My cocaine abuse destroyed my septum and my marriage

At my lowest point, I was walking down Brentwood High Street begging for £1, so I could buy a can of cider or a box of pills.

I was desperately looking for something to take the edge off my anxiety and withdrawal from codeine – a powerful and addictive painkiller.

I remember wondering how on earth I had got to this point.

Until my drug-taking completely took over, I had worked as a successful City trader, earning as much as £180,000 a year – more than I ever dreamt of when I left school.

My childhood was fairly normal, but I started experimenting with drugs at school, aged 15, as a way to fit in. I wasn’t academic so I left without any qualifications and went to work in Petticoat Lane Market in the East End of London when I was 16, selling children’s clothes. 

I was pretty entrepreneurial and knew how to make a living. But when I saw some friends who’d started jobs on the trading floor walking around the market in their designer clothes and coloured trading jackets, I thought, ‘I want some of that.’

So, I sent off about 100 CVs and eventually got a job as a runner in Cannon Street on the trading floor.

I loved the job from day one. I relished the fast-paced atmosphere and the sounds of the trading floor – it could be pretty noisy! It was very different to my job in the market; my stall in the East End felt a million miles away.

My career really started to take off in 1998 when I was working as a broker for a large company. I had a substantial client base made up of a hedge fund, and several propriety traders at large investment banks.

The high-speed nature of the role meant that I always needed to be ‘on the ball’. Part and parcel of that meant entertaining clients in the city and this involved lots of alcohol and cocaine.

It was just the way it was in the City; everyone was doing it and no-one ever questioned it.

At the height of my broking career, I was pretty much spending all I earned on cocaine. In the midst of all this, I met my now ex-wife and we had two children.

My wife was aware of my cocaine problem – but I managed to hide the full extent of it. Meanwhile, I loved being a dad. I looked forward to taking them to soft play centres and to see their grandparents at weekends and in the holidays. 

Sadly, this didn’t stop me. I would often go missing for days at a time – I completely ‘lost myself’.

Though I was aware that things were getting out of control, I was still in denial about having a drug problem. Others in the office were also ‘using’, but it was clear that I was becoming a liability and my behaviour was reckless. I was taking too many risks and I just wasn’t able to think clearly.

As the desk manager, I would mislead my colleagues and then they would have to cover up my mistakes.

My career started to go wrong when I failed a drug test in 2008 and essentially got banned from the City. Although I would bring in huge revenue to any new ‘desk’ hiring me, the risk of employing me was fast outweighing the potential returns.

I moved to Spain and started to work on the unregulated markets, with the intention of stopping taking drugs. However, within one day I was ‘using’ again. 

I was spending more than I was making – some months I wasn’t able to pay the rent or my kids’ school fees. I was sleeping all day and staying up all night.

After two and a half years in Spain, it was clear we couldn’t stay there any more because my life was completely unmanageable. I had started using harder drugs and things got progressively worse. It got to the point where neither my family or my colleagues wanted to be around me.

We returned to the UK and my family got together and gave me the ultimatum to go to rehab. My health was deteriorating and it had got to the point where I couldn’t even snort cocaine anymore as my septum was destroyed. 

The damage to my septum was obvious, but I was so addicted to ‘using’ that I didn’t really think too much about it, which shows just how serious my problem was. 

So, soon, I was sent to a facility in Arizona. Although it probably sounds shocking and selfish, I didn’t take it seriously as I knew I wasn’t ready to stop taking drugs. I didn’t go for me – I went for everyone else.

All I left there with was an education on different drugs.

It was at this point that my wife decided she had enough and my marriage ended. Unemployed once again, I moved out of the family home and back in with my father.

My drug use escalated to a new level and I was drinking dangerous amounts of alcohol. I began abusing opiate medication in the form of codeine. 

At this point I couldn’t see a way out – my physical dependency was so strong that if I didn’t take drugs then and there, I was sick.

My health was continuing to decline and the effect of the high numbers of tablets I was consuming led me to develop a stomach ulcer, which eventually burst and forced me to spend three weeks in intensive care.

I didn’t tell the hospital about my drug use – they didn’t know that my ulcer had burst because of codeine use and I was wrongly diagnosed with Crohn’s disease, as my bowel and stomach were so corroded. Ironically, there was no form of detox – I was given a continuous opiate dose via an intravenous drip, so I was very comfortable.

I continued to use drugs for another six years until I was admitted to hospital again – this time for surgery to repair the previous stomach ulcer wound, which had re-opened from continued codeine damage.

During this visit, doctors became concerned that I wouldn’t ‘make it’. I weighed less than seven stone, I was malnourished, jaundiced and extremely anaemic. I was broken both physically and emotionally. I quite literally had nothing.

13 months later in June 2017, I entered a different treatment facility. Something had changed for me. My denial had been broken and I knew this was my only chance to live.

I was at this rehab for 12 weeks and I made the decision that from then on I was going to live my life free of substances.

Since then, I have stayed clean. Now four years later, my life is now completely different. I have rebuilt the relationship with my children. I have a new partner and I am due to get married next year. My family trust me and life is good. 

