Doctors Suing Food And Drug Administration Over Ivermectin

 by Alice Giordano via The Epoch Times (emphasis ours),

A Washington law firm has filed a federal lawsuit against the Food and Drug Administration (FDA) for interfering with the use of ivermectin as a treatment for COVID-19.

The lawsuit was filed by Boyden Gray & Associates on behalf of three doctors who were disciplined for prescribing human-grade ivermectin to patients.

The firm’s founder, attorney Boyden Gray, is a former legal adviser to the Reagan and Bush administrations.

Gray told The Epoch Times that the FDA had violated well-established law that allows doctors to prescribe an FDA-approved drug as an off-label treatment.

Ivermectin was no different, he said. It was approved by the FDA in 1966.

“Congress recognized the importance of letting doctors be doctors and expressly prohibited the FDA from interfering with the practice of medicine,” Gray said.

“That is exactly what the FDA has done time and time again throughout this pandemic, assuming authority it doesn’t have and trying to insert itself in the medical decisions of Americans everywhere.”

The three plaintiffs in the case are Dr. Paul Marik of Virginia, Dr. Mary Bowden of Texas, and Dr. Robert Apter of Arizona.

Marik is a founder of the Front Line COVID-19 Critical Care 21 Alliance (FLCCC), a national nonprofit that promotes alternative COVID-19 treatments to the government-touted vaccine.

“The FDA has made public statements on ivermectin that have been misleading and have raised unwarranted concern over a critical drug in preventing and treating COVID-19,” Marik told The Epoch Times. “To do this is to ignore both statutory limits on the FDA’s authority and the significant body of scientific evidence from peer-reviewed research.”

According to Marik, more than 80 medical trials conducted since the outbreak of COVID-19 show that ivermectin is a safe and effective treatment for the virus.

Gray said the FDA has engaged in unlawful interference with the use of ivermectin and should be held accountable for that.

The lawsuit included several statements made by the FDA that Gray said show that the administration interfered with the use of ivermectin.

They include an Aug. 21, 2021, Twitter post by the agency: “You are not a horse. You are not a cow. Seriously, y’all. Stop it.”

The post, with an image of a horse and a doctor, has a headline that reads, “Why you should not use ivermectin to treat or prevent COVID-19.”

Marik, Bowden, and Apter are among a number of U.S. doctors across the United States who have been disciplined for prescribing ivermectin.

Marik, a critical care specialist, was suspended by Sentara Norfolk General Hospital for prescribing ivermectin as a COVID-19 treatment. Bowden, an ear, nose, and throat specialist, was suspended from the Houston Medical Hospital. Apter was under investigation by both the Washington Medical Commission and Arizona Medical Board for prescribing ivermectin.

Marik was recently informed that he was under investigation by the medical licensing board in Virginia.

Gray filed the lawsuit in U.S. District Court in Texas.

The doctors are seeking a permanent injunction that would prohibit the FDA from interfering with the use of ivermectin for the treatment of COVID-19.

https://www.zerohedge.com/covid-19/doctors-suing-food-and-drug-administration-over-ivermectin

With Border Cities Swamped, Biden To Bus Migrants Deeper Into US

 With border cities overwhelmed by a record surge in migration, the Department of Homeland Security is planning to start transporting migrants into cities away from the border, according to DHS documents reviewed by NBC News.  

Los Angeles has been designated as the first city to be the recipient of the transported migrants, with Albuquerque, Houston, Dallas and others to follow. In a statement to NBC, DHS said "no decision has been made." 

Away from microphones, DHS officials jokingly refer to the scheme as the "Abbott plan," according to an unidentified official who spoke to NBC. That's a reference to Texas governor Greg Abbott, who earlier this year sent at least 10 busloads of illegal immigrants to Washington, D.C. as a means of redistributing the wealth of inbound Latin American diversity.  

At the time, Customs and Border Protection commissioner Chris Magnus said Abbott's shipping of immigrants made CBP's job more difficult. 

Texas taxpayers paid for those buses, but the federal embrace of the Abbott plan will put all taxpayers on the hook for who knows how much. The new scheme will be managed by the Southwest Border Coordination Center, a joint undertaking of CBP, the Federal Emergency Management Agency (FEMA), Immigration and Customs Enforcement and other agencies. 

The busing plan is Washington's answer to overflowing shelters run by charitable and nongovernmental organizations in border cities. In April, CBP tallied a record-breaking 234,088 migrant encounters.  

