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City dwellers “more likely to die in hospital” after stroke – US study

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Compared to those living in urban areas, stroke patients treated at rural hospitals were one third less likely to undergo a procedure to remove a blood clot that caused the stroke and were more likely to die of stroke before leaving the hospital.

Researchers examined national data on almost 800,000 adults hospitalised after a stroke between 2012 and 2017.

In their paper, published in the American Stroke Association’s Stroke journal, the researchers warn that this urban-rural divide may be getting worse. This gap, the paper states, could be caused by the slower take-up of newer treatments and technologies, and because rural hospitals are less well-resourced and have poorer access to specialist care. Rural hospitals may also be more likely to lack specialised clinical support, such as dedicated stroke units.

Other causes for poorer stroke care could be a lack of clinical expertise in urban areas, due to difficulties attracting and retaining experienced staff, and poorer access to emergency services and longer responses to emergency calls due to distance.

“The lack of access to specialists is often a limiting factor in adequate care for rural stroke patients, and in this case, that could mean a neurologist to guide the initial care, an interventional neurologist or radiologist to do a procedure, or having a neurosurgeon available for backup in case of any complications,” said Gmerice Hammond, author of the study and a cardiology fellow at Washington University School of Medicine.

“Clinicians need to work to improve access to high-quality stroke care for individuals in rural areas. That means partnerships between hospitals for rapid transfer, as well as telehealth when appropriate. And clinical leaders and policymakers should prioritize improving access, care and outcomes for stroke in rural communities.”

The study had some limitations, including a lack of data on the severity of patients’ strokes, or factors that would determine whether a patient received advanced therapies, sich as the size of the clot and where it is located.

Karen Joynt Maddox, senior author of the study and assistant professor of medicine at Washington University School of Medicine, calls the differences in care, and the lack of improvement over the five-year period, ‘striking’.

“Future studies using more detailed clinical data will be important to follow up on our findings and to determine why patients in rural areas aren’t receiving advanced therapies. Is it because their stroke severity is different? Or because delays in getting to the hospital meant they weren’t eligible by the time they arrived?

“Those questions can’t be answered with administrative data, but they’re very important to look into so that we can develop effective solutions.”

Legal

Capacity for decisions in life and love: part 1

Under Article 8 of the Human Rights Act we all have a right to enjoy a private and family life. The need for relationships and intimacy is an essential part of most of our lives but for individuals living with an acquired brain injury, this can be far more complex, as Georgina Moorhead of Irwin Mitchell explains.

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Dating and Sexual Relationships

The law states that people have capacity to engage in sexual relationships if they understand the physical context. In other words, they should understand the basic mechanics of the acts involved, the risk of pregnancy or sexually transmitted disease and the ability of either party to say no at any stage.

In the context of serious injury litigation, we commonly encounter Claimants who have a strong desire for romantic relationships.

Unfortunately, the cognitive issues they face, which often include difficulty concentrating, poor memory, poor language skills and reduced problem- solving abilities, in addition to disinhibition, impulsivity and impaired reading of social cues, can present significant challenges in both dating and forming romantic relationships.

Cognitive impairments can also impact an individual’s ability to fully comprehend issues such as safe sex and consent.

For professionals involved in such cases, it is crucial to respond by sourcing appropriate support in order to maximise an individual’s capacity to engage in dating safely, whether in person or online.

I recently represented a young man affected by many of these issues. He had a strong desire to be in a relationship but exhibited impulsive behaviour which frequently overrode his ability to exercise caution or appropriate dating behaviour.

His lack of capacity manifested in him having difficulty understanding and utilising appropriate online communication, inappropriate and excessive use of dating sites and accessing inappropriate websites. He was also unable to consistently read social cues and adapt his behaviour/ make decisions accordingly. For all these reasons, the Claimant was considered to be at risk online.

We therefore arranged a specific capacity assessment, following which protective measures were introduced and input was arranged to help monitor and manage my client’s risk from online activity.

He also benefited from input from brain injury specialist support workers with whom he was able to openly discuss his online activity and increase his understanding of the need for him to exercise caution. Ultimately, he had capacity to date and enter romantic relationships but there was a very clear need for support to enable him to do so safely.

In this case, I worked closely with Irwin Mitchell’s Court of Protection team, who appointed a property and financial Deputy for my client.