When I had been ‘clean’ for three years, I started the process of getting my face and nose re-built and was weeks away from the surgery when we went into lockdown. I’m still waiting for it to be rescheduled.

I have been left with terrible breathing problems and a speech impediment as a result of my cocaine use – it makes me very self-conscious.

I now work as an admissions coordinator for Step by Step Recovery, an addiction treatment centre. My role involves answering the telephone and I am the first point of contact for clients reaching out for help.

Most of the people who call the helpline don’t believe there is a way out and I am able to use my experience to help others – I am committed to being a decent member of society.

I get phone calls from people from all walks of life. Solicitors, teachers, medical professionals, other traders who are lost and broken just like I was.

My outlook on life and how I feel is so very different to how it used to be.

Today I do not live in the same level of fear, shame and chaos that comes with addiction. I now go to bed at night and look forward to tomorrow.

Looking back, there is nothing I could have told myself when I was in active addiction – I wouldn’t have listened to anyone.

But I believe that anyone can change their lives no matter how hopeless and desperate they feel. I wouldn’t swap what I’ve got now for anything.

Step by Step Recovery has an outpatient clinic in Harley Street, London, and a residential rehab in Essex – learn more at stepbysteprecovery.co.uk.

Do you have a story you’d like to share? Get in touch by emailing [email protected] 

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New genetically encoded sensor helps detect drugs of abuse

A genetically encoded sensor to detect hallucinogenic compounds has been developed by researchers at the University of California, Davis. Named psychLight, the sensor could be used in discovering new treatments for mental illness, in neuroscience research and to detect drugs of abuse. The work is published April 28 in the journal Cell.

Compounds related to psychedelic drugs such as LSD and dimethyltryptamine (DMT) show great promise for treating disorders such as depression, post-traumatic stress disorder, and substance use disorder. These drugs are called psychoplastogens because of their ability to rapidly alter brain connections. But drugs that can cause hallucinations require very careful use and monitoring of patients.

Currently, the most effective way to test an experimental drug to see if it causes hallucinations is the "head twitch" assay in rodents.

Scientific studies on psychedelic drugs have been conducted since the 1940s, but we still don't have an effective cellular assay for them."

David Olson, Study Co-Author and Assistant Professor, Department of Chemistry, College of Letters and Science, UC Davis

The work grew out of collaboration between graduate students working with Lin Tian, associate professor at the UC Davis School of Medicine, and Olson's laboratory. "This collaboration was really driven by graduate students," Tian said.

Tian's lab develops fluorescent indicators for neural chemicals in the brain such as serotonin and dopamine. These neuromodulators allow the brain to react quickly to changing conditions, Tian said. Like neuromodulators, both psychedelic drugs and those used to treat mental illness either mimic or block the action of these neuromodulators, thus can have profound impacts on brain function.

Measuring chemicals in the brain

The psychLight biosensor is based on the serotonin 2A receptor (HT2AR). Within the brain, serotonin released from neurons and picked up by serotonin receptors on other neurons acts to regulate mood. Both psychedelic drugs and drugs used to treat psychiatric disorders act through the serotonin 2A receptor.

Jason (Chunyang) Dong, a graduate student in Tian's lab in the Department of Biochemistry and Molecular Biology, worked with graduate students Calvin Ly and Lee Dunlap in Olson's lab to engineer a modified version of the HT2A receptor with a fluorescent component.

When psychLight binds to serotonin or a hallucinogenic ligand it changes its conformation, causing the fluorescence to increase. Non-hallucinogenic ligands can also bind to psychLight but lead to a different fluorescence profile.

Researchers can use psychLight to see how naturally occurring neuromodulators like serotonin, or hallucinogenic drugs, act on different parts of the brain. They could also use it to screen candidate drugs for those which activate the HT2A receptor and could cause hallucinations. When psychLight is expressed in cells and those cell cultures are exposed to a hallucinogenic drug, they light up.

The sensor can be used to look for pharmaceutical potential without the side effect of hallucinations, Tian said.

High-throughput screening

The researchers set up a high-throughput system to use cells expressing psychLight to screen compounds for hallucinogenic activity and for binding of the HT2A receptor. Using this, they showed that a previously untested compound, AAZ-A-154, activates the receptor but is not hallucinogenic. Subsequent tests in animal models confirmed that AAZ-A-154 shows promise as an antidepressant.

Seven Biosciences, a company founded by Tian and former graduate student Grace Mizuno, is working with UC Davis InnovationAccess to license the psychLight technology and develop it for commercial use. Delix Therapeutics, founded by Olson, is developing AAZ-A-154 and hopes to apply the psychLight assay to search for new pharmaceutical drugs.

Source:

University of California Davis Health

Journal reference:

Dong, C., et al. (2021) Psychedelic-inspired drug discovery using an engineered biosensor. Cell. doi.org/10.1016/j.cell.2021.03.043.

