Scientists Develop Oral Vaccine Against Salmonella Infection

COVID-19 mostly kills through an overreaction of the immune system, whose function is precisely to fight infections, say scientists who have decoded the mechanisms, symptoms, and diagnosis of the disease caused by the SARS-Cov-2 coronavirus.

In a study published in the journal Frontiers in Public Health, the researchers explained step-by-step how the virus infects the airways, multiplies inside cells, and in severe cases causes the immune defences to overshoot with a "cytokine storm".

This storm is an over-activation of white blood cells, which release too-great amounts of cytokines -- inflammation-stimulating molecules --into the blood, they said.

"Similar to what happens after infection with SARS and MERS, data show that patients with severe COVID-19 may have a cytokine storm syndrome," said study author Daishun Liu, Professor at Zunyi Medical University in China.

"The rapidly increased cytokines attract an excess of immune cells such as lymphocytes and neutrophils, resulting in an infiltration of these cells into lung tissue and thus cause lung injury," Liu said.

The researchers explained that the cytokine storm ultimately causes high fever, excessive leakiness of blood vessels, and blood clotting inside the body.

It also causes extremely low blood pressure, lack of oxygen and excess acidity of the blood, and build-up of fluids in the lungs, they said.

The researchers noted that white blood cells are misdirected to attack and inflame even healthy tissue, leading to failure of the lungs, heart, liver, intestines, kidneys, and genitals.

This multiple organ dysfunction syndrome (MODS) may worsen and shutdown the lungs, a condition called acute respiratory distress syndrome, (ARDS), they said.

This, the researchers explained, happens due to the formation of a so-called hyaline membrane -- composed of debris of proteins and dead cells -- lining the lungs, which makes absorption of oxygen difficult.

Most deaths due to COVID-19 are therefore due to respiratory failure, they said.

The researchers explained that in the absence of a specific antiviral cure for COVID-19, the goal of treatment must be to the fight the symptoms, and lowering the mortality rate through intensive maintenance of organ function.

For example, an artificial liver blood purification system or renal replacement therapy can be used to filter the blood through mechanical means, they said.

The team noted that especially important are methods to supplement or replace lung function, for example with non-invasive mechanical ventilation through a mask, ventilation through a tube into the windpipe, the administration of heated and humidified oxygen via a tube in the nose, or a heart-lung bypass.

The researchers stressed the importance of preventing secondary infections.

They noted that SARS-Cov-2 also invades the intestines, where it causes inflammation and leakiness of the gut lining, allowing the opportunistic entry of other disease-causing microorganisms.

The researchers advocate that this should be prevented with nutritional support, for example with probiotics -- beneficial bacteria that protect against the establishment of harmful ones -- and nutrients and amino acids to improve the immune defences and function of the intestine.

"Because treatment for now relies on aggressive treatment of symptoms, preventative protection against secondary infections, such as bacteria and fungi, is particularly important to support organ function, especially in the heart, kidneys, and liver, to try and avoid further deterioration of their condition," Liu added.

California, May 13: A fasting-mimicking diet could be more effective at treating some types of cancer when combined with vitamin C, suggests a new study conducted by the scientists from USC and the IFOM Cancer Institute in Milan.

In studies on mice, researchers found that the combination delayed tumour progression in multiple mouse models of colorectal cancer; in some mice, it caused disease regression. The results were published in the journal Nature Communications.

"For the first time, we have demonstrated how a completely non-toxic intervention can effectively treat an aggressive cancer," said Valter Longo, the study senior author and the director of the USC Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences.

"We have taken two treatments that are studied extensively as interventions to delay ageing-- a fasting-mimicking diet and vitamin C -- and combined them as a powerful treatment for cancer," added Longo.

The researchers said that while fasting remains a challenging option for cancer patients, a safer, more feasible option is a low-calorie, plant-based diet that causes cells to respond as if the body were fasting.

Their findings suggest that a low-toxicity treatment of fasting-mimicking diet plus vitamin C has the potential to replace more toxic treatments.

Results of prior research on the cancer-fighting potential of vitamin C have been mixed. Recent studies, though, are beginning to show some efficacy, especially in combination with chemotherapy.

In this new study, the research team wanted to find out whether a fasting-mimicking diet could enhance the high-dose vitamin C tumour-fighting action by creating an environment that would be unsustainable for cancer cells but still safe for normal cells.

"Our first in vitro experiment showed remarkable effects. When used alone, fasting-mimicking diet or vitamin C alone reduced cancer cell growth and caused a minor increase in cancer cell death. But when used together, they had a dramatic effect, killing almost all cancerous cells," said Longo.

Longo and his colleagues detected this strong effect only in cancer cells that had a mutation that is regarded as one of the most challenging targets in cancer research.

These mutations in the KRAS gene signal the body is resisting most cancer-fighting treatments, and they reduce a patient's survival rate. KRAS mutations occur in approximately a quarter of all human cancers and are estimated to occur in up to half of all colorectal cancers.