Katie Strong, a partner in Irwin Mitchell’s Court of Protection team explains that: “Capacity is decision specific and so over time, the level of support and supervision will be kept under review and reduced in the event my client regains capacity in this area.  As well as the specialist support team, we have instructed a neuropsychologist to monitor the client’s capacity and provide support to him as well as his support team in managing the risks.”  

Considerations in Litigation

We are all familiar with the presumption of capacity under the Mental Capacity Act 2005. In serious injury litigation involving brain injured individuals in particular, complex issues often arise when we are acting for clients who have been placed in a vulnerable position (through no fault of their own) and their ability to make reasoned, informed decisions simultaneously reduced.

Such cases inevitably prompt legal professionals to think ‘outside the box’. For example, does an individual require subscriptions for dating agency sites, psychological support or professional IT support to assist in the management of online risk? Does the Case Manager need to act as an intermediary with dating agencies? Is there a role for support workers? There is no ‘one size fits all’ approach and, as always, cases should mould around the individual involved and their particular circumstances.

For example, if a client demonstrates a desire to be in a long- term relationship and to have children, the legal team should consider obtaining expert evidence which addresses the need for any future support that may be required with childcare, both in the context of a successful relationship and relationship breakdown.

An assessment of how well they may manage the end of a relationship and cope with the emotional and psychological challenge may also impact their future care needs, and we may need to prompt our care experts to include additional future contingency care during such periods.

Ultimately, the Courts have consistently held that the requisite standard for capacity to consent to sexual relationships and marriage is deliberately not a high one. We cannot prevent our clients from making decisions we consider to be unwise but we do have several tools at our disposal to protect and support whatever capacity they do have. Our role is to ensure that our client is able to maximise their independence so far as possible.

Read part 2 of this article series – exploring issues regarding capacity to cohabit and marry in more depth.

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MS update

A round up of the latest developments in Multiple Sclerosis (MS) research.

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MS risk higher for people living in urban areas, new research reveals

In Italy, a study has found that air pollution could be a risk factor for the development of MS.

The research, which was presented at the European Academy of Neurology (EAN) Virtual Congress, detected a reduced risk for MS in individuals residing in rural areas that have lower levels of air pollutants known as particulate matter (PM). It showed that the MS risk, adjusted for urbanisation and deprivation, was 29% higher among those residing in more urbanised areas.

The study sample included over 900 MS patients within the region, and MS rates were found to have risen 10-fold in the past 50 years, from 16 cases per 100,000 inhabitants in 1974 to almost 170 cases per 100,000 people today. Whilst the huge increase can partly be explained by increased survival for MS patients, this sharp increase could also be explained by greater exposure to risk factors.

The analysis was conducted in the winter, as this is the season with the highest pollutant concentrations, in the north-western Italian region of Lombardy, home to over 547,000 people.

Commenting on the findings at the EAN Virtual Congress, lead researcher Professor Roberto Bergamaschi explained, “It is well recognised that immune diseases such as MS are associated with multiple factors, both genetic and environmental.

“Some environmental factors, such as vitamin D levels and smoking habits, have been extensively studied, yet few studies have focused on air pollutants. We believe that air pollution interacts through several mechanisms in the development of MS and the results of this study strengthen that hypothesis.”

The term particulate matter (PM) is used to describe a mixture of solid particles and droplets in the air and is divided into two categories. PM10 includes particles with a diameter of 10 micrometres of smaller and PM2.5 which have a diameter of 2.5 micrometres or smaller.

Both PM10 and PM2.5 are major pollutants and are known to be linked to various health conditions, such as heart and lung disease, cancer, and respiratory issues. According to the World Health Organisation, 4.2 million deaths occur every year because of exposure to ambient (outdoor) air pollution.

Three different areas were compared within the study region based on their levels of urbanisation, of which two areas were found to be above the European Commission threshold of air pollution.

Professor Bergamaschi added: “In the higher risk areas, we are now carrying out specific analytical studies to examine multiple environmental factors possibly related to the heterogeneous distribution of MS risk.”

The number of people living with MS around the world is growing, with more than 700,000 sufferers across Europe alone. The vast majority (85%) of patients present with relapsing remitting MS, characterised by unpredictable, self-limited episodes of the central nervous system. Whilst MS can be diagnosed at any age, it frequently occurs between the ages of 20-40 and is more frequent in women. Symptoms can change in severity daily and include fatigue, walking difficulty, numbness, pain and muscle spasms.

