person with the right antidepressant."

More information: Mingzheng Wu et al, Dopamine pathways mediating affective state transitions after sleep loss, Neuron (2023). DOI: 10.1016/j.neuron.2023.10.002. www.cell.com/neuron/fulltext/S0896-6273(23)00758-4

https://medicalxpress.com/news/2023-11-sleepless-night-rapidly-reverse-depression.html

Colorectal cancer: Aspirin found to activate protective genes

 LMU researchers have identified a signaling pathway by which aspirin can inhibit colorectal cancer.

Colorectal cancer (bowel cancer) is the third most common form of cancer worldwide, with around 1.9 million newly diagnosed cases and 900,000 deaths every year. Therefore, preventive substances represent an urgent clinical need. Aspirin/acetylsalicylic acid has proven to be one of the most promising candidates for the prevention of colorectal cancer.

Among other findings, studies have shown that when patients with cardiovascular diseases took low doses of aspirin over several years, it reduced their risk of colorectal cancer. Furthermore, aspirin can inhibit the progression of colorectal cancer. Now a team led by Heiko Hermeking, Professor of Experimental and Molecular Pathology at LMU, has investigated which molecular mechanisms mediate these effects.

As the researchers report in the journal Cell Death and Disease, aspirin induces the production of two tumor-suppressive microRNA molecules (miRNAs) called miR-34a and miR-34b/c. To do this, aspirin binds to and activates the enzyme AMPK, which in turn alters the transcription factor NRF2 such that it migrates into the cell nucleus and activates the expression of the miR-34 genes.

For this activation to succeed, aspirin additionally suppresses the oncogene product c-MYC, which otherwise inhibits NRF2.

Overall, the results show that the miR-34 genes are necessary for mediating the inhibiting effect of aspirin on colorectal cancer cells. Aspirin was thus unable to prevent migration, invasion, and metastasis in miR-34-deficient cancer cells. It was already known that the miR-34 genes are induced by the transcription factor p53 and mediate its effects.

"Our results show, however, that activation of the miR-34 genes by aspirin takes place independently of the p53 signaling pathway," says Hermeking.

"This is important because the p53-encoding gene is the most commonly inactivated tumor suppressor gene in colorectal cancer. In most other kinds of cancer, moreover, p53 is inactivated by mutations or viruses in the majority of cases. Aspirin could therefore be employed therapeutically in such cases in the future."

More information: Chunfeng Liu et al, Salicylate induces AMPK and inhibits c-MYC to activate a NRF2/ARE/miR-34a/b/c cascade resulting in suppression of colorectal cancer metastasis, Cell Death & Disease (2023). DOI: 10.1038/s41419-023-06226-9

https://medicalxpress.com/news/2023-11-colorectal-cancer-aspirin-genes.html

At least 14% of Americans have long COVID, research suggests

 One in seven people in the US reported having had long COVID by the end of 2022, suggests a large-scale investigation of long COVID and symptom prevalence by academics at UCL and Dartmouth.

Having had long COVID is associated with anxiety and low mood, as well as an increased likelihood of continued physical mobility problems and challenges with memory, concentration or understanding, according to the findings published in PLOS ONE.

The risk of anxiety and low mood appeared to be lower for those who have been vaccinated, including for those who have had long COVID.

Co-author Professor Alex Bryson (UCL Social Research Institute) said, "Little is known about long COVID and its impact on health and well-being, but there is a growing body of evidence that many people experience persistent and concerning symptoms."

"Here, we have found that long COVID continues to affect millions of people in the US, with some groups much more affected than others. Those who have ever had long COVID remain more likely to report low mood, challenges in carrying out daily tasks, and challenges with memory, concentration and understanding, compared to people who have never had long COVID."

The researchers reviewed data from 461,550 people who responded to the US Census Bureau's Household Pulse Survey from June to December 2022. They were comparing people who said they had never had COVID-19, with those who had had a COVID-19 infection without lingering symptoms, and those who currently or previously had long COVID.

In line with the World Health Organization (WHO), they defined long COVID as the continuation or development of new symptoms at least three months after the initial infection.

The researchers found that nearly half (47%) of people surveyed reported having had COVID-19 at some point, while 14% of the total had had long COVID at some point, half of whom (7% of the total) still had long COVID symptoms when answering the survey. The findings suggest that one in three people who contract COVID-19 may end up with long COVID symptoms. The researchers caution that a limitation of their study is that it relies on people self-reporting symptoms, while some people surveyed may have had COVID-19 without knowing it.

The researchers found that people who had ever had long COVID were more likely to have negative affect (anxiety, depression, worry or a lack of interest in things), as well as physical mobility problems and problems dressing and bathing, all of which were self-reported by answering a questionnaire. Having had long COVID was also associated with self-reported problems with memory or concentration, and with understanding or being understood.

