It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Tuesday, October 11, 2022
The poorest people live almost 4 years less than the wealthiest
A study of CIBERESP published in Scientific Reports has developed the first life tables in Spain based on socioeconomic levels
CONSORCIO CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED MP
People with fewer financial resources live between 3 and 4 years less than richer people, according to the conclusions of a study carried out by several groups from the Epidemiology and Public Health Area (CIBERESP) of the Networking Biomedical Research Centre (CIBER-ISCIII). The paper has been published in the prestigious scientific journal Scientific Reports of the Nature Publishing Group, and has been funded by the Carlos III Health Institute (ISCIII) and the Spanish Association Against Cancer (AECC).
The research teams from the National Centre of Epidemiology of the ISCIII, the Biosanitary Research Institute of Granada, the University of Granada and the Andalusian School of Public Health have developed the first life tables in Spain based on socioeconomic levels, which will be very useful when studying the survival rates of different diseases such as cancer.
Analysing the relationship between levels and life expectancy, the authors have determined that women and men living in the most deprived areas live between 3.2 and 3.8 years less, respectively, than their counterparts in the least deprived areas. Furthermore, it has been calculated that on average women live 5.6 years more than men (82.9 years for women compared to 77.3 for men). Per province, it is observed that life expectancy is greater in the north of the peninsula, in both sexes, and in the provincial capitals compared to rural areas.
To carry out this study, all-cause mortalities were analysed from the 35,960 census tracts in Spain during the 2011-2013 period and mortality models were stratified according to sex, age group and socioeconomic levels.
The level of wealth or poverty of each area was measured using an index developed by the Spanish Society of Epidemiology, including information from six indicators mainly related to employment and education: percentage of manual workers (employed and unemployed), casual workers, percentage of population without secondary education and main residences without internet access.
According to Daniel Redondo, researcher from the CIBERESP at the Biosanitary Research Institute of Granada and the Andalusian School of Public Health, “Understanding the association between life expectancy and socioeconomic status could help in developing appropriate public health programmes. Furthermore, the life tables we produced are needed to estimate cancer specific survival measures by socioeconomic status”.
Introducing the health inequality perspective, key
Producing life tables based on socioeconomic levels for the first time in Spain will enable us from now on to study survival rates in cancer and other chronic illnesses by introducing the health inequality perspective, as other European countries such as the United Kingdom have been doing. This will contribute to a greater knowledge and understanding of the factors that influence in the prognosis of certain diseases in our country.
María José Sánchez, head of the group of the CIBERESP at the Andalusian School of Public Health states “Our life tables are essential to calculating life expectancy and estimating cancer survival, as inequalities in this disease persist and have a financial impact on health care costs.” For this purpose, tables are needed to estimate this survival rate based on cancer registries that record net survival, probability of death, and years of life lost due to the disease, among other factors.
The life tables generated are available to researchers in the repository of GitHub:
Association of socioeconomic deprivation with life expectancy and all-cause mortality in Spain, 2011–2013
Ketamine and depression: A mechanism of the antidepressant revealed
by Institut du Cerveau (Paris Brain Institute)
Mediation Results. Boxplots showing the IQRs for belief-updating biases (normalized by estimation error magnitude) and Montgomery-Åsberg Depression Rating Scale scores 24 h before and 1 wk after ketamine treatment. The black lines inside the boxplots show the median values, and the jitter elements left of each boxplot show the individual patients. EE indicates estimation error. Credit: JAMA Psychiatry (2022). DOI: 10.1001/jamapsychiatry.2022.2996
Researchers from Inserm, CNRS, Sorbonne University and clinicians from the AP-HP and at Paris Brain Institute identified one of the mechanisms explaining the ketamine effect as an antidepressant. Ketamine, usually used as an anesthetic, was administered to patients with severe resistant depression.
This treatment led patients to present an increased ability to overcome their negative beliefs about themselves and the world when researchers presented them positive information. These results, published in JAMA Psychiatry, open new therapeutic avenues for the management of antidepressant-resistant mood disorders.