NBC's revelation of the Biden administration plan comes the same week that a massive migrant caravan has begun a thousand-mile trek from Mexico's Guatemala border to the Rio Grande. Numbering upwards of 12,000, the group paused Wednesday in the town of Huixtla while the Mexican government issued work visas that will ease their travel throughout Mexico and up to the U.S. border. 

On Friday, Biden is expected to sign an international declaration on migration at the poorly-attended "Summit of the Americas" that he's hosting in Los Angeles. According to AP, the declaration will "call for more pathways to legal status, mechanisms to reunite families, more efficient and humane border controls and improved information sharing."

https://www.zerohedge.com/political/border-cities-swamped-biden-bus-migrants-deeper-us

Dogs inhale immunotherapy to test lung cancer treatment

 A protein that the body naturally produces could become an important new immunotherapy drug in the cache of cancer-fighting tools available to oncologists. UC Davis cancer researchers for both companion dogs and humans joined scientists from other institutions to study a new approach that triggers the body's defense mechanisms, its T-cells and natural killer (NK) cells, to respond and destroy cancer.

Surgical oncologist Robert J. Canter with UC Davis Comprehensive Cancer Center and canine oncologist Robert B. Rebhun with the UC Davis School of Veterinary Medicine are corresponding authors for a study just published in the Journal for ImmunoTherapy of Cancer.

In the first-of-its-kind Phase 1 clinical trial, 21 pet dogs of various breeds that had metastatic lung disease resulting from osteosarcoma or melanoma were treated with protein interleukin-15 (IL-15). Although previously recognized for immunotherapy properties, IL-15 has undergone few human clinical trials because of toxicity risks associated with concentrated doses.

"No one previously had administered IL-15 as an inhaled treatment in dogs to deliver it directly to the site of the cancer. We came up with that idea as a means of reducing exposure to the rest of the body, in order to improve the benefit-risk ratio, to improve the immune stimulating effects, and to reduce toxicity," Canter explained. "In this study, we used interleukin-15 to reinvigorate the immune system to make it recognize the cancer cells that had evaded the immune system and eliminate them."

The research shows that amplified concentrations of IL-15 can stimulate immune system defenses against some types of cancers in dogs. IL-15 is one of several types of cytokines -- substances that have signaling and regulating functions in immune system activity.

"As part of our comparative oncology research, we are strong advocates of clinical trials in companion dogs, especially for immunotherapy, as a way to speed bench-to-bedside translation," said Canter, who is chief of the UC Davis Division of Surgical Oncology and co-director of the comparative oncology training program at UC Davis. "The cancers that afflict dogs, including sarcomas, brain tumors, lymphoma and melanoma, are incredibly similar to cancers that humans develop."

UC Davis received a $2 million National Cancer Institute grant to fund the comparative oncology training program to support the next generation of oncology researchers collaborating on curing cancer in both humans and dogs. For instance, osteosarcoma and melanoma that develop elsewhere in the body commonly spread to the lung, in dogs as well as humans.

Methodology

In the study, conducted between October 2018 and December 2020, the dogs inhaled a mist containing IL-15 twice daily. Doses were increased over time, to help determine not only effectiveness, but also tolerable levels and the ceilings above which toxicity would result. Dogs exhibited significant responses within 14 days after they began inhaling the IL-15 mist.

Tumors shrank dramatically in two dogs in the study, including one that went into complete remission for more than a year. Cancer that had been growing rapidly in five other dogs stabilized for several months. "Our overall response rate, the clinical benefit rate, was close to 40%," Canter said.

For that and other reasons, additional studies are needed, noted Rebhun, a professor in the UC Davis School of Veterinary Medicine's Department of Surgical and Radiological Sciences.

"The inhaled IL-15 responses that we've seen in dogs are better than prior human studies, but clinical benefit is seen in less than half of the dogs. Using IL-15 in people has led to potentially favorable immune responses but has not yielded good tumor responses. This indicates that combining IL-15 with other immunotherapies may result in additive or synergistic responses," said Rebhun, who holds the Maxine Adler Endowed Chair in Oncology and is the associate director of the cancer program in the Center for Companion Animal Health.

Key findings

In his view, the study yielded two significant findings: the therapy was well tolerated, and even a short two-week course of inhaled IL-15 could lead to sustained suppression of advanced and diffuse metastatic cancer. Both he and Canter noted that in eventual clinical application, IL-15 likely would be used not as a standalone therapy, but as a reinforcement in combination with other treatments.