Novartis builds case for MS drug ofatumumab as FDA decision looms

Swiss drug maker Novartis has reported new data with its MS drug ofatumumab showing that it can suppress disease activity for up to two years, as it waits for an FDA decision on the drug in June.

New results from the firm’s clinical trials programme for ofatumumab (OMB157) showed that 47% of patients with relapsing MS had no evidence of disease activity (NEDA) in the first year after treatment, rising to almost 88% in the second year.

Ofatumumab – a CD20-targeting antibody – is already used as an intravenous treatment for chronic lymphocytic leukaemia (CLL) under the Arzerra brand name but has seen its use in that indication lowered due to increased competition.

Novartis believes the subcutaneous version of the drug can make sales of over $1billion per year as an MS therapy, and challenge other new therapies like Roche’s fast-growing Ocrevus (ocrelizumab), which also targets CD20 and brought in CHF 3.7 billion ($3.8 billion) in only its second full year on the market.

If approved, ofatumumab would become the first B-cell-targeting therapy for relapsing forms of MS that can be self-administered by patients at home once a month. A verdict is also due from the European Medicines Agency (EMA) in the first half of 2021.

Earlier results from a pair of phase 3 trials – ASCLEPIOS 1 and 2 – showed that the antibody was more effective at cutting relapses than Sanofi’s once-daily oral MS drug Aubagio (teriflunomide), reducing the rate by 50.5% and 58.5% respectively in the two studies.

The new findings were presented at the virtual European Academy of Neurology (EAN) congress, and showed that Aubagio was also less effective at banishing disease activity. In the first year 34.5% of patients on Sanofi’s drug achieved NEDA, rising to 48.2% in year two.

ASCLEPIOS clinical investigator Prof Ludwig Kappos of University Hospital Basel said: “Achieving no evidence of disease activity is widely recognised as an important treatment goal for MS therapies.”

If approved, ofatumumab won’t have the same breadth of approved indications as Ocrevus, as Roche’s drug can be used in both relapsing and primary progressive forms of MS.

There’s also a big difference between the two drugs when it comes to their dosing. Patients will have to decide whether they prefer to self-inject ofatumumab once a month or visit a clinic for an intravenous infusion of Ocrevus every six months.

The Covid-19 pandemic could be a lift for Novartis on the dosing issue, given the reduced access to healthcare services, although lockdowns are now beginning to be lifted.

Novartis Pharma president Marie-France Tschudin said last month that “now more than ever, bringing a B-cell therapy that’s highly efficacious and administered at home is highly attractive.”

“Our goal is that when patients come back, we’ll make it easy for them to start on ofatumumab,” she added.

Novartis acquired the drug from GlaxoSmithKline and Genmab in 2015 in a $1 billion deal.

Higher blood NfL levels indicate worse disability over time in MS, study suggests

A large population study in Sweden has suggested that higher blood levels of the neurofilament light chain (NfL) protein at diagnosis are predictive of worse disability over time in people with multiple sclerosis.

The study, “Plasma neurofilament light levels are associated with the risk of disability in multiple sclerosis,” was published in the journal Neurology.

NfL levels are commonly used as a marker for nervous system injury, with NfL protein released when neurons become damaged.

Previous research has suggested NfL as a prognostic biomarker in MS, however, most of these studies measured NfL levels in cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord, which is not feasible as a routine clinical test due to its invasive nature.

Other studies have shown that NfL levels in blood are closely related to levels in CSF, raising the possibility that blood NfL levels could have prognostic value in MS. However, whether these levels can predict long-term outcomes in MS has not been extensively evaluated.

“In a disease like MS that is so unpredictable and varies so much from one person to the next, having a non-invasive blood test like this could be very valuable, especially since treatments are most effective in the earliest stages of the disease,” Ali Manouchehrinia, PhD, of the Karolinska Institutet, Sweden, and a study co-author, said.

To address blood NfL as potential marker of likely disability worsening over time (a prognostic marker), researchers measured blood NfL levels in 4,385 people with MS, including 3,664 with relapsing-remitting MS (RRMS), 511 with secondary progressive MS (SPMS), and 129 with primary progressive MS (PPMS). The remaining 81 individuals did not have their MS type recorded in the data analysed.

