Scientists Succeed in Regrowing Frog Legs

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Using a mix of drugs and a regenerative seal, scientists were able to successfully regrow frog legs, as reported in Science Advances. This represents an eventual step towards possibly regrowing limbs in humans.

On adult frogs, which are naturally unable to regenerate limbs, the researchers were able to trigger regrowth of a lost leg using a five-drug cocktail applied in a silicone wearable bioreactor dome that seals in the treatment over the stump for just 24 hours. That brief treatment sets in motion an 18-month period of regrowth that restores a functional, near-complete leg.

In humans and mammals loss of a large and structurally complex limb cannot be restored by any natural process of regeneration in humans or mammals. In fact, we tend to cover major injuries with an amorphous mass of scar tissue, protecting it from further blood loss and infection and preventing further growth.

The Tufts University researchers triggered the regenerative process in African clawed frogs by enclosing the wound in a silicone cap, which they call a BioDome, containing a silk protein gel loaded with the five-drug cocktail.

Each drug fulfilled a different purpose, including tamping down inflammation, inhibiting collagen production which would lead to scarring, and encouraging the new growth of nerve fibres, blood vessels, and muscle. The combination and the bioreactor provided a local environment and signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.

A dramatic growth of tissue was observed in many of the treated frogs, re-creating an almost fully functional leg which was able to respond to stimuli, though the “toes” grown had no bones.

“It’s exciting to see that the drugs we selected were helping to create an almost complete limb,” said Nirosha Murugan, research affiliate at the Allen Discovery Center at Tufts and first author of the paper. “The fact that it required only a brief exposure to the drugs to set in motion a months-long regeneration process suggests that frogs and perhaps other animals may have dormant regenerative capabilities that can be triggered into action.”

Within the first few days after treatment, they detected the activation of known molecular pathways that are normally used in a developing embryo.
Activation of these pathways could allow the burden of growth and organisation of tissue to be handled by the limb itself, similar to that in an embryo, rather than require ongoing therapeutic intervention over the many months it takes to grow the limb.

Animals naturally capable of regeneration live mostly in an aquatic environment. The first stage of growth after loss of a limb is the formation of a blastema, a mass of stem cells at the end of the stump, which is used to gradually reconstruct the lost body part. The wound is rapidly covered by skin cells within the first 24 hours after the injury, protecting the reconstructing tissue underneath.

“Mammals and other regenerating animals will usually have their injuries exposed to air or making contact with the ground, and they can take days to weeks to close up with scar tissue,” said Tufts University Professor David Kaplan, co-author of the study. “Using the BioDome cap in the first 24 hours helps mimic an amniotic-like environment which, along with the right drugs, allows the rebuilding process to proceed without the interference of scar tissue.”

Previous work using just progesterone with the BioDome resulted in a spike-like limb.

The five-drug cocktail is a major step toward the restoration of fully functional frog limbs and suggests further exploration of drug and growth factor combinations could lead to regrown limbs that are even more functionally complete.

“We’ll be testing how this treatment could apply to mammals next,” said corresponding author Professor Michael Levin at Tufts University.

“Covering the open wound with a liquid environment under the BioDome, with the right drug cocktail, could provide the necessary first signals to set the regenerative process in motion,” he said. “It’s a strategy focused on triggering dormant, inherent anatomical patterning programs, not micromanaging complex growth, since adult animals still have the information needed to make their body structures.”

Source: Tufts University

An Updated Look at the Link Between Alcohol and Epilepsy

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A new meta-analysis has established an association between alcohol and epilepsy, in contrast to previous studies which reported conflicting results on the relationship.

Epilepsy is one of the most common neurological conditions, with an annual incidence of 40–70 per 100 000 people in industrialised countries. It is also a  disease that is highly stigmatised.

A number of studies have focused on how alcohol consumption leads to provoked seizures, commonly resulting from alcohol withdrawal, or heavy intoxication. Very few of these however focused on the link between alcohol consumption and unprovoked seizures. A 2010 meta-analysis found that alcohol users were more prone to developing unprovoked seizures – but data from recent cohort studies contradict these findings. A 2018 meta-analysis suggested that the relationship may only hold true for heavy drinkers.

Now, using more accurate diagnostic methods and recent data, a team of scientists from Pusan National University, South Korea, conducted an updated meta-analysis to conclusively clarify the relationship between alcohol consumption and unprovoked seizures and epilepsy.

