Month: July 2021

Categories : Cardiovascular Disease Metabolic DisordersTags :

Are Lower Haemoglobin Levels Protective?

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Credit: Wikimedia CC0

A new study challenges the view that high haemoglobin levels are always desirable for health. 

A study based on two large human cohorts as well as experimental work supported the idea that lower haemoglobin levels may protect against both obesity and metabolic syndrome. The phenomenon may be related to the body’s adaptive response to low-oxygen conditions, which is exploited by endurance athletes in high-altitude training.

Haemoglobin levels vary from one individual to another, with normal levels in Finnish population ranging from 117 to 155 grams per litre in females and 134 to 167 grams per litre in males.

A recent study showed that individual differences in haemoglobin levels are strongly associated with metabolic health in adulthood. The haemoglobin levels were associated with body mass index, glucose metabolism, blood lipids and blood pressure. Subjects with lower haemoglobin levels were healthier in terms of metabolic measures. The study examined haemoglobin values within the normal range.  

“We found a clear association between hemoglobin levels and key cardiovascular traits, and the associations became more pronounced as the subjects aged,” said principal investigators Professor Juha Auvinen, doctoral student Joona Tapio and postdoctoral researcher Ville Karhunen.  

The effect of lower haemoglobin observed in the study is related to a mild oxygen deficiency in the body and the corresponding hypoxia inducible factors (HIF) response which is activated as a result. The research team of Professor Peppi Karppinen is internationally known for its studies on this phenomenon. The finding reinforces the understanding of the central role that the HIF response has in regulating the body’s energy metabolism.

“Haemoglobin levels are a good measure of the body’s ability to carry oxygen. A mild lack of oxygen activates the HIF response, which makes the body’s energy metabolism less economical and thus may protect against obesity and unfavourable metabolism,” explained study leader Prof Karppinen.

Prof Karppinen’s team has already shown in previous research that activation of the hypoxia response protects mice from obesity, metabolic syndrome, fatty liver and atherosclerosis. This is the first study to show the link between oxygen deficiency and a wide range of metabolic health markers in humans as well.

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health,”explained co-leader of the study Professor Marjo-Riitta Järvelin.

“We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death,” said Prof Karppinen.

The study was based on a large cohort of people born in Northern Finland in 1966, which followed the health of 12 000 people since birth. The results were also replicated in The Cardiovascular Risk in Young Finns Study cohort material, which covers more than 1800 individuals. 

“Although this study uses multiple methods to establish links between lower body oxygen levels and metabolic health, it is very challenging to establish causality for the observed associations in human data. However, combining evidence from different components of the study, the results support that hypoxia response may also play an important role in peoples’ metabolic health”, explained study co-leader Professor Marjo-Riitta Järvelin.

Professor Peppi Karppinen said, “We also already know that in people living high above sea level, low oxygen levels in the habitat cause long-term activation of the HIF response. These people are slimmer, and they have better sugar tolerance and a lower risk of cardiovascular death.”

A question for future research is how to reduce the body’s oxidation levels if needed. This would be to achieve a permanent low-level activation of the HIF response and thus obesity protection. According to Prof Karppinen, the HIF enzymes that prompt a hypoxic response could potentially be used as targets of obesity and metabolism drugs in humans. Currently they are being used in Asia to treat renal anaemia.

Source: University of Oulu

Journal information: Auvinen, J., et al. (2021) Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia. Science Advances. doi.org/10.1126/sciadv.abi4822.

Categories : Medical IndustryTags :

Clicks Reports Losses of R5 Billion from Riots and Looting

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Photo by Michael Longmire on Unsplash
Photo by Michael Longmire on Unsplash

Pharmacy and health and beauty retail group Clicks has reported estimated losses of R5 billion resulting from damage to and looting of stores at shopping malls and distribution centres across South Africa, according to BusinessTech.