For comparison, NfL levels were measured in a control group of 1,026 non-MS people of similar age and sex to the MS group.

Results showed that blood NfL levels varied significantly with age in all groups. After adjusting for this, NfL levels were significantly higher in all MS groups than in controls — the median NfL levels were 8.5 picograms (pg)/mL in controls, and 17.1 pg/mL in RRMS patients, 18.4 pg/mL in those with SPMS, and 14.7 pg/mL in PPMS patients.

Researchers then calculated whether higher NfL levels were predictive of worsening disability, as assessed by reaching various benchmarks on the Expanded Disability Status Scale (EDSS) during a median of five years of follow-up.

High NfL blood levels were defined based on the values measured in controls, and multiple cut-off values were also assessed. The statistical models used for these calculations were adjusted taking into account other relevant factors, including sex, age, disease duration, and MS treatment.

Overall, high NfL levels were significantly predictive of sustained EDSS worsening (greater disability). Depending on the cut-off used, the risk of disability worsening rose by 40% to 65% in people with high blood NfL levels, compared to those with lower levels.

High NfL levels were also significantly associated with a risk of reaching an EDSS score of 3.0, indicating moderate disability without walking impairment. Similar results were found for reaching an EDSS score of 4.0, indicating significant disability with mild walking impairment.

At some cut-offs, high NfL was significantly associated with a risk of reaching an EDSS score of 6.o (corresponding to needing an aid to walk 100 meters, about 330 feet). As findings weren’t entirely significant, a definitive conclusion cannot be drawn from this data and future studies will be needed to help clarify whether blood NfL levels can predict more severe disability, the researchers noted.

Similarly, high NfL levels were significantly predictive of progression from RRMS to SPMS at some cut-offs, but not at others, making it difficult to draw reliable conclusions and again highlighting a need for further research.

Taken together, the “findings suggest that [blood] NfL measurement can usefully provide additional predictive power in the form of an easily accessible and easy-to-measure biomarker for monitoring of disease activity and potentially treatment response in MS,” researchers wrote.

Nonetheless, “more research is needed before a blood test could be used routinely in the clinical setting, but our results are encouraging,” Manouchehrinia concluded.

Preliminary research on Covid-19 in people with MS offers some reassurance

One area that has caused concern most recently for those in the MS community is the impact of Covid-19. However, preliminary results from Italy has shown that people with MS who contracted the virus did no worse than the general population.

Researchers in the country have been collecting data to understand the relationship between MS and Covid-19, whether having the condition increases the risk of a more severe impact of the virus, and whether taking disease modifying drugs may add any extra risk.

The Italian Multiple Sclerosis Society (AISM), the Italian Multiple Sclerosis Foundation (FISM), and the Multiple Sclerosis Study Group of the Italian Neurological Society set up an online platform to record and collect data about those with MS in Italy who have been diagnosed with Covid-19 or have developed symptoms (suspected Covid-19). MS neurologists across Italy were asked to input data and share patient outcomes.

Early results from the data collected so far have now been published. Preliminary data includes 232 people with MS, 57 of which have tested positive for Covid-19 and 175 who have suspected Covid-19. Of the 232 people studied, 211 were taking a disease modifying drug.

The data recorded the severity of Covid-19 in these 232 people:

  • 223 (96%) had a mild infection
  • 4 (2%) had a severe infection
  • 6 (3%) had a critical infection

Of those who were critical, one person recovered, and five died. The people who died tended to be older (50+) and had other health conditions.

It’s too early to say from this data whether DMDs make a difference to Covid-19 recovery, but it does not suggest that the current DMD advice should be changed.

Although this research is preliminary and the numbers are fairly small, these results are reassuring for people with MS, suggesting that having MS doesn’t increase your likelihood of a more severe Covid-19 infection and the majority are likely to have a mild infection, the same as the general population.

Evobrutinib lowers MS relapse rates over 2 years of use, trial data shows

Trial data has shown that the investigational oral medication evobrutinib leads to a sustained reduction in relapse rates in people with relapsing MS.

These findings were presented in a poster at the 2020 congress of the European Academy of Neurology (EAN), which was held virtually due to the COVID-19 pandemic.