For this meta-analysis, appearing in Drug and Alcohol Dependence, the researchers included a total of eight studies, of which five were case-control studies and three were cohort studies. They analysed the data to assess the dose-response relationship between alcohol intake and epilepsy.
The results suggested that overall, compared to non-drinkers, alcohol drinkers were at a significantly higher risk of developing epilepsy, which increased with alcohol intake. These findings are consistent with previous meta-analyses.

An important finding was that cohort studies did not show a positive association between alcohol intake and epilepsy. In fact, 2 out of 3 cohort studies suggested that alcohol intake reduces the risk of epilepsy.

More large cohort studies are needed to prove a causal relationship between alcohol drinking and epilepsy, as well as a threshold of onset, said second author Professor Yun Hak Kim.

Source: EurekAlert!

NICD Warns of Malaria Being Misdiagnosed as COVID

Mosquito
Photo by Егор Камелев on Unsplash

The National Institute for Communicable Diseases has warned that, as South Africa enters its peak malaria season, cases of malaria are being misdiagnosed as COVID. Both malaria and COVID have similar non-specific early symptoms such as fever, chills, headaches, fatigue and muscle pain. Undiagnosed and untreated malaria rapidly progresses to severe illness and can be fatal.

Speaking at a media briefing on Wednesday, principal NICD medical scientist Dr Jaishree Raman said that Gauteng has seen a slight increase of malaria cases recently. 

Dr Raman noted that COVID “has pulled resources from the malaria programmes, reducing active surveillance and case investigation, which is reducing the ability [to] classify cases accurately.”

However, the NICD does not know the exact source of the malaria. “Data cleaning and case classification is ongoing, so at the moment, we cannot say whether the uptick in cases is due to locally-acquired or imported malaria,” she said.

The NICD advises that any individual that prevents with fever or ‘flu-like illness, if they reside in a malaria-risk area in Limpopo, KwaZulu-Natal and Mpumalanga or have travelled to a malaria-risk area, especially Mozambique, in the past six weeks, must be tested for malaria by blood smear microscopy or malaria rapid diagnostic test. If they test positive for malaria, the patient must be started on malaria treatment, immediately.

The NICD also advises patients to remember to inform their healthcare provider of their recent travel, especially to neighbouring countries and malaria risk areas in South Africa.  

‘Taxi malaria’, transmitted by hitch-hiking mosquitoes, should be considered in a patient with unexplained fever who has not travelled to a malaria-endemic area, but is getting progressively sicker, with a low platelet count.

Source: NICD

New Guidelines for Brain Cancer Care

Credit: National Cancer Institute

New guidelines for managing and treating brain metastases have been published in the Journal of Clinical Oncology and are set to improve care for cancer patients and extend and improve the quality of their lives.

The new guidelines come from an expert panel assembled by the American Society of Clinical Oncology (ASCO). The panel included a diverse range of top cancer doctors, as well as a patient representative.

The guidelines reflect the enormous advances in care for brain metastases  over the last few decades. In the 1970s, early attempts to develop guidelines largely emphasised steroids and whole-brain radiation therapy, without controlled, randomised studies to guide the use of surgery and chemotherapy.

Far more encompassing and far more evidence-based, the new guidelines will help doctors and patients make the best treatment decisions and achieve the best outcomes.

“When I started in this field 30 years ago, the average survival with brain metastases was 4 months, and most patients died from the brain disease. With improvements in therapies, fewer than one-quarter of patients die from the brain metastases, and some patients live years or are even cured,” said David Schiff, MD, a co-chair of the ASCO panel and the co-director of UVA Cancer Center’s Neuro-Oncology Center. “Equally importantly, the use of advanced localised radiation techniques and new targeted chemotherapies and immunotherapies have improved the quality of survival for most patients suffering from brain metastases.”

Up to 30% of cancer patients will have it spread to the brain, where it can be extremely difficult to treat. In the United States, approximately 200 000 new brain metastases are diagnosed each year.

The likelihood of a solid tumour spreading to the brain varies by cancer type, with approximately 20% of lung cancers spreading to the brain within a year after diagnosis. For patients with breast cancer, renal cell cancer or melanoma, that number is up to 7%. That is in addition to the patients found to have brain metastases at the time of their initial diagnosis.

Bringing together a diverse range of disciplines, the ASCO panel incorporated the results of more than 30 randomised trials published since 2008. The resulting guidelines cover everything from when surgery is appropriate and when and in what form radiation should be used to those circumstances in which medication alone may be employed.