"All of the canine patients in this study had advanced metastatic cancer, and the majority already had received prior chemotherapy, radiation therapy and, in some cases, immunotherapy. Studies are ongoing now to see whether we can predict which patients might respond to this therapy based on properties of the tumor or the patient's immune status," Rebhun said.

"This may help us identify patients that might respond to this therapy, as well as help us understand how to potentially combine other immunotherapies to improve response rates. We are grateful to the extremely dedicated clients who sought any and all possible care for their pets, elected to enroll them in this study, and even delivered the inhaled IL-15 to their dogs at home -- in hopes that it could benefit their dog, other dogs, or possibly even people with advanced metastatic cancer," Rebhun said.

Other authors of the study included UC Davis researchers Daniel York, Sylvia M. Cruz and Sean J. Judge, along with Colorado State University scientists Rachel V. Brady and Jenna H. Burton, and Louisiana State University researcher Sita S. Withers.

As part of the grant for the study, the National Institutes of Health supplied the recombinant IL-15, which it expressed from source materials. The study was supported in part by National Institutes of Health/National Cancer Institute grants U01CA224166-01, R03CA252793, K01OD026526, and T32CA251007. This work was also supported in part by funds from UC Davis Comprehensive Cancer Center and the University of California Davis Flow Cytometry Shared Resource laboratory with funding from NCI P30 CA093373 (cancer center) and S10 OD018223 (Astrios Cell Sorter) and S10 RR 026825 (Fortessa Cytometer) grants, with technical assistance from Bridget McLaughlin and Jonathan Van Dyke. Additional support came from the UC Davis Center for Companion Animal Health and from Maxine Adler Endowed Chair funds.

Story Source:

Materials provided by University of California - Davis Health. Note: Content may be edited for style and length.

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Journal Reference:

1. Robert B Rebhun, Daniel York, Sylvia Margret Cruz, Sean J Judge, Aryana M Razmara, Lauren E Farley, Rachel V Brady, Eric G Johnson, Jenna H Burton, Jennifer Willcox, Luke A Wittenburg, Kevin Woolard, Cordelia Dunai, Susan L Stewart, Ellen E Sparger, Sita S Withers, Alicia A Gingrich, Katherine A Skorupski, Sami Al-Nadaf, Amandine T LeJeune, William TN Culp, William J Murphy, Michael S Kent, Robert J Canter. Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response. Journal for ImmunoTherapy of Cancer, 2022; 10 (6): e004493 DOI: 10.1136/jitc-2022-004493

https://www.sciencedaily.com/releases/2022/06/220609155822.htm

Hormones contribute to sex disparities in bladder cancer, study shows

 Male sex hormones interfere with the body's ability to fight bladder cancer, likely explaining why males experience higher cancer rates and more deadly disease, according to a new study co-led by a Cedars-Sinai Cancer investigator.

These findings, published in Science Immunology, could represent a significant step toward unraveling why disparities in cancer incidence, prognosis and treatment response exist between males and females. Males are more likely than females to develop most types of cancer. This is most evidently displayed in bladder cancer rates; studies show males are three to five times more likely than females to develop it.

"Historically, it was thought males may have higher cancer rates because they are more likely to engage in behaviors that predispose them to cancer, such as smoking," said Xue Li, PhD, a senior and corresponding author of the study and research scientist at Cedars-Sinai. "We observed that biology of sex, not just behavior, is an important factor in cancer development."

Androgens, sex hormones produced in higher amounts in males, promote the development of the reproductive system. Li and a team of investigators discovered that androgens interfere with the adaptive immune system, which comprises cells that remember how to respond to pathogens with which the body has previously come into contact. Androgens seem to block the activity of tumor-killing cells called CD8+ T cells, the investigators report.

Li and colleagues studied a mouse bladder cancer model in which more aggressive tumors arise in male mice, mimicking the incidence observed in humans. With this model, they experimented with removing various immune cells in mice of both sexes. When they removed CD8+ T cells, the male and female differences in cancer severity disappeared. This suggested that the way androgens interact with CD8+ T cells contributes to the sex differences in bladder cancer. Furthermore, the team found tumors grew more aggressively in mice with higher levels of androgens.