Clocks said that it has been forced to close all of its 110 stores in KwaZulu-Natal and 130 of its stores in Gauteng, with long lines reported at those stores that have remained open in the province. Nationwide, 279 stores have been closed and 52 have been damaged. Guidance for those needing medication is available on its website, and online deliveries have been affected as its warehouse is in Johannesburg.

106 vaccination sites have been closed across the country, the group said in a statement, as looting and vandalism continued into Wednesday, predominantly in KwaZulu-Natal and Gauteng. They advise that all vaccination sites are now accepting walk-in appointments. Dis-Chem has advised that its vaccination sites in KwaZulu-Natal are closed, as well as three of its seven sites in Gauteng.

The group had previously been forced to close its stores in September 2020 due to threats from the EFF over allegations of racism in its advertising.

Clicks has 760 stores and over 600 in-store pharmacies around country.

“The disruption of services means affected Clicks stores will be temporarily unable to administer vaccinations and provide medication to customers, along with public sector medicine pick-up points being temporarily unavailable.

“Contingency plans are being put in place to provide alternative arrangements for delivery of chronic medication and rescheduling of vaccinations, where possible,” the group said.

The unrest began with protests against the arrest and incarceration of former president Jacob Zuma, but has since degenerated into looting and destruction.

Clicks said that the full cost of the looting and damages to stores is still to be determined given the ongoing unrest.

Source: BusinessTech

Categories : Cardiovascular DiseaseTags :

Probing the Electrical Connections Between Heart Cells

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Photo by Robina Weermeijer on Unsplash

Harvard Medical School researchers have updated our understanding on how electrical impulses in the heart travel from cell to cell. Their findings are published in the journal Biophysics Reviews.

Disturbances of the bioelectrical processes behind heart’s rhythm can result in cardiac arrhythmias, a common ailment that can lead to illness and death.

A pacemaker within the heart takes the role of an electrical clock, signalling the heart to contract. The whole muscle moves simultaneously, because each individual cell inside of it contracts in a coordinated manner and within a short time interval.

To accomplish this, the pacemaker’s initial electrical impulse rapidly propagates through cells across the heart.

“If one cell is excited electrically and the other is not, the excited cell becomes positively charged inside, and the resting cell is still negatively charged inside. As a consequence, a voltage gradient builds up between the cells,” explained study author André Kléber. “If you have a voltage gradient and a pathway with a low electrical resistance, a local current will flow.”

The connections between cells which make up the low resistance pathway and facilitate the current flow are called gap junctions. Each is made up of numerous channels, which are formed when specific proteins from one cell connect to and fuse to the proteins from another cell. According to Kléber, the fusing proteins look like placing the tips of your fingers on one hand to the fingers on the other hand.

The researchers investigated the properties of gap junctions and connexins, their constituent proteins. Kléber explained that one reason why gap junction channels are interesting is because they are a highly dynamic system in equilibrium. The creation of the channels equals the destruction.
“The turnover is very short,” he said. “On one hand, the system is very stable during your whole life. On the other hand, if you measure it, it is constantly cycling in periods of a few hours.”

The proteins found in gap junctions are also important for processes not directly related to cell-cell connections, like mitochondrial function, which produces energy, and trafficking, which transports molecules from their synthesis site to their site of action in the cell interior.

“You have to refrain from the idea that if you define the role of a protein in the body, that it has only a single function,” said Kléber. “Nature is much, much smarter than human beings.”

Source: American Institute of Physics

Journal information: Kléber, A.G & Jin, Q., (2021) Coupling between cardiac cells—An important determinant of electrical impulse propagation and arrhythmogenesis. Biophysics Reviews. doi.org/10.1063/5.0050192.

Categories : Addiction COVIDTags :

No Smoking Uptick in COVID Pandemic – Unlike Other Disasters

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Photo by Elsa Olofsson on Unsplash


Unlike other population-level stressful events such as natural disasters, COVID has not resulted in a net increase in smoking, according to a new study from the International Tobacco Control (ITC) Project, at the University of Waterloo.