Depression is the most common psychiatric disorder: it is estimated that 5 to 15% of the French population will experience a major depressive episode during their lifetime. All age groups and all social backgrounds are affected.
The disease is characterized by sadness and loss of hedonic feelings that positive events do not improve. Depressed patients progressively develop negative beliefs about themselves, the world, and the future, that may develop into suicidal thoughts. These negative beliefs remain even when the patient receives positive information.
About one-third of people with depression do not respond to the most prescribed antidepressants, leading to a diagnosis of treatment-resistant depression (TRD). For these people, finding new and effective therapies is a priority.
Ketamine, a commonly used anesthetic, has been shown to influence resistant depression. While conventional antidepressant treatments take time to be efficient (on average three weeks), ketamine has a rapid antidepressant effect, only a few hours after administration. The mechanisms associated with this fast-acting antidepressant effect are still unknown.
To identify these mechanisms, Dr. Hugo Bottemanne and the research team co-led at the Paris Brain Institute by Pr Philippe Fossati and Liane Schmidt, Inserm researcher, coordinated a clinical study involving 26 antidepressant-resistant patients (TRD) and 30 healthy controls.
During the protocol, patients and healthy subjects were first asked to estimate the probability of 40 "negative" events which could occur in their lives (e.g., have a car accident, get cancer, or lose their wallet).
After being informed of the actual occurrence risks in the general population, patients and healthy subjects were again asked to estimate the probability of these events occurring in their lives. The research team was interested in the updating of beliefs after getting information. Results showed that healthy subjects tended to update their initial beliefs more after receiving factual and positive information, which was not the case in the depressed patient population.
In the suite of the study, TRD patients received three administrations of ketamine at a subanesthetic dose (0.5 mg/kg over 40 minutes) in one week. Only four hours after the first administration, patients' ability to update their beliefs after receiving a positive information was increased. They became less sensitive to negative information and recovered an ability to update their knowledge com parable to that of control subjects.
Moreover, improvement in depressive symptoms after ketamine treatment was associated with these changes in belief updating, suggesting a link between clinical improvement and changes in this cognitive mechanism. "In other words, the more patients' belief updating ability was increased, the greater the improvement in symptoms was".
In conclusion, in this study, patients with antidepressant-resistant depression showed a significant decrease in symptoms and became more receptive to "positive" experiences after one week of ketamine treatment.
This work highlights for the first time a cognitive mechanism potentially involved in the early effect of ketamine. It paves the way to new research on antidepressant therapies modulating the mechanisms of belief updating.
More information: Hugo Bottemanne et al, Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression, JAMA Psychiatry (2022). DOI: 10.1001/jamapsychiatry.2022.2996
IMAGE: SESAME SEED-SIZED BRAIN-LIKE ORGANOIDS ARE GROWN IN THE LAB FROM HUMAN CELLS. THEY ARE PROVIDING INSIGHTS INTO THE BRAIN AND UNCOVERING DIFFERENCES THAT MAY CONTRIBUTE TO AUTISM IN SOME PEOPLE.view more
CREDIT: TREVOR TANNER
(Salt Lake City) - Whatever you do, don’t call them “mini-brains,” say University of Utah Health scientists. Regardless, the seed-sized organoids—which are grown in the lab from human cells—provide insights into the brain and uncover differences that may contribute to autism in some people.
“We used to think it would be too difficult to model the organization of cells in the brain,” says Alex Shcheglovitov, PhD, assistant professor of neurobiology at U of U Health. “But these organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain.”
The research describing the organoids and their potential for understanding neural diseases publishes in Nature Communicationson Oct 6with Shcheglovitov as senior author and Yueqi Wang, PhD, a former graduate student in his lab, as lead author. They carried out the research with postdoctoral scientist Simone Chiola, PhD, and other collaborators at the University of Utah, Harvard University, University of Milan, and Montana State University.
Investigating autism
Having the ability to model aspects of the brain in this way gives scientists a glimpse into the inner workings of a living organ that is otherwise nearly impossible to access. And since the organoids grow in a dish, they can be tested experimentally in ways that a brain cannot.