The most surprising finding, however, was observed when the team performed genetic sequencing of CD8+ T cells from the tumors, Li said. The CD8+ T cells in males showed more signs of exhaustion and dysfunction due to androgen activity. Androgen deprivation therapy, a common clinical treatment for prostate cancer, was effective in reducing bladder tumor size in male mice and improved the efficacy of immunotherapy.

The findings may explain in part why male and female patients respond differently to a type of cancer therapy called an immunotherapy, which helps the body's CD8+ T cells attack cancer cells.

"T cells are like soldiers commissioned to kill tumor cells. However, they can become exhausted, so immunotherapy is used to rejuvenate them," Li said. "Unfortunately, many cancer patients do not respond to immunotherapy. These findings suggest male patients may benefit more from immunotherapy when combined with androgen deprivation therapy."

Li and colleagues plan to continue studying how and when androgen-inhibiting therapy may aid bladder cancer treatment. Similar to other cancers like breast cancer and prostate cancer that are affected by sex hormones, hormone therapy for bladder cancer may work best when given early in the course of the disease.

Funding: The study was funded by grants from the National Institutes of Health (R01 CA213290, R01 CA262069, R01 CA255334, R01 CA262338, R01 AI077283, R01 DK110477, U01 DK131377, R21 CA249701, and K08AI139375), a Young Investigator Award from the Prostate Cancer Foundation, the Damon Runyon Clinical Investigator Award, the Doctoral Foreign Study Award from the Canadian Institutes of Health Research (201810DFS-422133-63414), a Graduate Fellowship from the Medical University of South Carolina Hollings Cancer Center, and the Ohio State University Comprehensive Cancer Center Tumor Immunology T32 Training Program (2T32CA09223-16A1).

Story Source:

Materials provided by Cedars-Sinai Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Hyunwoo Kwon, Johanna M. Schafer, No-Joon Song, Satoshi Kaneko, Anqi Li, Tong Xiao, Anjun Ma, Carter Allen, Komal Das, Lei Zhou, Brian Riesenberg, Yuzhou Chang, Payton Weltge, Maria Velegraki, David Y. Oh, Lawrence Fong, Qin Ma, Debasish Sundi, Dongjun Chung, Xue Li, Zihai Li. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Science Immunology, 2022; DOI: 10.1126/sciimmunol.abq2630

https://www.sciencedaily.com/releases/2022/06/220609195008.htm

Existing cancer therapy in narrow use shows significant activity against other cancers

 A drug used to target IDH1 mutations in select cancers also appears to inhibit the wild-type form of the enzyme, under certain conditions. This feature explains why a large group of different cancers are vulnerable to the drug. This discovery opens up the possibility that the drug, Ivosidenib or AG-120, could become more broadly applicable against a variety of cancers, given that mutant IDH1 is present in just 1% of cancers. The findings were recently published in Nature Cancer.

"Historically, only a few groups have cared about wild-type IDH1," said Jordan Winter, MD, Division Chief of Surgical Oncology at University Hospitals (UH) Seidman Cancer Center and senior author on the study. Dr. Winter is also John and Peggy Garson Family Endowed Chair in Pancreatic Cancer Research and Jerome A. and Joy Weinberger Family Master Clinician in Surgical Oncology. "IDH1 therapeutic investigations have principally focused on the development of mutant IDH1 inhibitors. Less than a handful of reports have focused on wild-type IDH1 inhibition. We showed, along with a few others, that wild-type IDH1 is an important target. We think that Ivosidenib, previously called AG-120, may be applicable to the large majority of cancers-the one percent with mutant IDH1 and the remaining 99% with wild-type IDH1."

Fundamental to this discovery is the observation that cancer cells rely on IDH1 metabolism to thrive in a harsh and nutrient-deprived tumor microenvironment. Nutrient limitation universally present in pancreatic tumors could open a new therapeutic window, explains the study's first author Ali Vaziri-Gohar, PhD, Postdoctoral Fellow in the Department of Surgery at Case Western Reserve University School of Medicine.

"Wild-type IDH1 activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu," he said. "We found that IDH1 is very important for cancer cells' survival in a stressful microenvironment. When the cancer cells have less oxygen and less glucose or glutamine, anything that hurts them, they need a defense mechanism to protect them, which is this important molecule IDH1."