However, the researchers also found that although nearly half of smokers reported that COVID caused them to consider quitting, the vast majority of smokers did not change their smoking habits during the early phase of the COVID pandemic.

Stress is known to be a significant risk factor for smoking, especially in females. The study surveyed 6870 smokers and vapers in  Australia, Canada, England, and the United States between April and June 2020. The team investigated the association between COVID and thoughts about quitting smoking, changes in smoking, and factors related to positive changes such as attempting to quit or reducing smoking.

Only 1.1 per cent of smokers in the four countries attempted to quit and 14.2 percent reduced smoking, but this was offset by the 14.6 percent who increased smoking, with 70.2 percent reported no change.

“It is important to note that population-level stressful events, such as 9/11 and natural disasters, have often led to increased smoking,” said Geoffrey Fong, professor of psychology at Waterloo and principal investigator of the ITC Project. “So, our findings that there was no net increase in smoking in response to COVID may actually represent a positive result for public health.”

The study found that those who considered quitting smoking due to COVID were mostly females, ethnic minorities, those under financial stress, current vapers, less dependent smokers, those with greater concern about personal susceptibility of infection, and those who believed COVID is more severe for smokers.

According to study co-author Fong, this latter finding may explain why a significant uptick in smoking was seen in the COVID pandemic, compared to past tragedies.

“Unlike other population stressors such as earthquakes, which are unrelated to smoking, COVID severity is indeed linked to smoking,” Fong said. “Public health officials have mentioned the link as yet another reason for smokers to quit, and over 80 percent of smokers across the four countries believed that smoking made COVID more severe. And this led to the lack of an increase in smoking, unlike what we have seen after other tragedies.”

Source: EurekAlert!

Journal information: Gravely, S., et al. (2021) Smokers’ cognitive and behavioural reactions during the early phase of the COVID-19 pandemic: Findings from the 2020 ITC Four Country Smoking and Vaping Survey. PLOS ONE. doi.org/10.1371/journal.pone.0252427.

Categories : COVID HospitalsTags :

Heparin Benefit Seen in Moderately Ill COVID Patients

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Photo by Marcelo Leal on Unsplash
Photo by Marcelo Leal on Unsplash

New trial results show that early administration of the blood thinner heparin to moderately ill hospitalised COVID patients with could halt the thrombo-inflammation process, reducing the risk of severe disease and death.

COVID is characterised by inflammation and abnormal clotting in the blood vessels, especially the lungs, and is believed to contribute to progression to severe disease and death. 

The study is available as a preprint on MedRxiv and was led by investigators at St. Michael’s Hospital, a site of Unity Health Toronto, and the University of Vermont’s Larner College of Medicine.

Heparin, an anticoagulant, is indicated for both the prevention and treatment of thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism as well as atrial fibrillation. Heparin is also used to prevent excess coagulation during procedures such as cardiac surgery, extracorporeal circulation or dialysis. Heparin also has a wide range of off-label uses in hospitals. “This study was designed to detect a difference in the primary outcome that included ICU transfer, mechanical ventilation or death,” said study co-principal investigator  Mary Cushman, MD, MSc, professor of medicine at the UVM Larner College of Medicine.
The open-label randomised international multi-centre clinical RAPID Trial (also known as the RAPID COVID COAG – RAPID Trial) examined the benefits of administering a therapeutic full dose of heparin versus a prophylactic low dose to hospitalised patients with moderate COVID.

The primary outcome was a composite of ICU admission, mechanical ventilation, or death up to 28 days. Safety outcomes included major bleeding. Primary outcome occurred in 16.2% of patients with therapeutic full dose heparin, and 21.9% with low dose heparin (odds ratio [OR], 0.69). Four patients (1.8%) with therapeutic heparin died vs 7.6% with prophylactic heparin (OR, 0.22).