Shcheglovitov’s team used an innovative process to investigate effects of a genetic abnormality associated with autism spectrum disorder and human brain development. They found that organoids engineered to have lower levels of the gene, called SHANK3, had distinct features.
Even though the autism organoid model appeared normal, some cells did not function properly:
Neurons were hyperactive, firing more often in response to stimuli,
Other signs indicated neurons may not efficiently pass along signals to other neurons,
Specific molecular pathways that cause cells to adhere to one another were disrupted.
These findings are helping to uncover the cellular and molecular causes of symptoms associated with autism, the authors say. They also demonstrate that the lab-grown organoids will be valuable for gaining a better understanding of the brain, how it develops, and what goes wrong during disease.
“One goal is to use brain organoids to test drugs or other interventions to reverse or treat disorders,” says Jan Kubanek, PhD, a co-author on the study and an assistant professor of biomedical engineering at the U.
Building a better brain model
Scientists have long searched for suitable models for the human brain. Lab-grown organoids are not new, but previous versions did not develop in a reproduceable way, making experiments difficult to interpret.
To create an improved model, Shcheglovitov’s team took cues from how the brain develops normally. The researchers prompted human stem cells to become neuroepithelial cells, a specific stem cell type that forms self-organized structures, called neural rosettes, in a dish. Over the course of months, these structures coalesced into spheres and increased in size and complexity at a rate similar to the developing brain in a growing fetus.
After five months in the lab, the organoids were reminiscent of “one wrinkle of a human brain” at 15 to 19 weeks post-conception, Shcheglovitov says. The structures contained an array of neural and other cell types found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.
Like a human embryo, organoids self-organized in a predictable fashion, forming neural networks that pulsated with oscillatory electrical rhythms and generated diverse electrical signals characteristic of a variety of different kinds of mature brain cells.
“These organoids had patterns of electrophysiological activity that resembled actual activity in the brain. I didn’t expect that,” Kubanek says. “This new approach models most major cell types and in functionally meaningful ways.”
Shcheglovitov explains that these organoids, which more reliably reflect intricate structures in the cortex, will allow scientists to study how specific types of cells in the brain arise and work together to perform more complex functions.
“We’re beginning to understand how complex neural structures in the human brain arise from simple progenitors,” Wang says. “And we’re able to measure disease-related phenotypes using 3D organoids that are derived from stem cells containing genetic mutations.”
He adds that using the organoids, researchers will be able to better investigate what happens at the earliest stages of neurological conditions, before symptoms develop.
CAPTION
Single neural rosette-derived organoids develop multiple brain cell types and have an organization and neural activity never seen before in models of this kind.
CREDIT
Trevor Tanner
Single neural rosette-derived organoids model aspects of the brain (IMAGE)
The organoids contained an array of neural and other cell types found in the cerebral cortex, the outer most layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.
CREDIT
Yueqi Wang
Visit UBrain browser to visualize the cells and electrical responses detected in organoids.
Support for the work came from the National Institutes of Health, Brain Research Foundation, Brain and Behavior Research Foundation, Whitehall Foundation, University of Utah Neuroscience Initiative, and University of Utah Genome Project Initiative.
About University of Utah Health
University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $458 million research enterprise and trains the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.
Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes
ARTICLE PUBLICATION DATE
6-Oct-2022
Creating a mouse embryo from stem cells to learn more about the mammalian development process
Correct self-organization is necessary for proper morphogenesis. a, Time course of the assembly of ETX embryos stained to reveal E-cadherin (monochrome), Oct4 (red) and Gata4 (green). The bottom row of images are magnifications of the images above and show E-cadherin staining around a nascent cavity, as indicated by the dashed yellow lines. The dashed green line indicates the boundary between the ES and XEN compartment. Scale bar, 5 μm. b, Representative images showing Oct4 (red), Gata4 (green), E-cadherin (monochrome) and DAPI (gray) staining in day 4 cadherin OE ETX structures formed by combining E-cadherin OE ES cells with P-cadherin OE TS cells and wild-type XEN cells. ETX structures formed by combining wild-type cells were used as a control. Scale bars, 100 μm. c, Comparison and quantification of joined cavity formation in cadherin OE and control ETX structures. n = 361 (control group) and n = 253 (cadherin OE group). N = 5 for each condition. The data are presented as means ± s.d. Statistical significance was determined by unpaired two-tailed Student’s t-test. d, Representative image showing Oct4 (red), Gata4 (green), laminin (monochrome) and DAPI (blue) staining in day 4 cadherin OE ETX structures formed by combining E-cadherin OE ES cells with P-cadherin OE TS cells and wild-type XEN cells. ETX structures formed by combining wild-type cells were used as a control. Scale bars, 100 μm. e, Quantification of the structures that contained continuous or discontinuous laminin. n = 40 ETX structures per condition. N = 3. The data are presented as means ± s.d. Statistical significance was determined by unpaired two-tailed Student’s t-test. f, Self-organization principles in stem cell-derived ETX embryos. Differential expression of E-, K- and P-cadherins enables the sorting of ES (epiblast-like), XEN (VE-like) and TS (TE-like) stem cells. Wild-type ES cells with low E-cadherin expression and wild-type TS cells with low P-cadherin expression exhibited detrimental global sorting efficiency. This could be overcome by overexpressing E-cadherin in ES cells and P-cadherin in TS cells to increase the efficiency of ETX embryo formation. Proper morphogenesis, including cavity formation, basement membrane formation (purple) and symmetry breaking can only be observed in well-sorted structures. Numerical data are available as source data. Credit: Nature Cell Biology (2022). DOI: 10.1038/s41556-022-00984-y
A team of researchers at the California Institute of Technology, working with one colleague from The Francis Crick Institute and another from the University of Cambridge, both in the U.K., has developed a way to grow mouse embryos without using mouse eggs or sperm to learn more about early mammalian development. In their paper published in the journal Nature Cell Biology, the group describes using several types of stem cells to grow mouse embryos.
Prior research has shown that mammalian embryos differentiate into different types of cell masses as they develop. Researchers have also found that stem cells are involved in the processes but the mechanisms responsible are still unknown. In this new effort, the researchers used three different kinds of stem cells to grow a mouse embryo that matured to the point of having a beating heart and the beginnings of a brain.
To create such embryos, the researchers first studied communications between stem cell groups in naturally developing mouse embryos. They learned to recognize the elements that went into such communications and the means by which it was carried out. In essence, they "deciphered the code." They then isolated three main types of stem cells that made up the cell masses in early embryo development: pluripotent, which eventually grow to become body tissue, and two other types that grew to become the amnionic sac and placenta. They also noted the quantities of each type of stem cell.
The next step was to attempt to create a mouse embryo from scratch using the three types of stem cells in a lab setting. With careful tending, the researchers grew an embryo that matured enough to allow for study of its development.
To test further, the researchers repeated the procedure but added genetically engineered cells to see how it impacted maturation of the embryo. They found they could replicate some of the same brain development issues that have been seen in human embryos. They suggest their work could also help explain what goes wrong when mice (or people) miscarry.
More information: Min Bao et al, Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension, Nature Cell Biology (2022). DOI: 10.1038/s41556-022-00984-y
Schematic representation of single and combined antibiotic and aPDT treatment options for infections. Antibiotics serve an important role in medicine, successfully treating many common bacterial infections. However, their use leads to increased resistance, necessitating more dangerous antibiotic classes and higher doses. Likewise, aPDT can successfully eliminate bacteria, regardless of antibiotic resistance, but is not always applicable at large doses due to drug and light side effects. These two treatments used concurrently have been found to significantly lower average antibiotic resistance and broaden the resistance distribution, permitting the use of smaller doses of each for a more effective treatment. Credit: Proceedings of the National Academy of Sciences (2022).DOI: 10.1073/pnas.2208378119
Antibiotics are standard treatments for fighting dangerous bacterial infections. Yet the number of bacteria developing a resistance to antibiotics is increasing. Researchers from Texas A&M University and the University of São Paulo are overcoming this resistance with light.