In laboratory experiments, Dr. Winter, Dr. Vaziri-Gohar, and colleagues demonstrated that genetically suppressing IDH1 reduced growth of pancreatic cancer cells in cell culture under low nutrient conditions and in mouse models of pancreatic cancer. They found, too, that the FDA-approved inhibitor of mutant IDH1, Ivosidenib, was surprisingly potent against the wild-type form of the protein-especially when paired with the important condition of low magnesium. This latter point had been overlooked in prior studies.

Dr. Vaziri-Gohar said that this finding was a bit of scientific serendipity.

"Initially, we were using this drug as a negative control," he explained. "Then we found we can use this drug against cancers that have wild-type isoforms if we reduced levels of magnesium. We tested this hypothesis in cell culture and saw that when the magnesium levels reduced in the tissue culture, they responded to the inhibitor with and lowered activity of the enzyme. This in turn decreased cancer cell survival. However, under the normal cell culture conditions with standard magnesium levels found in the blood or culture media, they didn't respond to this drug. We then realized that magnesium levels were much lower in tumors than in standard culture conditions, so that the drug was actually effective against pancreatic and other cancers when given to animals harboring these tumors."

The presence of low magnesium enhanced allosteric inhibition by the drug, and ambient low glucose levels enhanced cancer cells' dependence on wild-type IDH1. Thus, two conditions present in tumors rendered them sensitive to the drug: low magnesium and low nutrients.

Drs. Winter and Vaziri-Gohar have now tested Ivosidenib in mouse models of pancreatic, colorectal, ovarian and lung cancer, as well as melanoma. In each of these instances, the anti-tumor effect of Ivosdenib was comparable or superior to a previous study of anti-IDH1-mutant tumor therapy. Other drugs developed as mutant-IDH1 inhibitors similarly were effective against tumors without the mutation. In the immunocompetent mouse pancreatic cancer model, Ivosidenib improved median survival by more than two fold. It was also important to the study that these findings were replicated in a completely separated lab, in an experiment performed on the other side of the Atlantic Ocean. A respected mouse model researcher, Dr. Jennifer Morton of the Beatson Institute in Scotland, performed this experiment in a genetically engineered mouse that develops pancreatic cancer.

The next step in the team's research is a clinical trial, made possible by funding from the Gateway for Cancer Research and the John and Peggy Garson Family. Along with his colleague Dr. David Bajor, Dr. Winter plans to enroll 15 patients with resectable pancreatic cancer in a Phase I trial of Ivosidenib in combination with standard of care, FOLFIRINOX. Patients will receive three months of treatment prior to surgery, gauging their response to therapy via imaging, biochemical blood markers and ultimately through pathology once surgery is complete.

"The primary endpoint is just to determine safety of the drug with the existing chemotherapy regimen, because it's never been given together," Dr. Winter, who is also a professor in the Department of Surgery at Case Western Reserve School of Medicine and Member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center, explained. "We're going to compare it to patients who get chemotherapy prior to surgery without the Ivosidenib. However, one of the great things about this trial is that because all of the patients are going to be undergoing surgery, we are going to have all the tumors to analyze and we will be able to assess the tumors for the same metabolic changes previously observed in the lab. We're going to be looking at those same data points, those same markers of response in the patients' tumors to try to demonstrate the biologic activity inside pancreatic cancer in the patients."

Dr. Vaziri-Gohar says he's thankful for the spirit of collaboration across institutions that has allowed the project to progress to this point.

"Beyond the science, it was so gratifying to work with so many people towards a common goal," he said. "That's the most important thing to me. That we worked as a team and hopefully our discovery will help patients. We are so lucky that we have all of these researchers and institutions involved."

Dr. Winter is optimistic about what might be achieved.

"In our hands and in pre-clinical models, wild-type IDH1 represents a true metabolic vulnerability in cancer cells and is a bona fide therapeutic target across a wide range of wild-type IDH1 cancers," he said. "Mutant-IDH1 inhibitors, including FDA-approved Ivosidenib, are potent wild-type IDH1 inhibitors under conditions present in tumors. Since pancreatic and other tumors share this feature, these drugs are compelling investigational agents for these expanded indications."