Posted in: Drug Discovery & Pharmaceuticals | Biochemistry | Fluorescence

Tags: Antidepressant, Assay, Biochemistry, Biosensor, Brain, Cell, Compound, Depression, Dopamine, Drug Discovery, Drugs, Fluorescence, High-throughput screening, Laboratory, Ligand, Medicine, Molecular Biology, Neurons, Neuroscience, Post-Traumatic Stress Disorder, Receptor, Research, Serotonin, Stress, students, Substance Use Disorder, Therapeutics

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Two repurposed drugs and a blue dye show potential as SARS-CoV-2 entry inhibitors

A new multidisciplinary study from Australia, published in the open-access journal mBio, shows that three compounds used to treat cystic fibrosis, dry eye, and a specific medical dye may lead to future strategies for the treatment of coronavirus disease (COVID-19).

The ongoing pandemic of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a health emergency that necessitates the continued use of vaccines, but also the development of new drugs to prevent or treat this disease.

However, the latter seems to be a much more complicated issue. Due to the time and cost constraints pertinent to the development of new medications, a drug repurposing process has been posited as a somewhat reasonable approach for now, which entails using drugs that have already been approved for other treatment purposes.

We already know that SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) as a receptor to engage with host cells, and a high affinity for the aforementioned receptor was noted for the receptor-binding domain (RBD) of the viral spike glycoprotein. This is an event that can be targeted by potential inhibitors of infection.

Consequently, Professor Michael Jennings and Associate Professor Thomas Haselhorst at the Institute for Glycomics of Griffith University in Australia led a research team that used a combination of biophysical and computer-based methods in their quest for drugs that halt the binding of SARS-CoV-2 to host cells.

Evans blue (cyan) is shown bound at the interface between the SARS-CoV-2 Spike (green) and its host receptor ACE2 (grey). Image credit: A/Prof Thomas Haselhorst

Molecular modeling strategy

The methodological approach included computational and biophysical compound library screens in order to reveal potential entry inhibitors that can bind to the receptor for SARS-CoV-2, ACE2, and the SARS-CoV-2 spike glycoproteins. The researchers have also developed a biophysical assay to appraise the potential of identified compounds to block the SARS-CoV-2 spike protein RBD-ACE2.

More specifically, this study has employed a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to pinpoint those that bind to human ACE2 or the SARS-CoV-2 spike glycoprotein RBD. A Vero-E6 cell-based assay was used to assess infection blockade by candidate entry inhibitors.

Consequently, molecular modeling screening examined 57,641 compounds and concentrated on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein (and vice versa). Furthermore, SPR screening used immobilized human ACE2 and SARS-CoV-2 spike glycoprotein in order to evaluate their binding to a library of 3,141 compounds.

Registered drugs and dyes

In this study, the researchers report a series of ligands that bind with KD (i.e., equilibrium dissociation constant) in the low nanomolar to the low micromolar range to the human ACE2 protein. Molecular modeling used in this paper supports the hypothesis that these compounds are able to bind in the same region of ACE2 that SARS-CoV-2 uses as a cellular receptor.

Twelve binders of ACE2 and six binders of RBD were found to compete with the RBD-ACE2 interaction in an SPR-based competition assay. Among them, there were registered drugs and dyes used for various biomedical applications, and all 22 identified compounds provide scaffolds for the development of novel chemical entities in the treatment of COVID-19.

These scientists have also found that three of them – Evans blue (medical dye), lumacaftor (cystic fibrosis), and sodium lifitegrast (dry eye) – were found to halt viral infection of cells in the culture and, hence, may be further appraised for repurposing as treatment agents or even to steer the development of new drugs.

Blueprints for novel antiviral compounds

In summary, the specific compounds revealed in this study can be considered as viable candidates for additional evaluation of inhibiting SARS-CoV-2 viral entry in primary human airway cellular model systems and ACE2-humanized animal models.

“All identified drugs in this study have potential to provide blueprints for the development of new antiviral compounds for the treatment of COVID-19”, said Dr. Christopher J. Day, the first author on this paper.

“The promising outcome of this research is thanks to significant funding received from the Queensland Government and the City of Gold Coast. Each provided $100,000 to the Australian node of iCAIR®’s COVID-19 project to develop treatments against SARS-CoV-2”, said the co-author of the study Professor Mark von Itzstein.

In conclusion, the compounds identified here comprise high-affinity ligands of ACE2 and spike glycoprotein that are actually registered drugs, as well as a specific dye used for biomedical applications. All of them may be considered as candidates for repurposing or as chemical scaffolds in order to produce entry blockers to either prevent or cure COVID-19.

Source:
  • Marshall, D. (2021). Eye and cystic fibrosis drugs identified among drugs with potential to guide new COVID-19 treatments. Griffith University News. https://news.griffith.edu.au/2021/04/19/eye-and-cystic-fibrosis-drugs-identified-among-drugs-with-potential-to-guide-new-covid-19-treatments/
Journal reference:
  • Day, C.J. et al. (2021). Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions. mBio. https://doi.org/10.1128/mBio.03681-20  

Posted in: Drug Trial News | Medical Research News | Disease/Infection News | Pharmaceutical News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Assay, Cell, Compound, Coronavirus, Coronavirus Disease COVID-19, Cystic Fibrosis, Drug Repurposing, Drugs, Dry Eye, Enzyme, Eye, Fibrosis, Glycoprotein, Pandemic, Protein, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome

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Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university – University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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Inhibition of Meprin Β enzyme can trigger the development of Alzheimer's disease, cancer

Researchers at Johannes Gutenberg University Mainz (JGU) in Germany and the Institute of Molecular Biology of Barcelona in Spain have discovered how the blood plasma protein fetuin-B binds to the enzyme meprin β and used a computer model to visualize their findings.