The guidelines emphasise the importance of local therapies (surgery or stereotactic radiosurgery) for symptomatic brain metastases and lay out when these options are feasible. They highlight situations in which local therapy or whole brain radiotherapy can be deferred in place of chemotherapy, targeted therapy or immunotherapy depending on tumour type and molecular features. They also lay out how, in many cases, doctors can avoid the cognitive toxicity of whole brain radiotherapy by using either stereotactic radiosurgery or hippocampal-avoidant whole brain radiotherapy with the drug memantine.

“Patients with brain metastases may initially see a neurosurgeon, radiation or medical oncologist. The rigorous analysis underpinning these guidelines will provide each subspecialist a comprehensive picture of the treatment options appropriate for a given patient,” Dr Schiff said. “The result will allow patients the optimal personalised approach to maximise long-term control of brain metastases with good functional outcome.”

 Additional information is available at the ASCO website.

Source: EurekAlert!

Long-term Marijuana Use Could Impact Male Fertility

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Chronic use of marijuana could greatly impact male fertility and reproductive outcomes, according to a new study appearing in Fertility & Sterility. This is the first study to assess the impacts of typical substance use on testicular function via a mode of delivery, and dosage.

Robust research in animal models has shown that cannabis negatively impacts male fertility. Researchers monitored the reproductive systems of healthy male nonhuman primates following exposure to THC, the main psychoactive ingredient in marijuana.

The nonhuman primates in the study received a THC edible once daily over the course of seven months. Their THC dose was based on published medical marijuana acclimation recommendations for humans, and was increased every 70 days in alignment with the animals’ sperm development cycle. Dose adjustments were made until it reached the equivalent of a heavy medical marijuana dose in humans. Semen samples were collected at baseline before initiation of THC, and again at the end of each THC dosing timepoint.

The study found that THC use was linked to significant adverse impacts to the animals’ reproductive hormones, including decreased levels of testosterone and severe testicular shrinkage. “Specifically, we observed a greater than 50% decrease in testicular size,” said senior author Jamie Lo, MD, MCR. “Unfortunately, these effects appeared to worsen as the THC dose was increased, suggesting a possible dose-dependent effect.”

These results align with Dr Lo’s previous studies indicating similar THC-associated impacts to female reproductive hormones and the menstrual cycle.

“These early findings are concerning from a clinical standpoint,” said study lead author Jason Hedges, MD, PhD. “Even moderate doses could have a profound impact on fertility outcomes. While family planning may not be top of mind for those in their late teens and early 20s, the longer-term effects of THC on male reproductive health are not well-defined; it is possible that THC could cause lasting impacts that may alter family planning later in life.”

The researchers will continue to explore the relationship between THC and reproductive health in both male and female nonhuman primates, examining longer term THC exposure impacts, including changes to sperm count and motility, and whether discontinuing use of THC products could reverse adverse effects.

Source: Ohio Health & Science University

Study Confirms COVID Vaccination does not Affect Fertility in IVF

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Vaccination against COVID did not affect fertility outcomes in patients undergoing in-vitro fertilisation (IVF), according to a new study. The findings, which were published in Obstetrics & Gynecology, add to the growing body of evidence providing reassurance that COVID vaccination does not affect fertility.

Investigators compared rates of fertilisation, pregnancy, and early miscarriage in IVF patients who had received two doses of vaccines manufactured by Pfizer or Moderna with the same outcomes in unvaccinated patients.

“The study found no significant differences in response to ovarian stimulation, egg quality, embryo development, or pregnancy outcomes between the vaccinated compared to unvaccinated patients.” said first author Devora Aharon, MD.

The study involved patients whose eggs were frozen and then thawed for in vitro fertilisation and womb transfer, and patients who underwent medical treatment to stimulate the development of eggs. The two groups of patients who underwent frozen-thawed embryo transfer (214 vaccinated and 733 unvaccinated) had similar rates of pregnancy and early pregnancy loss. The two groups of patients who underwent ovarian stimulation (222 vaccinated and 983 unvaccinated) had similar rates of eggs retrieved, fertilisation, and embryos with normal numbers of chromosomes, among several other measures.

The authors of the study anticipate that the findings will ease the anxiety of people considering pregnancy. 

Patients undergoing IVF treatment are closely tracked, enabling the researchers to capture early data on the implantation of embryos in addition to pregnancy losses that might be undercounted in other studies.

Previous studies have found that COVID vaccination helped protect pregnant persons (already at greater risk from severe illness and death from COVID) from severe illness, conferred antibodies to their infants, and did not raise the risk of preterm birth or foetal growth problems.