Story Source:

Materials provided by University Hospitals Cleveland Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Ali Vaziri-Gohar, Joel Cassel, Farheen S. Mohammed, Mehrdad Zarei, Jonathan J. Hue, Omid Hajihassani, Hallie J. Graor, Yellamelli V. V. Srikanth, Saadia A. Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S. Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A. Flask, Mahsa Zarei, Rui Wang, Luke D. Rothermel, Andrea M. P. Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P. Morton, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Joseph M. Salvino, Jonathan R. Brody, Jordan M. Winter. Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors. Nature Cancer, 2022; DOI: 10.1038/s43018-022-00393-y

https://www.sciencedaily.com/releases/2022/06/220609155820.htm

1 in 500 men carry extra sex chromosome, for higher risk of several common diseases

 Around one in 500 men could be carrying an extra X or Y chromosome -- most of them unaware -- putting them at increased risk of diseases such as type 2 diabetes, atherosclerosis and thrombosis, say researchers at the universities of Cambridge and Exeter.

In a study published in Genetics in Medicine, researchers analysed genetic data collected on over 200,000 UK men aged 40-70 from UK Biobank, a biomedical database and research resource containing anonymised genetic, lifestyle and health information from half a million UK participants. They found 356 men who carried either an extra X chromosome or an extra Y chromosome.

Sex chromosomes determine our biological sex. Men typically have one X and one Y chromosome, while women have two Xs. However, some men also have an extra X or Y chromosome -- XXY or XYY.

Without a genetic test, it may not be immediately obvious. Men with extra X chromosomes are sometimes identified during investigations of delayed puberty and infertility; however, most are unaware that they have this condition. Men with an extra Y chromosome tend to be taller as boys and adults, but otherwise they have no distinctive physical features.

In today's study, the researchers identified 213 men with an extra X chromosome and 143 men with an extra Y chromosome. As the participants in UK Biobank tend to be 'healthier' than the general population, this suggests that around one in 500 men may carry an extra X or Y chromosome.

Only a small minority of these men had a diagnosis of sex chromosome abnormality on their medical records or by self-report: fewer than one in four (23%) men with XXY and only one of the 143 XYY men (0.7%) had a known diagnosis.

By linking genetic data to routine health records, the team found that men with XXY have much higher chances of reproductive problems, including a three-fold higher risk of delayed puberty and a four-fold higher risk of being childless. These men also had significantly lower blood concentrations of testosterone, the natural male hormone. Men with XYY appeared to have a normal reproductive function.

Men with either XXY or XYY had higher risks of several other health conditions. They were three times more likely to have type 2 diabetes, six times more likely to develop venous thrombosis, three times as likely to experience pulmonary embolism, and four times more likely to suffer from chronic obstructive pulmonary disease (COPD).

The researchers say that it isn't clear why an extra chromosome should increase the risk or why the risks were so similar irrespective of which sex chromosome was duplicated.

Yajie Zhao, a PhD student at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the study's first author, said: "Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this. This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases -- diseases that may be preventable."

Professor Ken Ong, also from the MRC Epidemiology Unit at Cambridge and joint senior author, added: "Genetic testing can detect chromosomal abnormalities fairly easily, so it might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern.

"We'd need more research to assess whether there is additional value in wider screening for unusual chromosomes in the general population, but this could potentially lead to early interventions to help them avoid the related diseases."

Professor Anna Murray, at the University of Exeter, said: "Our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past."

Previous studies have found that around one in 1,000 females have an additional X chromosome, which can result in delayed language development and accelerated growth until puberty, as well as lower IQ levels compared to their peers.

The research was funded by the Medical Research Council.

Story Source:

Materials provided by University of Cambridge. The original text of this story is licensed under a Creative Commons License. Note: Content may be edited for style and length.

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Journal Reference:

1. Yajie Zhao, Eugene J. Gardner, Marcus A. Tuke, Huairen Zhang, Maik Pietzner, Mine Koprulu, Raina Y. Jia, Katherine S. Ruth, Andrew R. Wood, Robin N. Beaumont, Jessica Tyrrell, Samuel E. Jones, Hana Lango Allen, Felix R. Day, Claudia Langenberg, Timothy M. Frayling, Michael N. Weedon, John R.B. Perry, Ken K. Ong, Anna Murray. Detection and characterization of male sex chromosome abnormalities in the UK Biobank study. Genetics in Medicine, 2022; DOI: 10.1016/j.gim.2022.05.011

https://www.sciencedaily.com/releases/2022/06/220610140856.htm

How the brain controls symptoms of sickness

 When someone gets an infection, most people think it's the immune system kicking into gear when they feel some of the body's natural defenses like a fever, chills, or fatigue. What most people don't know is that it's actually the brain behind all of this.