The researchers tailored antimicrobial photodynamic therapy (aPDT)—a chemical reaction triggered by visible light—for use on antibiotic-resistant bacteria strains. Results showed the treatment weakened bacteria to where low doses of current antibiotics could effectively eliminate them.
"Using aPDT in combination with antibiotics creates a synergy of interaction working together for a solution," said Vladislav Yakovlev, University Professor in the Department of Biomedical Engineering at Texas A&M and co-director of the project. "It's a step in the right direction against resistant bacteria."
The research results were published in Proceedings of the National Academy of Sciences (PNAS).
Ultraviolet light was first used to sterilize bacteria over 100 years ago. The treatment was based on the work of Niels Finsen, who won the Nobel Prize in Physiology in 1903 for using filtered sunlight—the higher frequency or ultraviolet spectrum—as a cure for skin tuberculosis. Phototherapy advances faded in popularity a few decades later when antibiotics became the weapon of choice against bacteria.
Antibiotic-resistant bacteria showed up soon after antibiotics were first used. If antibiotic treatment stops before bacteria are fully killed, the remaining bacteria develop a resistance or immunity to the antibiotic. That immunity transfers to every new bacteria cell, so more potent antibiotics or new treatment methods are needed to overcome the growing resistance.
"Photodynamic therapy was a forgotten tool," Yakovlev said. "Yet, bacteria cannot overcome it. There is no resistance."
Some human cancer cell therapies already use aPDT to prevent the growth of abnormal cells, but treating resistant bacteria with it is still a novel approach.
The researchers began their work by choosing the bacteria and the three main parts of aPDT needed to combat it: molecular oxygen, light, and a photosensitizer—something that creates a reaction between oxygen and light. An already FDA-approved dye called methylene blue served as the photosensitizer. The light sources were specially constructed panels of 25 LEDs in reflective cones built by the Technical Support Laboratory of the São Carlos Institute of Physics. Methicillin-resistant Staphylococcus aureus served as the bacteria, and the researchers grew cultures with the blue dye in them to ensure the photosensitizer alone would not affect the bacteria.
Most of the lab work occurred in the Texas A&M Health Science Center under Paul de Figueiredo, professor in the Department of Microbial Pathogenesis and Immunology in the College of Medicine.
At first, the team used aPDT by itself at various light strengths, durations, and in a specific series of follow-up treatments to log the bacteria's response. The idea was to find the lowest dose and shortest series that could weaken the bacterial membranes and other resistance mechanisms. Cell recoveries and reproductions revealed how many generations it took before antibiotic resistance returned. Next, the researchers added measured levels and combinations of antibiotics at different time intervals after aPDT treatments to note the weakened bacteria's responses.
"The use of antibiotics with aPDT is a unique idea," Yakovlev said. "We can use lower doses of both to achieve our goal in contrast to using one or the other at higher doses that could have side effects."
The goal is to shorten the treatment time and reduce the dosage to the lowest levels needed.
Getting medical care down to one doctor visit is especially important to Vanderlei Bagnato, professor in the Department of Physics and Materials Science at São Paulo and co-director of the project. He is trying to improve recovery odds for populations in remote areas of Brazil where patients might only see a doctor once per illness, without any chance for follow-up care.
The U.S. Department of Defense is following the project closely because battlefield wound infections also happen in remote locations and must be dealt with quickly.
So far, the results are positive. The resistant bacteria, weakened by aPDT treatments, were killed with far lower doses of current antibiotics. As a benefit, these therapies reduced the need for battling resistant bacteria with more potent and expensive antibiotics that take years to produce. Future work for the project will involve more timing and dosage investigations and tests on other resistant bacteria strains to see if the effectiveness is universal.
"Imagine the real-life applications," Yakovlev said. "You visit a doctor, who uses an ointment and shines a light on the infected area, and then you're done. It would be a quick and harmless treatment as needed."New drug candidate fights off more than 300 drug-resistant bacteria
More information: Jace A. Willis et al, Breaking down antibiotic resistance in methicillin-resistant Staphylococcus aureus : Combining antimicrobial photodynamic and antibiotic treatments, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2208378119