The study also provided clues about why previous studies of vitamin C as a potential anticancer therapy showed limited efficacy. By itself, a vitamin C treatment appears to trigger the KRAS-mutated cells to protect cancer cells by increasing levels of ferritin, a protein that binds iron.

But by reducing levels of ferritin, the scientists managed to increase vitamin C's toxicity for the cancer cells. Amid this finding, the scientists also discovered that colorectal cancer patients with high levels of the iron-binding protein have a lower chance of survival.

"In this study, we observed how fasting-mimicking diet cycles are able to increase the effect of pharmacological doses of vitamin C against KRAS-mutated cancers," said Maira Di Tano, a study co-author at the IFOM, FIRC Institute of Molecular Oncology in Milan, Italy.

"This occurs through the regulation of the levels of iron and of the molecular mechanisms involved in oxidative stress. The results particularly pointed to a gene that regulates iron levels: heme-oxygenase-1," added Tano.

The research team's prior studies showed that fasting and a fasting-mimicking diet slow cancer's progression and make chemotherapy more effective in tumour cells while protecting normal cells from chemotherapy-associated side effects. The combination enhances the immune system's anti-tumour response in breast cancer and melanoma mouse models.

The scientists believe cancer will eventually be treated with low-toxicity drugs in a manner similar to how antibiotics are used to treat infections that kill particular bacteria, but which can be substituted by other drugs if the first is not effective.

To move toward that goal, they say they needed to first test two hypotheses: that their non-toxic combination interventions would work in mice, and that it would look promising for human clinical trials.

In this new study, they said that they've demonstrated both. At least five clinical trials, including one at USC on breast cancer and prostate cancer patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs.

Colorado, Jul 24: A new study has found that physical stress in one's job may be associated with faster brain ageing and poorer memory.

Aga Burzynska, an assistant professor in the Department of Human Development and Family Studies, and her research team connected occupational survey responses with brain-imaging data from 99 cognitively normal older adults, age 60 to 79. They found that those who reported high levels of physical stress in their most recent job had smaller volumes in the hippocampus and performed poorer on memory tasks. The hippocampus is the part of the brain that is critical for memory and is affected in both normal ageing and in dementia.

Their findings were published this summer in Frontiers in Human Neuroscience under the research topic 'Work and Brain Health Across the Lifespan.'

"We know that stress can accelerate physical ageing and is the risk factor for many chronic illnesses," Burzynska said. "But this is the first evidence that occupational stress can accelerate brain and cognitive ageing."

She added that it is important to understand how occupational exposures affect the ageing of our brains.

"An average American worker spends more than eight hours at work per weekday, and most people remain in the workforce for over 40 years," Burzynska said. "By pure volume, occupational exposures outweigh the time we spend on leisure social, cognitive and physical activities, which protect our ageing minds and brains."

Physical demands at work

Burzynska explained that the association between "physical stress" and brain/memory were driven by physical demands at work. These included excessive reaching, or lifting boxes onto shelves, not necessarily aerobic activity. This is important because earlier work by Burzynska and her colleagues showed that leisure aerobic exercise is beneficial for brain health and cognition, from children to very old adults. Therefore, the researchers controlled for the effects of leisure physical activity and exercise.

As expected, leisure physical activity was associated with greater hippocampal volume, but the negative association with physical demands at work persisted.

"This finding suggests that physical demands at work may have parallel yet opposing associations with brain health," Burzynska explained. "Most interventions for postponing cognitive decline focus on leisure, not on your job. It's kind of unknown territory, but maybe future research can help us make some tweaks to our work environment for long-term cognitive health."

She added that the results could have important implications for society.

"Caring for people with cognitive impairment is so costly, on economic, emotional and societal levels," Burzynska said. "If we can support brain health earlier, in middle-aged workers, it could have an enormous impact."

The researchers considered and corrected for several other factors that could be related to work environment, memory and hippocampus, such as age, gender, brain size, educational level, job title, years in the occupation and general psychological stress.

One piece of the puzzle

"The research on this topic is so fragmented," Burzynska said. "One previous study linked mid-life managerial experience with greater hippocampus volume in older age. Another showed that taxi drivers had larger hippocampi than a city's bus drivers, presumably due to the need to navigate. In our study, job complexity and psychological stress at work were not related to hippocampal volume and cognition. Clearly, our study is just one piece of the puzzle, and further research is needed."

The magnetic resonance imaging (MRI) data used for the study was collected at the University of Illinois Urbana-Champaign between 2011 and 2014.

CSU researchers now can collect MRI data with the new 3T scanner at the University's Translational Medicine Institute.

With this new capability, Burzynska, along with Michael Thomas and Lorann Stallones of CSU's Department of Psychology, is launching a new project, "Impact of Occupational Exposures and Hazards on Brain and Cognitive Health Among Aging Agricultural Workers," which will involve collecting MRI brain scans and identifying risk and protective factors that could help the agricultural community age successfully. The project recently obtained funding as an Emerging Issues Short-Term Project from the High Plains Intermountain Center for Agricultural Health and Safety.

The Department of Human Development and Family Studies is part of CSU's College of Health and Human Sciences.