These results could lead to the development of new drugs to treat serious diseases such as Alzheimer's and cancer. Meprin β releases proteins from cell membranes, thus controlling important physiological functions in the human body.

However, a dysregulation of this process can trigger the development of Alzheimer's and cancer. Meprin β is regulated by fetuin-B binding to the enzyme when required, thereby preventing the release of other proteins. Presenting their findings in the journal Proceedings of the National Academy of Sciences, the researchers are now the first to describe this binding in detail.

The team at Mainz University produced both meprin β and fetuin-B in insect cells and then allowed them to react with one other in a test tube. By means of measurement of enzyme kinetics and biophysical analyses, the researchers determined that this reaction resulted in an exceptionally stable, high-molecular-mass complex.

Their colleagues in Barcelona subsequently managed to crystallize the complex and determine its three-dimensional structure using X-ray crystallography. This involved X-rays being fired at the protein crystals, which allowed the atomic structure of the crystals to be calculated from the diffraction of the X-rays. A computer model of the structure was then generated.

"Thanks to the model, we can now see exactly how meprin β and fetuin-B bind together," said Professor Walter Stöcker, who conducted the research at JGU together with Dr. Hagen Körschgen and Nele von Wiegen. "This research represents an excellent starting point for gaining a better understanding of diseases such as Alzheimer's and for developing the drugs to combat them."

Meprin β is already known to be involved in the formation of so-called beta-amyloid plaques, which are a characteristic feature of the condition. Moreover, people with Alzheimer's disease have relatively little fetuin-B in their blood, which in turn may lead to a lack of regulation of meprin β.

If it is possible to develop a drug that binds to the enzyme and inhibits it in a similar way to fetuin-B, this could be a new way of treating Alzheimer's."

Walter Stöcker, Professor, Johannes Gutenberg University Mainz (JGU), Germany

Source:

Johannes Gutenberg University Mainz

Journal reference:

Eckhard, U., et al. (2021) The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2023839118.

Posted in: Medical Research News | Medical Condition News

Tags: Alzheimer's Disease, Blood, Cancer, Cell, Crystallography, Diffraction, Drugs, Enzyme, Molecular Biology, Protein, Research, X-Ray

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Study reveals molecular mechanisms of drug resistance in Mycobacterium tuberculosis

A consortium of researchers from Russia, Belarus, Japan, Germany and France led by a Skoltech scientist have uncovered the way in which Mycobacterium tuberculosis survives in iron-deficient conditions by utilizing rubredoxin B, a protein from a rubredoxin family that play an important role in adaptation to changing environmental conditions.

The new study is part of an effort to study the role of M. tuberculosis enzymes in developing resistance to the human immune system and medication. The paper was published in the journal Bioorganic Chemistry.

According to the World Health Organization, every year 10 million people fall ill with tuberculosis and about 1.5 million die from it, making it the world's top infectious killer. The bacterium that causes TB, Mycobacterium tuberculosis, is notorious for its ability to survive within macrophages, cells of the immune system that destroy harmful bacteria.

Continuing spread of drug resistance of M. tuberculosis to widely used therapeutics over recent decades became a substantial clinical problem. In this regard, the identification of novel molecular drug targets and deciphering the molecular mechanisms of drug resistance are of pivotal importance.

Natallia Strushkevich, Assistant Professor at the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE), and her colleagues studied the crystal structure and function of rubredoxin B (RubB), a metalloprotein that ensures the proper functioning of cytochrome P450 (CYP) proteins essential to bacterial survival and pathogenicity.

The team hypothesizes that M. tuberculosis switched over to more iron-efficient RubB to survive iron starvation when granulomas are formed (these are largely unsuccessful attempts at defense against TB by the immune system).

During the long-term co-evolution with mammals, M. tuberculosis developed a variety of strategies to subvert or evade the host innate immune response, from recognition of the bacterium and phagosomal defenses within infected macrophages, to adaptive immune responses by antigen presenting cells. Iron assimilation, storage and utilization is essential for M. tuberculosis pathogenesis and also involved in emergence of multi- and extensively-drug resistant strains. Heme is the preferable iron source for M. tuberculosis and serves as a cofactor for various metabolic enzymes."

Natallia Strushkevich, Assistant Professor, Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE)

Based on our finding, we linked rubredoxin B to heme monoooxygenases important for metabolism of host immune oxysterols and anti tubercular drugs. Our findings indicate that M. tuberculosis has its own xenobiotics transformation system resembling human drug metabolizing system," explains Natallia Strushkevich.

According to Natallia: New targets for drug design efforts are in great demand and the cytochrome P450 enzymes have emerged as novel targets for the development of tuberculosis therapeutic agents.