Source: EurekAlert!

Ozone Therapy in a Complex Periodontal Inflammation Case

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A new treatment approach for tissue inflammation around the dental root and root canal has been implemented, which uses ozone therapy. When used in a complex clinical case, the method helped save a patient’s tooth. 

Inflammation of the dental pulp and the periodontium, if not localised only on the inside or the outside but affects both areas, can be extremely difficult to completely cure a tooth. Such cases are difficult to diagnose, therefore, professional literature contains only a few descriptions of them, and there are no general treatment recommendations. Some dentists prefer to focus on the internal canals first, while others suggest treating the pulp and the periodontium simultaneously. A dentist from RUDN University implemented a single protocol for comprehensive pulp and periodontium treatment.

Explaining the problem, RUDN Associate Professor Maria Makeeva, PhD, said: “Inflammation of periodontal tissues often leads to tooth loss. In some cases, a lost tooth cannot be replaced with an implant, because the consequences of the infection worsen the implantation prognosis. Therefore, keeping the tooth is a more desirable outcome in this scenario.”

As described in described in Clinical, Cosmetic and Investigational Dentistry, the new approach was carried out in a patient (aged 44) with significant inflammation of the right mandibular canine. The patient was initially diagnosed with periodontium inflammation; the tooth was loose, and a flow of pus was seen. The first steps were typical for a periodontal inflammation treatment protocol: the patient was administered an antibiotic and then was instructed to rinse the tooth with chlorhexidine. The dentist also scaled the tooth. After that, the patient remained under observation for six months. Although the bleeding and pyorrhoea stopped, the dentist discovered tissue injury around the root of the tooth, which had caused bone destruction. It turned out that one narrow area had an 8mm deep periodontal pocket, and that the initial inflammation transferred to the internal tissues of the tooth.

A periodontologist and an endodontist together implemented a comprehensive treatment approach. After removing the dead pulp from the dental canals, which were then dried and treated with ozone for 24 seconds for better disinfection. After a week of dressing, the treatment was repeated, and the cavity was covered with a permanent filling made of a light-cured composite material. After cleaning, the periodontal pocket was rinsed, dried, and treated with ozone for 18 seconds. A recall examination in six months showed no inflammation of the tooth. Additionally, the bone tissue was recovering, and the periodontal pocket reduced to 4mm.

“Simultaneous inflammation of the pulp and periodontium tissues is very difficult to treat. It can be caused by several types of pathogens at the same time that migrate between tissues and worsen the prognosis. Our experience shows that such an infected tooth can be saved, but it requires close collaboration of a periodontologist and an endodontist, as well as a patient’s complete compliance with oral hygiene recommendations. One should also take into consideration possible bacterial resistance to antibiotics and therefore use additional antibacterial treatment, such as ozone,” explained Dr Makeeva.

Source: News-Medical.Net

Nanoparticle and Antibiotic Polytherapy Defeats AMR Bacteria

Polytherapy with PMB and cubosomes result in interactions with the bacterial OM in two consecutive ways: PMB initially interacts with the outer leaflet of OM via electrostatic interactions, leading to destabilised areas. Cubosomes then contact with the bilayer, causing further membrane perturbations via a lipid-exchange process. Credit: Monash University/Lai et al.

Researchers from Monash University have discovered a potential new method to circumvent antibiotic resistance, by means of a nanoparticle and antibiotic polytherapy. This approach could also reduce antibiotic intake.

The World Health Organisation (WHO) has declared antimicrobial resistance (AMR) to be among the top 10 global public health threats. A recent report found that in 2019, 1.27 million deaths were directly attributable to AMR infections – more than deaths from either HIV or TB.

AMR occurs when pathogens evolve to no longer respond to medicines, consequently infections become increasingly difficult or impossible to treat.

The study, which appears in Nature Communications, has found that the use of nanoparticles in combination with other antibiotics, is an effective strategy to improve bacterial killing.

For Gram-negative bacteria, polymyxins have been used as drugs of last resort as they disrupt the bacterial outer membrane (OM), causing it to become more permeable, causing cell contents to leak out and kill the bacteria.

The strategy involves administering polymyxin B (PMB) alongside cube-shaped nanoparticles called cubosomes. The PMB disrupted the OM first, but not enough to kill the cell. When the accompanying cubosome bound to the OM, disrupting it further, successfully killing the cell. Interestingly, loading PMB into the cubosomes as a carrier had little effect; in fact, the cubosome strengthened the OM.