“While we found that therapeutic heparin didn’t statistically significantly lower incidence of the primary composite of death, mechanical ventilation or ICU admission compared with low dose heparin, the odds of all-cause death were significantly reduced by 78 percent with therapeutic heparin,” said first author and co-principal investigator Michelle Sholzberg, MDCM, MSc, Head of Division of Hematology-Oncology, medical director of the Coagulation Laboratory at St. Michael’s Hospital of Unity Health Toronto, and assistant professor at the University of Toronto.

Co-principal investigator Peter Jüni, MD, director of the Applied Health Research Centre (AHRC) at St. Michael’s, and professor of medicine at the University of Toronto, said that the researchers also presented a meta-analysis of randomised evidence (including data from a large multiplatform trial of ATTACC, ACTIV-4a and REMAP-CAP), which clearly indicated that therapeutic heparin is beneficial in moderately ill hospitalised COVID patients. He added that an additional meta-analysis presented in the preprint showed that therapeutic heparin is beneficial in moderately ill hospitalised patients but not in severely ill ICU patients.

Unusually, the RAPID Trial was funded through grassroots efforts from various institutions, grants and even a GoFundMe campaign.

“We called this trial ‘The Little Engine that Could,’ because of the sheer will of investigators around the world to conduct it,” said Cushman.

Sholzberg said, “We believe that the findings of our trial and the multiplatform trial taken together should result in a change in clinical practice for moderately ill ward patients with COVID.”

Source: University of Vermont

Journal information: Michelle Sholzberg et al, Heparin for Moderately Ill Patients with Covid-19, MedRxiv (2021). DOI: 10.1101/2021.07.08.21259351

Categories : Hospitals Paediatrics Respiratory DiseasesTags :

80% of Childhood Asthma Hospital Presentations are Preventable

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Image by Bob Williams from Pixabay
Image by Bob Williams from Pixabay

Based on a comprehensive Australian survey, approximately 80 percent of asthma-related hospital presentations in school-aged children are potentially avoidable through a standardised comprehensive care pathway for children with asthma.

These preventative measures include using evidence-based clinical guidelines, ensuring that there is an asthma action plan in place; regular follow-up with GP; provision of asthma education to parents/carers; and establishing a community-based approach for continuity of care.

Senior author Dr Nusrat Homaira, respiratory epidemiologist at UNSW Sydney said, “During our research, we surveyed 236 nurses and 266 doctors across 37 hospitals in all 15 local health districts (LHDs) across New South Wales (NSW) to identify the existing care pathway following discharge from hospital for children with asthma.”

This study by researchers at UNSW Sydney identified major variations in the existing asthma care pathway, including:

Use of asthma clinical guidelines and Asthma Action Plan: Although clinical guidelines and Asthma Action Plans (AAPs) were used across all hospitals, on average, there were four to six different types of documents used in each (LHD), between hospitals in the same LHD and within departments in the same hospital. Such variations can be confusing for clinicians, as noted by a survey participant: “Conflicting advice given to asthma patients between general practitioners, emergency departments and sometimes paediatricians; patients are then confused about what to do in exacerbation of symptoms.”

GP follow-up: In most LHDs (75 percent) parents/carers were advised to have their child followed up with their GP within two to three days after hospital discharge, but in some areas, follow-up appointments could be recommended for over six days post-hospitalisation. Parents/carers were reportedly responsible for organising follow-up with their GP with no system to ensure they in fact attended.

Asthma education for parents/carers of asthmatic children: Formal asthma education (27 percent of respondents) were seldom provided to parents/carers during hospital stays; limited to asthma device techniques and rarely involved key topics such as basic knowledge of asthma, asthma control and the importance of regular medical review.

Communication with schools/childcare services: When children with asthma were discharged from hospitals, only four percent of the surveyed staff reported that schools or childcare services were notified of the child’s recent hospital presentation.