The classic approaches to block these enzymes are not straightforward. Finding the alternative redox partner, such as RubB, enables further understanding of their function in different host microenvironments. This knowledge could be exploited to identify new ways to block their function in M. tuberculosis.

Earlier research by the consortium showed that one of the CYPs enabled by RubB can act against SQ109, a promising drug candidate against multidrug-resistant tuberculosis. Another study focused on how Mycobacterium tuberculosis protects itself by intercepting human immune signaling molecules — a hurdle that limits drug discovery.

Source:

Skolkovo Institute of Science and Technology (Skoltech)

Journal reference:

Sushko, T., et al. (2021) A new twist of rubredoxin function in M. tuberculosis. Bioorganic Chemistry. doi.org/10.1016/j.bioorg.2021.104721.

Posted in: Molecular & Structural Biology | Microbiology | Biochemistry

Tags: Aging, Antigen, Artificial Intelligence, Bacteria, Biochemistry, Cytochrome P450, Drug Discovery, Drugs, Evolution, Immune Response, Immune System, Metabolism, Photonics, Protein, Research, Structural Biology, Therapeutics, Tuberculosis

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New biomarker of glucocorticoid action could help clinicians to tailor treatments

Researchers have uncovered pathways involved in the body's response to glucocorticoid treatments and identified a novel biomarker that could be used to monitor how these drugs work in patients, according to a clinical study published today in eLife.

A more reliable indicator of an individual's response to glucocorticoid drugs could be used to develop a clinically applicable test that could help tailor treatments and potentially minimize side-effects.

Glucocorticoids, such as cortisol, are a type of hormone with key roles in the body's response to stress. Glucocorticoid drugs are one of the most commonly prescribed treatments for a range of conditions, including for patients whose adrenal glands are unable to produce enough cortisol. The effects of glucocorticoids are complex, meaning the level of cortisol in the blood does not reliably reflect what is happening in the tissues. This makes it hard for medical professionals to know how to tailor treatments.

Side effects of glucocorticoid treatments are common in patients, indicating that current methods to monitor their action, which typically focus on clinical response or disease activity, are inadequate. We wanted to find some kind of biomarker that could be measured to monitor the action of glucocorticoids in individuals, with the hopes this will help clinicians understand how best to treat patients."

Dimitrios Chantzichristos, First Author, Head Physician, Section for Endocrinology-Diabetes-Metabolism, Sahlgrenska University Hospital, Sweden

The team studied patients with Addison's disease who lack the ability to produce their own cortisol. This allowed them to compare the activity in the tissues of the same patient both when their cortisol levels were low and when they were being restored by glucocorticoid treatments, helping account for variations between individuals.

Rather than focusing only on the metabolic products associated with glucocorticoid exposure, they also looked at gene expression and microRNAs in the patients using new computational approaches developed in collaboration with Dr Adam Stevens at the University of Manchester, UK. MicroRNAs are short strands of ribonucleic acid (RNA) that can regulate the expression of genes by interfering with protein production. The team analyzed these different factors in blood cells and body fat, an important metabolic tissue, as the patients' cortisol levels were changed, revealing close relationships between different elements involved in glucocorticoid action.

Among the elements they identified, a microRNA called miR-122-5p closely correlated with genes and metabolites that are regulated by the glucocorticoid treatments. To test this correlation, the team looked at miR-122-5p levels in blood from patients exposed to different levels of glucocorticoids from three independent studies and found the same pattern, supporting the idea that this microRNA could be a useful biomarker of glucocorticoid action.

"This potential biomarker can now be investigated in larger groups of patients with the aim to develop a clinically applicable test," concludes senior author Gudmundur Johannsson, Professor at the Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sweden. "Our work has also increased our understanding of the action of glucocorticoids, which may help uncover their role in many common diseases such as diabetes, obesity and cardiovascular diseases."

This study was a collaborative effort between researchers at the Universities of Manchester (UK), Edinburgh (UK), Copenhagen (Denmark) and Gothenburg (Sweden), as well as Newcastle University (UK) and Sahlgrenska University Hospital (Sweden).

Source:

eLife

Journal reference:

Chantzichristos, D., et al. (2021) Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. eLife. doi.org/10.7554/eLife.62236.

Posted in: Molecular & Structural Biology | Biochemistry

Tags: Addison's Disease, Biomarker, Blood, Cortisol, Diabetes, Drugs, Endocrinology, Gene, Gene Expression, Genes, Glucocorticoid, Hormone, Hospital, Medical Research, Medicine, Metabolism, Metabolites, MicroRNA, Nutrition, Obesity, Protein, Research, Rheumatism, Ribonucleic Acid, RNA, Stress

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Homelessness associated with increased HIV and HCV risk among people who inject drugs

HIV

Homelessness and unstable housing are associated with a substantial increase in HIV and hepatitis C virus (HCV) acquisition risk among people who inject drugs, according to research led by the NIHR Health Protection Research Unit in Behavioral Science and Evaluation at the University of Bristol.

The study, published in The Lancet Public Health today [26 March] found that, among people who inject drugs, recent homelessness and unstable housing were associated with a 55 percent and 65 percent increase in HIV and HCV acquisition risk, respectively.