The study, “Efficacy and Safety of the Bruton’s Tyrosine Kinase Inhibitor (BTKI) Evobrutinib in Relapsing Multiple Sclerosis Over 108 weeks: Open-label Extension to a Phase II Study,” was sponsored by Merck KGaA, the company developing evobrutinib.

Evobrutinib works by blocking the activity of Bruton’s tyrosine kinase (BTK), a protein that is important for the activation of certain types of immune cells — like B-cells — that drive inflammation which damages the nervous system in MS.

Its efficacy and safety were evaluated in a Phase 2 clinical trial (NCT02975349) that enrolled 267 people with relapsing MS, which includes relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS).

In the initial trial, which lasted 48 weeks, participants were randomly assigned to one of five groups: three groups were given evobrutinib at different doses (25 mg once daily, 75 mg once daily, or 75 mg twice daily); a fourth was given a placebo; and the fifth was given Tecfidera (dimethyl fumarate), an approved oral therapy by Biogen.

Results from this part of the trial showed that evobrutinib, at 75 mg twice daily (highest dose tested), significantly reduced the annualised relapse rate compared to placebo – 0.11 vs. 0.37 relapses/year – with 79% of participants on this dose group remaining relapse-free after 48 weeks.

Participants were then invited to enrol in an open-label extension study (OLE), where all received the active treatment at the dose determined to be the most effective and safe: in this case, evobrutinib at 75 mg twice daily.

Data presented at EAN comes from an analysis of 213 patients who completed at least 60 weeks of treatment in the OLE study.

For those initially randomised to evobrutinib at 75 mg twice daily, this represents a total of 108 weeks (just over two years) of treatment. In these 44 patients, the annualised relapse rate observed after 48 weeks (0.11 relapses/year) was consistent with that seen at 108 weeks (0.12 relapses/year).

Luciano Rossetti, head of global research and development for EMD Serono, said: ““These data demonstrate evobrutinib has a sustained high impact on annualised relapse rate over 108 weeks.”

Notably, the relapse rate for this highest dose of evobrutinib was lower than for all other tested doses of evobrutinib, suggesting that this dosing schedule is best for preventing relapses.

Mathematical modelling suggested that the efficacy of this highest dose is likely attributable to the percentage of BTK molecules that are physically inhibited by evobrutinib, a process referred to as “BTK occupancy.”

“The largest and most sustained reduction in [annualized relapse rate] was achieved when BTK occupancy was [greater than] 95%, observed in nearly all [98%] patients receiving [75 mg evobrutinib twice daily],” the researchers wrote.

No new safety concerns were observed in the OLE study. The most common side effect of evobrutinib’s use was nasopharyngitis (more commonly known as a cold).

In the initial trial, some participants experienced an increase in blood markers of liver damage, but these increases were only observed in the main study and were not found in the OLE.

“We are encouraged by evobrutinib’s breadth of consistent safety data, including no increase of serious infections in more than 1,200 patients [treated across all clinical studies of evobrutinib in MS and other conditions] up to two years,” Rossetti said.

Xavier Montalban, MD, PhD, with Vall d’Hebron University Hospital in Spain, and a trial investigator added: “The 108-week efficacy and safety data for evobrutinib through the double-blind and the OLE period are very robust.

“This, combined with the high selectivity of evobrutinib, suggests that evobrutinib may offer a promising approach to MS treatment.”

Evobrutinib is being further evaluated in two Phase 3 clinical trials, EVOLUTION RMS 1 (NCT04338022) and EVOLUTION RMS 2 (NCT04338061).

More than 1,800 people with relapsing MS will be enrolled and randomised to receive either evobrutinib or Sanofi‘s Aubagio (teriflunomide), or a placebo.

This reflects a change to the trials’ original protocol, which called for evobrutinib to be compared with Biogen’s Avonex (interferon beta-1a).

These trials, which are not yet recruiting participants, are expected to conclude in 2023.

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Update: Spinal cord injury research

Research into spinal cord injury (SCI) has continues at pace, with several exciting new findings in recent months, summarised here.

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Neural interface restores touch sensation after spinal cord injury 

A sensorimotor neural interface successfully restored touch sensation in a patient with quadriplegia resulting from a spinal cord injury, researchers report.

Dr Patrick D. Ganzer of Battelle Memorial Institute in Colombus, Ohio, said: “Neurotechnology and brain-computer interfaces are becoming an effective way to leverage residual neural signals for functional benefit following SCI, stroke, and several other dysfunctional states.”