Community services integration: The majority of participants (55 percent) were unaware of any community services for children with asthma in their local areas.

The survey identified marked variations in asthma care and management for children within different health districts, different hospitals in the same district and different departments within the same hospital in. The findings highlight opportunities to improve the health outcomes in children with asthma and reduce unnecessary burden on health systems from preventable asthma hospital presentations.

Source: EurekAlert!

Journal information: Chan, M., et al. (2021) Assessment of Variation in Care Following Hospital Discharge for Children with Acute Asthma. Journal of Asthma and Allergy. doi.org/10.2147/JAA.S311721.

Categories : HospitalsTags :

Attacks on Crisis-hit Hospitals Averted

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Photo by Pawel Janiak on Unsplash

As hospitals in violence-hit areas struggle with supplies and staffing, Police Minister Cele revealed that attacks on hospitals had been averted.

Speaking to eNCA, Minister Cele revealed that crime prevention intelligence had prevented attacks on healthcare infrastructure. “In KZN, yesterday… they were planning to burn the hospitals… literally planning to burn the hospitals with patients inside. So, that was averted,” he said.

Minister Cele made the comments while he was visiting an area hit by violence in Mamelodi, Tshwane.

During a briefing by the Justice, Crime Prevention and Security (JCPS) Cluster, State Security Minister Ayanda Dlodlo said that state security intelligence had prevented further destruction of buildings and infrastructure. This information was shared with the police. “We tried our best wherever we could and we affected a lot more than what you see on national television,” she said.

Netcare has had to scramble to secure medical supplies for its hospitals in KwaZulu-Natal. Netcare CEO Dr Richard Friedland said that they had flown in trauma nurses and medical supplies following their supplier’s inability to provide them as a result of the unrest. Dr Friedland said Netcare hospitals remained open despite staffing challenges.

“Like many other businesses, we have experienced some challenges due to staff shortages as a result of staff not being able to reach their place of work, however Netcare’s hospitals remain open throughout the country. We have treated a number of people for protest-related injuries, placing further pressure on an already constrained healthcare system, including emergency medical services,” he said.

The Democratic Nursing Organisation of South Africa (Denosa) has also reported that its members are facing challenges getting to and from work because of the violence.

Categories : Diseases, Syndromes and ConditionsTags :

Nose Drops of ‘Friendly’ Bacteria Protects Against Meningitis

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Photo by Mathilde Langevin on Unsplash
Photo by Mathilde Langevin on Unsplash

Researchers have shown that nose drops of genetically modified ‘friendly’ bacteria protect against a form of meningitis.

The study, published in the journal Science Translational Medicine, was led by Professor Robert Read and Dr Jay Laver from the NIHR Southampton Biomedical Research Centre and the University of Southampton, and is the first of its kind.

The researchers spliced a gene into a harmless bacteria type, which enabled it to remain in the nose for longer than normal, triggering an immune response. Then, via nose drops, they administered these altered bacteria into the noses of healthy volunteers. The results showed a strong immune response against bacteria that cause meningitis and long-lasting protection.

Meningitis protection

Meningitis occurs in people of all age groups but affects mainly infants, young children and the elderly. Meningococcal meningitis, a bacterial form of the disease, can lead to death in as little as four hours after symptom onset.

Around 10% of adults carry Neisseria meningitidis in the back of their nose and throat without any signs or symptoms. In certain people however, it can invade the bloodstream, potentially leading to life-threatening conditions including meningitis and septicaemia.

The ‘friendly’ bacteria Neisseria lactamica also lives in some people’s noses naturally. By occupying the nose, it denies a foothold to its close relative N. meningitidis.

Boosted immune response

The study is an extension of the team’s previous work aiming to exploit this natural phenomenon. Nose drops of N. lactamica in that previous study prevented N. meningitidis from settling in 60% of participants. The team sought to improve on this.