The study is the first systematic review and meta-analysis (a statistical method used to combine the results of multiple studies) to assess whether homelessness or unstable housing increases HIV or HCV risk among people who inject drugs. The researchers extracted and pooled data from 45 previous studies providing 70 estimates (26 for HIV and 44 for HCV) to work out a more robust measure of the risks.

Globally, there are an estimated 15.6 million people who inject drugs; over one in six are infected with HIV and over half have been infected with HCV. People who inject drugs are at high risk of HIV and HCV infection through the sharing of needles, syringes and other injecting equipment and experience high levels of homelessness and unstable housing.

Globally, an estimated 22 percent of people who inject drugs reported experiencing homelessness or unstable housing in the past year, with this increasing to 42 percent in England (having increased from 28 percent in the last decade), and 50 percent in North America.

A high proportion of people in unstable housing have substance misuse problems, with 30 percent reporting they used heroin in the last month in the UK, highlighting the overlapping risks of drug use and homelessness.

Previous research also suggests that homeless or unstably housed drug users are less likely to access HIV and HCV treatment and use opioid substitution therapy and needle-syringe programs, two important HIV and HCV prevention interventions. They may also be more likely to engage in high-risk injecting and sexual behaviours and more likely to have been recently imprisoned, another factor associated with increased HIV and HCV acquisition risk.

Chiedozie Arum, lead author from the University of Bristol, said: “Our study highlights the overlapping bio-social problems that worsen health inequalities among homeless people who inject drugs. Expanding access to prevention and treatment services and improving housing provision for this population should be prioritized.”

Dr. Jack Stone, Senior Research Associate from the University of Bristol and joint senior author, said: “Our findings suggest housing instability is an important driver of HIV and HCV transmission among people who inject drugs. Further research is now needed to better understand how homelessness or unstable housing increases the risk of HIV and HCV acquisition, and what interventions could have most impact in reducing this risk.”

Peter Vickerman, Professor of Infectious Disease Modelling from the University of Bristol and joint senior author, said “This research adds to the growing evidence on the damaging effect of housing instability on health and social outcomes. A comprehensive policy approach that not only provides housing but also addresses many of the interlinked health and social concerns of this population is necessary in order to reduce HIV and HCV risk.”

The study has important implications for policy and public health, including:

  • the need for housing interventions tailored to people who inject drugs that address their competing health and social concerns
  • the need for improved access to HIV and HCV prevention and treatment interventions among those who are homeless or unstably housed
  • the need for these interventions to be integrated within services that provide for the wide ranging health needs of these vulnerable populations
  • the need to reduce stigma towards homelessness and drug use that act as barriers to accessing care.

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Researchers identify new drug candidates for treating patients with severe COVID-19

University of Maryland School of Medicine (UMSOM) researchers have identified the most toxic proteins made by SARS-COV-2–the virus that causes COVID-19 – and then used an FDA-approved cancer drug to blunt the viral protein's detrimental effects.

In their experiments in fruit flies and human cell lines, the team discovered the cell process that the virus hijacks, illuminating new potential candidate drugs that could be tested for treating severe COVID-19 disease patients. Their findings were published in two studies simultaneously on March XX in Cell & Bioscience, a Springer Nature journal.

Our work suggests there is a way to prevent SARS-COV-2 from injuring the body's tissues and doing extensive damage."

Zhe "Zion" Han, PhD, Study Senior Author and Associate Professor of Medicine, Director of Center for Precision Disease Modeling, University of Maryland School of Medicine

He notes that the most effective drug against Covid-19, remdesivir, only prevents the virus from making more copies of itself, but it does not protect already infected cells from damage caused by the viral proteins.

Prior to the pandemic, Dr. Han had been using fruit flies as a model to study other viruses, such as HIV and Zika. He says his research group shifted gears in February 2020 to study SARS-COV-2 when it was clear that the pandemic was going to significantly impact the U.S.

SARS-COV-2 infects cells and hijacks them into making proteins from each of its 27 genes. Dr. Han's team introduced each of these 27 SARS-CoV-2 genes in human cells and examined their toxicity. They also generated 12 fruit fly lines to express SARS-CoV-2 proteins likely to cause toxicity based on their structure and predicted function.

The researchers found that a viral protein, known as Orf6, was the most toxic killing about half of the human cells. Two other proteins (Nsp6 and Orf7a) also proved toxic, killing about 30-40 percent of the human cells. Fruit flies that made any one of these three toxic viral proteins in their bodies were less likely to survive to adulthood. Those fruit flies that did live had problems like fewer branches in their lungs or fewer energy-generating power factories in their muscle cells.

For the remaining experiments, the researchers focused on just the most toxic viral protein, so they could figure out what cell process the virus hijacks during infection. Dr. Han's team found that the virus' toxic Orf6 protein sticks to multiple human proteins that have the job of moving materials out of the cell's nucleus–the place in the cell that holds the genome, or the instructions for life.

They then discovered that one of these human moving proteins, targeted by the virus, gets blocked by the cancer drug selinexor. The researchers tested selinexor on human cells and fruit flies making the toxic viral protein to see if the drug could help reverse the damage.