An estimated 50% of patients with a clinically complete SCI have a “sensory discomplete” SCI, where tactile stimuli evoke changes in cortical activity, despite the patient not being able to feel them. Brain-computer interfaces (BCIs) can reanimate paralysed muscles after SCI, but whether they can restore touch is unknown.

Dr. Ganzer and colleagues used a BCI to simultaneously reanimate both motor function and touch sensation in a chronically paralysed patient with a clinically complete SCI who could already use a BCI to move the hand.

While the patient was unable to perceive mechanical sensory stimuli below spinal level C6, sensory stimuli to the hand robustly modulated neural activity in the contralateral primary motor cortex (M1). This residual sensory neural activity was reliably decoded from M1 using a support vector machine (SVM), and a vibrotactile array on the affected bicep enabled sensory feedback that restored conscious touch perception to a detection rate over 90%.

A modified grasp and release test demonstrated real-time sensorimotor demultiplexing where the participant was able to perform the task using the system but not without using the system, the team reports.

Discussing the study’s findings, Dr Ganzer said: “It was initially surprising when we first discovered the subperceptual touch signal.

“These results demonstrate that even a small contingent of spared spinal fibres can be leveraged for functional benefit.

“The study’s overall results are interesting because the brain implant was not originally intended to record both touch and movement neural signals.

“Participants that have a ‘clinically complete’ SCI may have a small contingent of spared fibres remaining that are still transmitting a neural signal. Therefore, a very small quantity of spared fibres can potentially be leveraged for benefit, even though they might only be transmitting a faint signal.

“Additionally, the study’s findings can potentially inform future neural implant locations. Future neural interfaces can be placed in areas that encode a multitude of mixed neural signals that might be of value for the given technology. Regardless, information from neural interfaces should be maximized to enable new functional benefits in patients, even in new and unintended ways.

“The NeuroLife team at Battelle is currently working with our collaborators to develop a take-home BCI system. This would allow for the BCI to be used during activities of daily living outside of the laboratory setting.

“One of our recent achievements in this domain was a demonstration in the participant’s home using a portable miniatured version of the ‘muscle stimulation system.’ A computer tablet was able to control muscle stimulation to elicit hand movements during home activities.”

Dr Andrew Jackson, professor of neural interfaces at Newcastle University, Newcastle-upon-Tyne told Reuters Health: “The study rests on a surprising finding: touch stimuli that are imperceptible to a spinal cord-injured participant can nevertheless be ‘decoded’ from brain activity in the motor cortex. Previous brain imaging studies have suggested such signals can reach the brain even after injury, but this is the first study to reveal them in the activity of individual brain cells.

“There are two ways this could work in practice. First, the decoded sensory signals could be used to trigger some kind of sensory substitute, in this case a vibrotactile cuff acting on a part of the body that the patient can consciously feel.

“Second, the sensory signals could directly influence the electrical muscle stimulation, thereby implementing a sensorimotor feedback loop similar to the unconscious reflexes that allow us to maintain our grip on an object without having to think about it.

“While there are other ways to achieve this in principle, the nice thing about the current approach is that it only requires a single surgical implant to achieve both motor and sensory restoration.

“These approaches are still at an early stage of development. I anticipate seeing more studies like this one that find clever ways of exploiting and enhancing these surviving connections to restore function.”

Scientists regenerate neurons in mice with spinal cord injury and optic nerve damage

New research by scientists at the Lewis Katz School of Medicine Temple University (LKSOM) shows that gains in functional recovery from SCI injuries may be possible, thanks to a molecule known as Lin28, which regulates cell growth. In a study published online in the journal Molecular Therapy, the Temple researchers describe the ability of Lin28 – when expressed above its usual levels – to fuel axon regrowth in mice with SCI or optic nerve injury (ONI), enabling repair of the body’s communication grid.

Shuxin Li, senior investigator on the new study, explained: “Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries.

“We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity. It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration.”

To explore the effects of Lin28 on axon regrowth, Dr Li and colleagues developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye.

Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector (a type of carrier) for Lin28 to examine the molecule’s direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimetres beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

“We observed a lot of axon regrowth, which could be very significant clinically, since there currently are no regenerative treatments for spinal cord injury or optic nerve injury,” said Dr Li.