Here's what happens: The nervous system talks to the immune system to figure out that the body has an infection and then orchestrates a series of behavioral and physiological alterations that manifest as the unpleasant symptoms of sickness. For neuroscientists, long-standing questions have been: How and where does this happens in the brain? Harvard researchers from the labs of Catherine Dulac and Xiaowei Zhuang sought the answer in the brains of mice.

In a new study published in Nature, the researchers and their collaborators describe finding a small population of neurons near the base of the brain that can induce symptoms of sickness, including fever, appetite loss, and warm seeking behavior.

The neurons, which have not been previously described, are found in an area of the hypothalamus, a part of the brain known for controlling key homeostatic functions that keep the body in a balanced, healthy state. The researchers found these neurons have receptors that are capable of directly detecting molecular signals coming from the immune system, an ability most neurons don't have.

"It was important for us to establish this general principle that the brain can even sense these immune states," said Jessica Osterhout, a postdoctoral researcher in the Dulac Lab and the study's lead author. "This was poorly understood before."

The researchers found that the key area of the hypothalamus is located right next to a permeable section of the brain called the blood-brain barrier, which helps circulates blood to the brain.

"What's happening is that the cells of the blood-brain barrier that are in contact with the blood and with the peripheral immune system get activated and these non-neuronal cells secrete cytokines and chemokines that, in turn, activate the population of neurons that we found," said Dulac, Lee and Ezpeleta Professor of Arts and Sciences and Higgins Professor of Molecular and Cellular Biology.

The hope is that scientists can one day use the knowledge from how this mechanism works to target the process in humans to reverse it when it becomes aversive to someone's health.

A fever, for instance, is typically a healthy reaction that helps eliminate a pathogen. But when it gets too high, it can also become dangerous. The same can be said for loss of appetite or a lowered thirst, which can, at first, be beneficial. But a sustained lack of nutrients or hydration then start to impede recovery.

"If we know how it works, perhaps we can help patients who have difficulty with these kinds of symptoms, like chemo patients or cancer patients, for example, who have a very low appetite but there's really nothing we can do for them," Osterhout said.

The work originally started as an effort to look at what is known as the fever effect in autism patients. It's a phenomenon where autistic patients have a reduction in autistic symptoms when the patient have symptoms of an infection like a fever. The goal was to find the neurons that generate fever and link them to the neurons that are involved with social behavior.

Instead, Osterhout found many populations of neurons that are activated when an animal is sick. She zeroed in on about 1,000 neurons in ventral medial preoptic area of the hypothalamus because of their location next to the blood-brain barrier.

To find the different areas of neurons that become activated, Osterhout injected mice with pro-inflammatory agents, lipopolysaccharide or polycytidylic acid, which mimic bacterial or viral infection. She analyzed the areas of the brain that lit up in the brain scans.

Osterhout and colleagues then used a powerful and precise set of methods called chemo- and optogenetics to control and investigate the connectivity between the different neuronal populations. Using these tools, they were able to activate or silence these neurons on command in the brains of mice and pin down their function by seeing what happened.

The researchers found that using these tools they could increase body temperature in the mice, increase warmth seeking behavior, and decrease appetite. The report says the neurons they describe project to 12 brain areas, some of which are known to control thirst, pain sensation, and social interactions. This suggests that other sickness behaviors may also be affected by the neuron activity here.

During the experiments, the scientists also noticed increased activity and activation in this population of neurons when molecules from the immune system gave off increased signals. That suggests that the brain and the immune system were communicating with each other through paracrine signaling at the location they focused on -- the ventral medial preoptic area and the blood-brain barrier right next to it. Paracrine signaling is when cells produce a signal to trigger changes in nearby cells.

Osterhout said the process expanded her understanding of how neurons work.

"As a neuroscientist, we often think of neurons activating other neurons and not that these other paracrine type or secretion type methods are really critical," she said. "It changed how I thought about the problem."

Story Source:

Materials provided by Harvard University. Original written by Juan Siliezar. Note: Content may be edited for style and length.

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Journal Reference:

1. Jessica A. Osterhout, Vikrant Kapoor, Stephen W. Eichhorn, Eric Vaughn, Jeffrey D. Moore, Ding Liu, Dean Lee, Laura A. DeNardo, Liqun Luo, Xiaowei Zhuang, Catherine Dulac. A preoptic neuronal population controls fever and appetite during sickness. Nature, 2022; DOI: 10.1038/s41586-022-04793-z

https://www.sciencedaily.com/releases/2022/06/220608112501.htm