Selinexor, like many cancer drugs is itself toxic. However, after accounting for its toxic effects, the drug improved human cell survival by about 12 percent. Selinexor prevented early death in about 15 percent of the flies making the toxic viral protein. The drug also restored branches in the lungs and the energy-generators in the muscle cells. Selinexor is FDA-approved to treat certain blood cancers.

"More than 1,000 FDA-approved drugs are in clinical trials to test as treatments for Covid-19, and luckily a trial testing selinexor, the drug used in our study, is being performed already," says Dr. Han. "If this trial proves to be successful, our data will have demonstrated the underlying mechanism for why the drug works."

Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, commented, "Although we now have vaccines, it may still be a while before we will have Covid-19 infections under control, especially with the new variants emerging. We will need to tap into every tool in the arsenal available to protect people from needless sickness, disability or even death, and this study guides us towards a new target for potential therapeutics."

Source:

University of Maryland School of Medicine

Journal reference:

Lee, J-G., et al. (2021) Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor. Cell & Bioscience. doi.org/10.1186/s13578-021-00568-7.

Posted in: Medical Research News | Disease/Infection News

Tags: Blood, Cancer, Cell, Disability, Disease Modeling, Drugs, Fruit, Genes, Genome, HIV, Lungs, Mass Spectrometry, Medical Research, Medical School, Medicine, Muscle, Pandemic, Pharmacy, Protein, Remdesivir, Research, SARS, SARS-CoV-2, Spectrometry, Therapeutics, Virus

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Two new diabetes drugs may work better for Asian people

diabetes

Two relatively new but increasingly used diabetes drugs (with one of these classes also now approved for used in heart failure in people with or without diabetes) are possibly more effective in people with an Asian background than in people with a White background, according to new research.

The study—published in Diabetes Care and led by the University of Glasgow—found the diabetes drug classes GLP-1 receptor agonists and SGLT2 inhibitors may work better at lowering the risk of heart attack and stroke, and heart failure and death from heart disease, respectively.

People with an Asian background, including South Asian and East/Southeast people, experience a greater burden of type 2 diabetes compared with those with a White background.

Of the antihyperglycemic drug classes used to treat diabetes, drug classes GLP-1 receptor agonists and SGLT2 inhibitors are the only ones to show consistent benefits in cardiovascular outcomes. In this study, researchers meta-analyzed data from six trials of SGLT2is; four diabetes trials and two heart failure outcome trials. They also analyzed data from six diabetes outcome trials for the GLP-1 receptor agonist class.

The study found a greater benefit of GLP-1RA therapy on heart attack and stroke risks in people with an Asian background compared with those with a White background across all types of the drug tested. In addition, SGLT2i drugs had at least as good an effect on reducing risk of major cardiovascular events in people with diabetes in Asians, but potentially had a better effect on heart failure outcomes in this group compared with Whites in the heart failure trials.

Naveed Sattar, Professor of Metabolic Medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences, said: “These data show something potentially exciting for doctors treating Asians with diabetes. That Asians may benefit more from a class of drugs to lower heart attack and stroke risks in people with diabetes is exciting, since diabetes is more common in many Asian populations, and finding new ways to lower their cardiovascular risks is helpful.”

“At the same time, potentially better outcomes in Asians with heart failure with SGLT2 inhibitors is also exciting. Such findings now need confirmation and future trials should better categorize people with an Asian background into differing subgroups so that we can work out whether the findings apply to all people with an Asian background or specific subgroups.”

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Push is on for states to ban organ transplant discrimination

Griffin Dalrymple is an energetic 7-year-old who loves going to school in Eureka, Montana. But two years ago, the boy described by his mother, Jayci, as a "ball of fire" was suddenly knocked back by severe bacterial pneumonia that hospitalized him for two weeks.

As her son lay in the intensive care unit with a tube in his tiny lungs, Jayci began imagining worst-case scenarios. She worried that if Griffin ended up needing a lung transplant, he might be refused because he has Down syndrome.

"It was terrifying knowing that they could deny him certain lifesaving services," she said.

Denying organ transplants to people with intellectual and neurodevelopmental disabilities like Down syndrome or autism is common in the United States, even though it is illegal under the Americans with Disabilities Act.

According to one widely cited 2008 study, 44% of organ transplant centers said they would not add a child with some level of neurodevelopmental disability to the organ transplant list. Eighty-five percent might consider the disability as a factor in deciding whether to list the person.

After Griffin recovered, Jayci brought Montana lawmakers' attention to the issue. Largely as a result of her campaigning, the state is considering a bill that would ban physicians from denying an organ transplant based solely on a patient's disability. Last month, the bill — nicknamed "Griffin's Law" — passed the Montana Senate 50-0.

Although Montana has no transplant centers of its own, advocates hope this bill and others like it will draw attention to the issue and pressure physicians to examine why they are making certain decisions. Andrés Gallegos, chairman of the National Council on Disability, said he hopes such legislation will inspire "a change of heart so people understand that they are discriminating."