One of his goals in the near-term is to identify a safe and effective way of getting Lin28 to injured tissues in human patients. To do so, his team of researchers will need to develop a vector, or carrier system for Lin28, that can be injected systemically and then hone in on injured axons to deliver the therapy directly to multiple populations of damaged neurons.

Dr Li also wants to decipher the molecular details of the Lin28 signalling pathway. He said: “Lin28 associates closely with other growth signaling molecules, and we suspect it uses multiple pathways to regulate cell growth.”

‘Cell pores’ discovery gives hope to millions of brain and spinal cord injury patients

Brain and spinal cord injuries affect all age groups. Older people are more at risk of sustaining them from strokes or falls, while for younger age groups, major causes include road traffic accidents and injuries from sports.

The high-profile example of Formula 1 racing driver Michael Schumacher demonstrates the difficulties physicians currently face in treating such injuries. After falling and hitting his head on a rock while skiing in Switzerland in 2013, Schumacher developed a swelling on his brain from water rushing into the affected cells. He spent six months in a medically induced coma and underwent complex surgery, but his rehabilitation continues to this day.

The new treatment, developed by an international team of scientists working at universities in the UK, US, Canada, Sweden and Denmark, features in the latest edition of the scientific journal Cell.

Researchers used an already-licensed anti-psychotic medicine – trifluoperazine (TFP) – to alter the behaviour of tiny water channel ‘pores’ in cells known as aquaporins.

Testing the treatment on injured rats, they found those animals given a single dose of the drug at the trauma site recovered full movement and sensitivity in as little as two weeks, compared to an untreated group that continued to show motor and sensory impairment beyond six weeks after the injury.

The treatment works by counteracting the cells’ normal reaction to a loss of oxygen in the CNS – the brain and spinal cord – caused by trauma. Under such conditions, cells quickly become ‘saltier’ because of a build-up of ions, causing a rush of water through the aquaporins which makes the cells swell and exerts pressure on the skull and spine. This build-up of pressure damages fragile brain and spinal cord tissues, disrupting the flow of electrical signals from the brain to the body and vice versa.

However, the scientists discovered that TFP can stop this from happening. Focusing their efforts on important star-shaped brain and spinal cord cells called astrocytes, they found TFP prevents a protein called calmodulin from binding with the aquaporins. Normally, this binding effect sends the aquaporins shooting to the surface of the cell, letting in more water. By halting this action, the permeability of the cells is reduced.

Traditionally, TFP has been used to treat patients with schizophrenia and other mental health conditions. Its long-term use is associated with adverse side effects, but the researchers said their experiments suggested that just a single dose could have a significant long-lasting impact for CNS patients.

Since TFP is already licensed for use in humans by the US Federal Drug Administration (FDA) and UK National Institute for Health and Care Excellence (NICE) it could be rapidly deployed as a treatment for brain injuries. But the researchers stressed that further work would allow them to develop new, even better medicines based on their understanding of TFP’s properties.

According to the World Health Organisation (WHO), each year around 60 million people sustain a traumatic brain or spinal cord injury and a further 15 million people suffer a stroke. These injuries can be fatal or lead to long-term disability, psychiatric disorders, substance abuse or self-harm.

Professor Roslyn Bill of the Biosciences Research Group at Aston University said: “Every year, millions of people of all ages suffer brain and spinal injuries, whether from falls, accidents, road traffic collisions, sports injuries or stroke. To date, their treatment options have been very limited and, in many cases, very risky.

“This discovery, based on a new understanding of how our cells work at the molecular level, gives injury victims and their doctors hope. By using a drug already licensed for human use, we have shown how it is possible to stop the swelling and pressure build-up in the CNS that is responsible for long-term harm.

“While further research will help us to refine our understanding, the exciting thing is that doctors could soon have an effective, non-invasive way of helping brain and spinal cord injury patients at their disposal.”

Dr Zubair Ahmed of the University of Birmingham’s Institute of Inflammation and Ageing continued: “This is a significant advance from current therapies, which only treat the symptoms of brain and spinal injuries but do nothing to prevent the neurological deficits that usually occur as a result of swelling. The re-purposed drug offers a real solution to these patients and can be fast-tracked to the clinic.”