They also found that long COVID was more common in women than men, with rates also elevated among white people, middle-aged people, and people with lower incomes or educational attainment, while being most common in West Virginia (18% of the population) and least common in Hawaii (11%).

Long COVID was also much more common among people who had severe symptoms during the initial COVID-19 infection, as 31% of people who reported currently having long COVID said they initially had severe COVID-19 symptoms, compared to only 7% of the people who had COVID-19 without developing long COVID.

They say that further research is needed to better understand how long COVID causes its various potential symptoms, while better longitudinal data is also needed to understand the potential impacts of vaccinations on long COVID risks.

More information: Long COVID in the United States, PLoS ONE (2023). DOI: 10.1371/journal.pone.0292672

https://medicalxpress.com/news/2023-11-americans-covid.html

New study calls into question the superiority of stem cell therapy for treating knee pain

 Characterized by extensive damage to joints and debilitating pain, osteoarthritis (OA) impacts millions of people worldwide and has long posed a substantial clinical and economic burden.

In spite of advances in diagnosis, medications, and short-term pain management solutions, the elusive goal of a disease-modifying OA drug has remained out of reach. In recent years though, the use of stem cell therapy has gained traction as a promising alternative to surgery and for improving patients' quality of life.

Now, an Emory team of investigators in collaboration with other recruitment sites throughout the nation has explored the potential of mesenchymal stem cells as a game-changing treatment option for knee OA, one of the most common causes of chronic knee pain. This type of treatment seeks to harness the ability of a patient's own cells to repair damaged tissue. However, the availability of robust data from well-designed randomized controlled trials has been limited, particularly in comparison to the gold-standard of treatment for knee OA, corticosteroid injections (CSI).

The initial findings of this study, which were just published in Nature Medicine, describe a first-of-its-kind randomized clinical trial to identify the most effective source of cellular injections for knee OA. The research team compared three types of cellular preparations, including autologous bone marrow aspirate concentrate (BMAC), autologous stromal vascular fraction (SVF), and allogenic human umbilical cord tissue MSCs (UCT) against CSI.

The primary outcome measures were the visual analog scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain from baseline to one year. The question driving the research was whether cell therapies could outperform corticosteroids in the treatment of knee osteoarthritis at the one-year mark.

While the findings showed each group had a measurable improvement in pain and function, there was no significant advantage to using any of the tested cell products compared to the gold standard anti-inflammatory corticosteroid treatment at the 12-month follow-up regarding the change in VAS pain score from baseline. Similarly, the analysis of the KOOS pain score produced consistent results, with no significant differences between groups at the 12-month mark in the change in score from baseline.

"The study demonstrated no superiority of any cell therapy over corticosteroids in reducing pain intensity over the course of a year," says Scott D. Boden, MD, director of the Emory Orthopaedics and Spine Center, and a senior author on the study. "While there is much enthusiasm about the regenerative capacity of stem cells, the findings call into question the comparative effectiveness of various injections for knee osteoarthritis and underscores the importance of a personalized approach in selecting the right treatment for each patient's unique needs."

The study's extensive reach also extended to evaluating the safety of these procedures measuring every adverse reaction, ranging from mild joint discomfort and swelling to unrelated hospitalizations. Importantly, the study found no study-related serious adverse events or symptomatic knee infections across any of the treatment groups at any point during the follow-up.

According to Dr. Boden, future papers from the ongoing analysis of the data will determine if certain subgroups of patients might preferentially benefit from one of these treatments more than another. The findings offer an important step forward in answering key questions about the comparative effectiveness of certain OA treatment options, but more in-depth analysis using MRIs and cellular analysis of each injectate will continue to help inform standards of care.

More information: Ken Mautner et al, Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial, Nature Medicine (2023). DOI: 10.1038/s41591-023-02632-w

https://medicalxpress.com/news/2023-11-superiority-stem-cell-therapy-knee.html

No Longer Fringe: Home Schooling Revolution Reshaping American Education

 In the ever-evolving landscape of American education, a quiet revolution is taking place. Over the past six years, home schooling has surged by 51% - in stark contrast to the 7% rise in private school enrollment, and a 4% dip in public schools over the same period, according to an in-depth look by the Washington Post at thousands of school districts spanning 32 states which provide accurate data. 

Once limited to the peripheries of mainstream education, home schooling is rapidly emerging as a force to be reckoned with. Between the Covid lockdowns, pissed-off conservative parents who don't want their children indoctrinated by mentally ill activists.