They gave N. lactamica one of N. meningitidis’ key weapons; by giving it the gene for a ‘sticky’ surface protein that grips the cells lining the nose.
Those modified bacteria managed to remain longer and produced a stronger immune response. From at least 28 days, most participants (86%) still carried it at 90 days, it caused no adverse symptoms.

This is a promising find for this new way of preventing life-threatening infections, without drugs, especially in the face of growing antimicrobial resistance.

Dr Jay Laver, Senior Research Fellow in Molecular Microbiology at the University of Southampton, commented: “Although this study has identified the potential of our recombinant N. lactamica technology for protecting people against meningococcal disease, the underlying platform technology has broader applications.

“It is theoretically possible to express any antigen in our bacteria, which means we can potentially adapt them to combat a multitude of infections that enter the body through the upper respiratory tract. In addition to the delivery of vaccine antigens, advances in synthetic biology mean we might also use genetically modified bacteria to manufacture and deliver therapeutics molecules in the near future.”

Prof Read, Director of the NIHR Southampton Biomedical Research Centre said: “This work has shown that it is possible to protect people from severe diseases by using nose drops containing genetically modified friendly bacteria. We think this is likely to be a very successful and popular way of protecting people against a range of diseases in the future.”

Source: University of Southampton

Journal reference: Laver, J.R., et al. (2021) A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage. Science Translational Medicine. doi.org/10.1126/scitranslmed.abe8573.

Categories : Medical Research & Technology Neurodegenerative DiseasesTags :

MRI and Ultrasound Combo Opens Blood-brain Barrier

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In a mouse model study of MRI-guided focused ultrasound-induced blood-brain barrier (BBB) opening at MRI field strengths ranging from ­approximately 0 T (outside the magnetic field) to 4.7 T, the static magnetic field dampened the detected microbubble cavitation signal and decreased the BBB opening volume. Credit: Washington University School of Medicine in St. Louis

Using a combination of ultrasound, MRI field strength and microbubbles can open the blood-brain barrier (BBB) and allow therapeutic drugs to reach the diseased brain location with MRI guidance. 

Using the physical phenomenon of cavitation, it is a promising technique that has been shown safe in patients with various brain diseases, such as Alzheimer’s diseases, Parkinson’s disease, ALS, and glioblastoma.
While MRI has been commonly used for treatment guidance and assessment in preclinical research and clinical studies, until now, researchers did not know the impact that MRI scanner’s magnetic field had on the BBB opening size and drug delivery efficiency.

Hong Chen, associate professor of biomedical engineering at Washington University in St. Louis, and her lab have found for the first time that the magnetic field of the MRI scanner decreased the BBB opening volume by 3.3-fold to 11.7-fold, depending on the strength of the magnetic field, in a mouse model. The findings were in Radiology.

Prof Chen conducted the study on four groups of mice. After they were injected microbubbles, three groups received focused-ultrasound sonication at different strengths of the magnetic field: 1.5 T (teslas), 3 T and 4.7 T, and one group was never exposed to the field. 

The researchers found that the microbubble cavitation activity, or the growing, shrinking and collapse of the microbubbles, decreased by 2.1 decibels at 1.5 T; 2.9 decibels at 3 T; and 3 decibels at 4.7 T, compared with those that had received the dose outside of the magnetic field. Additionally, the magnetic field decreased the BBB opening volume by 3.3-fold at 1.5 T; 4.4-fold at 3 T; and 11.7-fold at 4.7 T. No tissue damage from the procedure was seen.

Following focused-ultrasound sonication, the team injected a model drug, Evans blue dye, to investigate whether the magnetic field affected drug delivery across the BBB. The images showed that the fluorescence intensity of the Evans blue was lower in mice that received the treatment in one of the three strengths of magnetic fields compared with mice treated outside the magnetic field. The Evans blue trans-BBB delivery was decreased by 1.4-fold at1.5 T, 1.6-fold at 3.0 T and 1.9-fold at 4.7 T when compared with those treated outside of the magnetic field.