If the bill passes the state House and is signed by the governor, Montana would become the 17th state to ban such discrimination. Seven other states and the federal government have similar bills pending, although some experts doubt such laws will be enforceable enough to eliminate discrimination.

With more than 100,000 people on the waiting list for organs nationwide, and average wait times extending three to five years for some organs, physicians have to frequently make heart-rending decisions about which patients are likely to benefit most.

According to a 2019 report from the NCD, many physicians and organ transplant centers worry that patients with intellectual or neurodevelopmental disabilities are more likely to have co-occurring conditions that would make a transplant dangerous, or that these patients' quality of life is unlikely to improve with a transplant. Others believe that these patients may not be able to comply with post-transplant requirements, such as taking immunosuppressive drugs.

But the report, which scoured research papers and medical reports, found that none of these concerns is universally true. Rather, disabled patients can benefit as much as any other patient, according to the NCD, an independent federal agency.

"If a determination is made to not include a person on the list only because that individual has a disability, that's blatant discrimination," said Gallegos.

Many intellectually disabled patients and their families see this firsthand. When Joe Eitl was born in 1983 with a congenital heart defect, his mother, Peg, was told that Joe would never be a candidate for a new heart because of his Down syndrome. So, when his heart failed in 2019, eight hospitals refused to even consider a transplant for Joe, who lives with his mother in Philadelphia.

Peg Eitl conceded that Joe's case was difficult, given he'd had prior reconstructive heart surgery that would complicate a transplant. She pleaded with transplant centers for more than a year and even considered suing them. Last October, Vanderbilt University agreed to perform the procedure. Joe came home Feb. 10 and is recovering.

"I think my greatest frustration was the value placed on someone with special needs," Peg Eitl said. "It pains me that they’re discounted as being less than and not as worthy."

Bioethicist David Magnus of Stanford University, who authored the 2008 study on the extent of transplant discrimination, said people like Peg Eitl shouldn't have to prove that Joe would benefit from a transplant. Because people with disabilities are a protected class in the United States, he said, "the burden is on people who want to discriminate."

But that doesn't appear to be the case in practice. In September, Magnus published a follow-up survey of more than 300 transplant programs. Of these, 71% said they would automatically disqualify an adult with an IQ under 35, which is considered severe intellectual disability, while 12% would disqualify a child at that level. Only about 20% of the institutions had formal guidelines regarding child patients.

Magnus suspects these numbers are low given that some physicians may be unwilling to admit to discrimination. He has not yet studied whether new state laws have affected physicians' likelihood to discriminate against disabled patients.

But Magnus doubts that laws like Montana's bill will be enforceable. Part of determining any patient's eligibility for a transplant, he said, is whether they or a caretaker can comply with post-transplant requirements such as remembering to take immunosuppressant drugs. If a person with a disability can't meet these criteria, that person might not be a good candidate.

"All of these are terribly difficult judgments," Magnus said.

Transplant surgeons need to maximize the limited supply of organs and ensure they survive in the patients who receive them. If they don't, "it's taking an organ from someone who could have benefited from it," said Dr. Marwan Abouljoud, president of the American Society of Transplant Surgeons.

Abouljoud said institutions have differing standards for weighing the importance of an intellectual disability in a transplant decision. Ideally, he said, the committee that determines whether to list someone for a transplant will include social workers and behavioral psychologists, as well as program leadership, who can find ways to help the person comply.

On Feb. 12, the transplant surgeons' society adopted a new statement supporting nondiscrimination and encouraging transplant centers to find ways to support these patients. "We will be urging states to adopt local policies on this," Abouljoud said.

Sam Crane, legal director at the Autistic Self Advocacy Network, which has written model legislation adopted by several states, said that some bills — including Montana's — address the concern about post-transplant care. They ban transplant centers from basing their decision solely on a person's ability to carry out post-transplant requirements and require an investigation into sources of support to help the patient comply.

But Crane said physicians could still come up with a pretext to avoid adding a disabled person to the transplant list if they believe a person without a disability would benefit more from receiving an organ.

"It's very difficult to prove discrimination in that sort of situation," she said.

Although a similar nondiscrimination bill has been introduced in the U.S. House of Representatives, Crane said advocates prefer to focus on state laws. Organizations like the autism group have taken the position that the ADA and other federal laws already prohibit this kind of discrimination, making federal legislation unnecessary. Gallegos added that states can also enact stricter requirements than the federal government and fit them to their specific medical systems.

Under state laws, patients can appeal to local courts for an emergency injunction or restraining order. These hearings can be conducted quickly, allowing a judge to decide whether to compel an institution to add a person to the transplant list.

That speed is what Jayci Dalrymple hopes Griffin's Law will achieve. "When you're needing to stop discrimination, you’re racing the clock," she said.

This article was reprinted from khn.org with permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonpartisan health care policy research organization unaffiliated with Kaiser Permanente.

Posted in: Healthcare News

Tags: Autism, Congenital Heart Defect, Disability, Down Syndrome, Drugs, Healthcare, Heart, Heart Defect, Heart Surgery, Intensive Care, Kidney, Lung Transplant, Lungs, Organ Donation, Pneumonia, Public Health, Research, Surgery, Syndrome, Transplant

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