The pandemic, with its sweeping disruptions to conventional schooling, undoubtedly served as a catalyst for this seismic shift. Schools across the country shuttered, forcing millions of families to grapple with remote learning and rethink the entire educational paradigm. Yet, as the pandemic wanes and schools reopen, shedding many of their COVID-19 constraints, the surge in home schooling has not only persisted but flourished.

"This is a fundamental change of life, and it’s astonishing that it’s so persistent," according to Nat Malkus, a senior fellow and deputy director of education policy at the American Enterprise Institute, a conservative-leaning think tank.

This trend isn't confined to specific regions or demographics; from the bustling streets of Upper Manhattan to the tranquil landscapes of Eastern Kentucky, families are increasingly opting to take the educational reins into their own hands.

The personal costs to home schooling are more than just tuition," Malkus said. "They are a restructuring of the way your family works."

The most home-schooled students live in Florida, which has 154,000 of them, while several states have seen growth exceeding 75% in the 2017-2018 school year.

While the Washington DC has seen the most state-wide growth, New York City takes the cake at the city-level.

In 24 of the city’s 33 school districts, home-schooled children increased by at least 200 percent over six years. The largest growth was seen in Brooklyn and in the Bronx, where some districts exceeded 300 percent growth.

Afua Brown, who lives in Harlem, pulled her daughter out of a public elementary school in 2015 after she was bullied in kindergarten. Private school was too expensive, so Brown tried her hand at home education for her daughter and younger son.

She eventually became a leader in the New York City Home Educators Alliance, where she watched the local home-school community expand dramatically. But while their ranks can feel large at the organization’s science fairs, picnics and ice skating days, Brown recognizes home-schoolers are still a tiny fraction of the city’s school-age kids. Her children were among 377 in the fall of 2022 in a school district, including Manhattan’s Upper West Side and part of Harlem, where public enrollment is close to 20,000. -WaPo

The data dismantles several preconceived notions about home schooling. First and foremost, the boom isn’t a mere reaction to failing public schools. The Post found no substantial correlation between a district's quality, as determined by standardized test scores, and its growth in home schooling. Surprisingly, even districts that consistently score high on standardized tests have seen spikes in home schooling.

Implications

The rise of home schooling is reshaping the very fabric of American education. On one hand, it empowers parents, offering them the autonomy to tailor their children's education. On the other, it poses challenges for the public education system, which relies on funding based on student enrollment.

"If [home-schooled] students are not enrolled in our district, we are not getting funding for them," said Krystal Goode, a high school social studies teacher and head of the Pulaski County Education Association.

Furthermore, the lack of oversight and regulation in many states raises questions about the quality and consistency of education received by home-schooled students. Without standardized tests or curriculum guidelines, ensuring that students receive a comprehensive education falls squarely on the shoulders of parents.

From left, brothers Nealan and Justice Boyd work to create a book about the arts, a project led by a local home schooling co-op run by their mother, Lori Boyd, in Pulaski County, Ky.

"I can tell you right now: Many of these parents don’t have any understanding of education," said Hillsborough County School Board member Lynn Gray. "The price will be very big to us, and to society. But that won’t show up for a few years."

While it's clear that home schooling has cemented its place in the American educational system, its trajectory remains to be seen. Will it continue its upward trend, further buoyed by policies and societal shifts? Or will it stabilize, finding its niche alongside public and private schools?

Meanwhile, WaPo's report comes as Portland, Oregon teachers begin a district-wide strike, shuttering schools for more than 45,000 students. Home Schooling FTW.

https://www.zerohedge.com/political/no-longer-fringe-home-schooling-revolution-reshaping-american-education

Alfasigma to buy Galapagos’ JAK drug for up to €170m

 Galapagos has signed a deal to jettison its troubled JAK inhibitor drug Jyseleca, agreeing to sell the rights to rheumatoid arthritis and ulcerative colitis therapy to Italy’s Alfasigma SpA in a deal valued at up to €170 million plus royalties.

Terms outlined in the letter of intent would consist of a €50 million upfront payment and potential milestones of €120 million, with Alfasigma in line to pay mid-single to mid-double digit royalties on European sales. Galapagos would also pay up to €40 million over the next couple of years to Alfasigma in return for Jyseleca (filgotinib) development activities.

If concluded, the deal will see Alfasigma take over the marketing authorisations for the JAK1 inhibitor in the EU and UK and absorb approximately 400 Galapagos employees involved in commercial, medical and development activities for the drug.

Once billed as a future blockbuster and rival to big-selling JAK drugs like Pfizer’s Xeljanz (tofacitinib), Jyseleca was hit by a series of setbacks, including a decision by the FDA to reject it as a rheumatoid arthritis therapy in 2020, over concerns it could damage male fertility.