Dr Alex Conner of the University of Birmingham’s Institute of Clinical Sciences said: “It is amazing that our work studying tiny water channels in the brain can tell us something about traumatic brain swelling that affects millions of people every year.”

Dr Mootaz Salman, Research Fellow in Cell Biology at Harvard Medical School, said: “This novel treatment offers new hope for patients with CNS injuries and has huge therapeutic potential. Our findings suggest it could be ready for clinical application at a low cost in the very near future”.

Brain-computer interface lets man with complete spinal cord injury feel and move his hand

In an exciting development, researchers from Battelle and The Ohio State University Wexner Medical Center are reporting that a man with clinically complete spinal cord injury can now move his paralysed hand and feel what he’s touching.

The man had a brain-computer interface chip implanted into the motor cortex of his brain six years ago and it was assumed that his injury was too severe to ever be able to tap the nerve signals related to touch.

However, the latest update reports an unfelt signal that was detected by the researchers, which does reach the brain via unexpected pathways, and which they can detect using the brain-computer interface. In turn, the signal is translated and directed to a haptic device that creates a vibration that produces a sense of touch. The development is reported in a published study in journal Cell.

The team that developed the technology is working on turning it into a system that can be used at home, as it is currently tethered to power supplies and computers.

“The authors have leveraged on a rarely appreciated aspect of spinal cord injury to provide a novel and important advancement in neurological functioning using a brain-computer interface,” said Dr Keith Tansey, Professor of Neurosurgery and Neurobiology at the University of Mississippi Medical Center.

“The notion that clinical completeness in spinal cord injury is very often neurophysiologically ‘discomplete’ acknowledges that activity in residual neural circuitry can be detected and utilised to both augment motor function but also to restore sensory perception from below the level of injury.”

Adults with traumatic spinal cord injury at increased risk for psychological morbidities, study suggests

Adults with traumatic spinal cord injuries (SCI) exhibited increased incidence of psychological morbidities and multimorbidity compared with those without such injuries, according to results of a study published in Mayo Clinic Proceedings.

Mark D Peterson of the department of physical medicine and rehabilitation at University of Michigan said: “Clinicians caring for adults with SCI need to be aware of the increased risk of developing mental health disorders in this patient population.

“This may be particularly important during social distancing due to Covid-19, as these patients often already experience social isolation.”

Although prior studies have established a relationship between age-related noncommunicable diseases, cognitive dysfunction and depression among populations without SCI, researchers have yet to study the extent to which psychological conditions are comorbid with age-related chronic diseases following SCI.

Further research is sparse regarding the natural history or incidence of psychological morbidities and chronic diseases among adults with SCI.

In the current study, the investigators sought to compare the longitudinal incidence of psychological morbidities and multimorbidity and chronic disease estimates among adults with vs. without SCI. They examined insurance claims of 6,847 privately insured beneficiaries with an ICD-9, Clinical Modification diagnostic code for a traumatic spinal cord injury who had medical coverage at any time between January 2001 and December 2017.

Results showed that compared with adults without a traumatic SCI, those with one had a higher incidence of adjustment reaction, anxiety disorders, depressive disorders, alcohol dependence, drug dependence, psychogenic pain, dementia, insomnia and psychological multimorbidity.

For example, incidence for those with vs. without a traumatic SCI was 19.3% vs. 14.1% for anxiety disorders, 29.3% vs. 9.3% for depressive disorders and 37.4% vs. 23.9% for psychological multimorbidity. The researchers reported significantly higher adjusted HRs of each psychological outcome for individuals with spinal cord injury, and these ranged from 1.18 (95% CI, 1.08-1.29) for anxiety disorders to 3.32 (95% CI, 1.93-5.71) for psychogenic pain.

Those with spinal cord injuries also had a significantly higher prevalence of all chronic diseases and chronic disease multimorbidity, except HIV infection/AIDS. The researcher’s propensity matched adults for age, education, race, sex and chronic diseases and still reported a significantly higher incidence of most psychological disorders and psychological multimorbidity among those with spinal cord injuries.

Of the findings, Peterson and colleagues said: “Future research and clinical efforts are needed to better understand the health care burden associated with these conditions in the traumatic [spinal cord injury] population.

“These findings should be used to inform the development of appropriate clinical screening algorithms and design of early behavioural interventions to reduce the risk for disease onset/progression in this higher risk population.”

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