“The dampening effect of the magnetic field on the microbubble is likely caused by the loss of bubble kinetic energy due to the Lorentz force acting on the moving charged lipid molecules on the microbubble shell and dipolar water molecules surrounding the microbubbles,” said Yaoheng (Mack) Yang, a doctoral student in Prof Chen’s lab and the lead author of the study.

“Findings from this study suggest that the impact of the magnetic field needs to be considered in the clinical applications of focused ultrasound in brain drug delivery,” Prof Chen said.

In addition to brain drug delivery, cavitation is also used in several other therapeutic techniques, such as histotripsy, the use of cavitation to mechanically destroy regions of tissue, and sonothrombolysis, a therapy used after acute ischaemic stroke. The magnetic field’s damping effect on cavitation is expected to affect the treatment outcomes of other cavitation-mediated techniques when MRI-guided focused-ultrasound systems are used.

Source: Washington University in St. Louis

Journal information: Yang, Y., et al. (2021) Static Magnetic Fields Dampen Focused Ultrasound–mediated Blood-Brain Barrier Opening. Radiology. doi.org/10.1148/radiol.2021204441. 

Categories : New Compounds and TreatmentsTags :

Immunotoxin Treatment Stops Liver Fibrosis

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A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Credit: Dr. David Kleiner, National Cancer Institute/NIH
A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Credit: Dr David Kleiner, National Cancer Institute/NIH

A new study successfully used immunotoxins to prevent the progression of liver fibrosis by targeting a protein specific to that disease.

Fibrosis, the buildup of collagen and scar tissue, can be caused by alcohol abuse and disease. University of California San Diego School of Medicine researchers and their collaborators are looking for ways to treat fibrosis by preventing liver cells from producing collagen. 

“So we thought…what if we take immunotoxins and try to get them to kill collagen-producing cells in the liver,” explained team lead Tatiana Kisseleva, MD, PhD, associate professor of surgery at UC San Diego School of Medicine. “If these antibodies carrying toxic molecules can find and bind the cells, the cells will eat up the ‘gift’ and die.”

The study focussed on immunotoxins designed to bind a protein called mesothelin, which is rarely found in the healthy human body. The protein is only produced by cancer cells and collagen-producing liver cells, known as portal fibroblasts.

Kisseleva teamed up with co-author Ira Pastan, MD, at the National Cancer Institute, part of the National Institutes of Health (NIH). Dr Pastan is co-discoverer of mesothelin and an expert on using immunotoxins to target the protein on cancer cells, and he leads several clinical trials using it in treating patients with ovarian cancer, mesothelioma and pancreatic cancer.

Since the immunotoxins specifically recognise human mesothelin, the researchers couldn’t use a traditional mouse model of liver fibrosis. So, they transplanted human liver cells isolated from patients to mice and treated them with the anti-mesothelin immunotoxin. Compared to untreated mice, 60 to 100 percent of human mesothelin-producing cells were killed by the immunotoxins, which also reduced the deposition of collagen.

Liver fibrosis treatment is very limited at present, with weight loss being currently the only known method for reducing liver fibrosis associated with non-alcoholic fatty liver disease. Alcoholic liver disease is most commonly treated with corticosteroids, but they are not highly effective. Early liver transplantation is the only proven cure, but it is rarely available.

“What we want to know now is, can this same strategy be applied to other organs?” Dr Kisseleva said. “Surprisingly enough, the same cells are responsible for fibrosis in the lung and kidneys. This is especially exciting because we already know from Dr Pasten’s cancer clinical trials that anti-mesothelin immunotoxins are safe in humans, potentially speeding up their application in other areas.”

The findings were published in Proceedings of the National Academy of Sciences

Source: University of California San Diego

Journal information:Nishio, T., et al. (2021) Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. PNAS. doi.org/10.1073/pnas.2101270118.