Shortly afterwards, former partner for the drug, Gilead Sciences, abandoned efforts to get US approval and paid Galapagos €160 million to take over various clinical trials and hand back rights to the drug in Europe. The programme has also suffered from failed studies in follow-up indications, including immune system disorders, lupus and Sjögren’s syndrome, as well as Crohn’s disease.

Jyseleca was at the heart of a $5 billion-plus R&D alliance between Gilead and Galapagos, signed in 2019, that has steadily contracted since then as a result of Jyseleca setbacks as well as other failed programmes, including idiopathic pulmonary fibrosis (IPF) therapy ziritaxestat, the flagship programme in the alliance.

Sales of Jyseleca, meanwhile, have been small, at €54 million in the first six months of 2023 and with a cost on sales of almost €8 million. Galapagos recently reduced its forecasts for full-year sales of the drug to €100-€120 million from €140-€160 million after deciding not to progress with European filings for Crohn’s and a Swiss application for ulcerative colitis.

The Alfasigma deal adds to a healthy cash pile at Belgium-based Galapagos and will also contribute to a cost-reduction drive aiming to slash its annual expenses by €150 to €200 million a year, with another 100 jobs set to go at the company.

For privately-held Alfasigma, meanwhile, the deal is further evidence of its plans for international expansion, coming just a few weeks after it negotiated a deal to buy Intercept Pharma and its Ocaliva (obeticholic acid) therapy for primary biliary cholangitis (PBC) for around $800 million.

“We believe this will benefit both companies and ensure that Jyseleca will continue to be available to patients who can benefit from it,” said Alfasigma’s chief executive, Francesco Balestrieri.

https://pharmaphorum.com/news/alfasigma-buy-galapagos-jak-drug-eu170m

Imfinzi faces Keytruda competition in biliary tract cancer

 MSD’s PD-1 inhibitor Keytruda has been approved by the FDA as a treatment for locally advanced unresectable or metastatic biliary tract cancer (BTC) in combination with chemotherapy, the first immunotherapy competitor to AstraZeneca’s Imfinzi for these patients.

The approval was based on the KEYNOTE-966 study, which found a statistically significant and clinically meaningful improvement in overall survival (OS) versus chemo alone in newly diagnosed BTC patients.

The results showed a 17% increase in OS for Keytruda (pembrolizumab), coming in at a median of 12.7 months for the combination versus 10.9 months for chemo alone.

Biliary tract cancer occurs in the bile ducts and gallbladder, with approximately 23,000 diagnoses in the US each year. Life expectancy is poor, with just 5% to 15% of patients expected to live beyond five years.

The disease can be asymptomatic in the early stages, so patients have often progressed to more severe disease before treatment starts, when options are limited and prognosis is poor.

It remains to be seen if the data with Keytruda will be strong enough to supplant Imfinzi (durvalumab), which was approved for BTC by the FDA last year on the back of data from the TOPAZ-1 trial, which showed a 20% improvement in OS with Imfinzi plus chemo compared to chemo alone. In that study, median OS came in at 12.8 months and 11.1 months, respectively.

At the time, Imfinzi was trumpeted as the first advance in the treatment of BTC in a decade, when it was found that dual chemo with cisplatin and gemcitabine was more effective than gemcitabine alone, which for years was the standard therapy for this type of cancer.

Imfinzi is also approved for forms of lung and liver cancer and said in its second-quarter update that BTC and hepatocellular carcinoma (HCC) – the most common form of liver cancer – were driving a health 57% increase in sales to almost $2 billion in the first half of this year.

Imfinzi and chemo had become the “undisputed standard of care within months,” said AZ’s head of oncology, Dave Fredrickson, in the update, adding that take-up of the regimen in Europe and Japan was “outpacing the US trajectory.”

OS benefit in kidney cancer

While Keytruda’s potential in BTC is hard to gauge, MSD (known as Merck & Co in the US) had more good news with the drug today from a clinical trial in renal cell carcinoma, a form of kidney cancer.

In the KEYNOTE-564 study, Keytruda has become the therapy to show a statistically significant improvement in OS compared to placebo when used as adjuvant therapy for RCC patients at high risk of recurrence after surgery to remove the cancer.

Keytruda is already approved for the indication, based on interim results reported in 2021 that showed a 32% improvement in disease-free survival (DFS) with the drug. The OS benefit isn’t being disclosed for now, but was “clinically meaningful,” according to MSD.

Adjuvant treatment moves use into patients with earlier-stage cancer, a key strategy for Merck and other cancer immunotherapy companies, as it expands the pool of patients eligible for treatment.

https://pharmaphorum.com/news/imfinzi-faces-keytruda-competition-biliary-tract-cancer