“This is a stunning finding in how we deliver medicine and how the medicine we take impacts us in the future,” said lead researcher Dr Hsin-Hui Shen. 

This approach also means that lower dosages of antibiotics could be used. “Instead of looking for new antibiotics to counteract superbugs, we can use the nanotechnology approach to reduce the dose of antibiotic intake, effectively killing multidrug-resistant organisms.”

It has been 30 years since the discovery of the last new antibiotic, and in coming years, the growing crisis of antibiotics resistance will result in increased mortality from basic infections because they have developed antimicrobial resistance.

Without effective antimicrobials, the WHO warns that the success of modern medicine in treating infections, including during major surgery and cancer chemotherapy, would be at increased risk.

While nanoparticles had been used for a long time before as antimicrobial carriers,  “but the use of nanoparticles in polytherapy treatments with antibiotics in order to overcome antimicrobial resistance has been overlooked,” explained Dr Shen. “The use of nanoparticles-antibiotics combination therapy could reduce the dose intake in the human body and overcome the multidrug resistance.”

Research will now progress to the testing phase.

Source: Monash University

Many Youths with Substance Use Disorder Also Have Autism Traits

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One in five teens and young adults seeking treatment for substance use may have traits characteristic of a previously unrecognised autism spectrum disorder (ASD), according to a study by researchers at Massachusetts General Hospital (MGH).

The study, published in The American Journal on Addictions, found that among patients with an average age of 18.7 years being treated in an outpatient substance use disorder (SUD) clinic, 20% had elevated scores on the Social Responsiveness Scale-2 (SRS-2), a parent- or teacher-reported measure that has been shown to reliably identify the presence and severity of social impairment among individuals along the autism spectrum, and to distinguish autism from other disorders.

Lead author James McKowen, PhD, said this is the first study examining the prevalence of autistic traits among young people with SUD.

“Usually studies of substance use disorder in autism are done in those with an autism diagnosis already,” he said. “We have looked at this question from the other side, asking how many people with substance use disorder have autism.”

The researchers asked parents of 69 youths reporting for the first time to a specialty outpatient psychiatric SUD clinic to fill out the SRS-2 form. The form is designed to measure an individual’s social awareness, cognition, communication and motivation, and restricted interests and repetitive behaviours.

Though few differences were found between those with elevated autistic trait scores and those with lower, non-autistic scores in terms of demographic or psychiatric factors, adolescents with higher SRS-2 scores had a nearly eightfold higher likelihood of stimulant use disorder, and a fivefold higher risk for opioid use disorder.

According to the researchers, the findings highlight the importance of assessing patients in a SUD treatment setting for autistic traits.

“For clinicians, the big takeaway point from this study is that we need to get better at screening and certainly training in the presence of autism spectrum disorder,” said Dr McKown. Clinicians treat the SUD “but don’t have specialty developmental training, particularly for issues around autism.”

The researchers are developing a free clinical therapy protocol that can help clinicians better address the issues of autistic traits in patients with SUD.

Source: Massachusetts General Hospital

Coffee Consumption Lowers Endometrial Cancer Risk

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Higher coffee consumption is linked with a lower risk of endometrial cancer, according to a new analysis which appears in the Journal of Obstetrics and Gynaecology Research. In addition, there was evidence that caffeinated coffee may provide better protection than decaffeinated coffee.

Risk factors for endometrial cancer include long-term exposure to excess oestrogen, obesity, nulliparity, diabetes mellitus, and hypertension, whereas protective factors include physical activity, aspirin intake, and certain dietary habits.

The analysis, which included 24 studies on coffee intake (12 case–control and 12 cohort studies), had 9833 new cases of endometrial cancer occurring in 699 234 individuals.

People in the highest category of coffee intake had a 29% lower relative risk of developing endometrial cancer than those in the lowest category. Additionally, women with a higher BMI or who smoked saw a greater benefit in risk reduction, though they still had a higher risk overall.

The authors of the analysis highlight several mechanisms that have been associated with the potential anti-cancer effects of coffee:

“Coffee contains many bioactive components, such as phenolic compounds. These polyphenols can increase the homocysteine concentrations in the plasma and inhibit DNA methylation in a dose-dependent manner, which prevents the downregulation of tumour suppressor proteins and DNA repair enzymes involved in carcinogenesis.”

They conclude that more studies with larger sample sizes are needed to better understand the effects of subgroups such as smoking status, as well as the benefits of coffee consumption in relation to endometrial cancer.

Source: Wiley