Day: May 9, 2023

Categories : Metabolic Disorders Obstetrics & GynaecologyTags :

Sons Born to Women with PCOS Can Also Encounter Health Problems

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Sons of women with polycystic ovary syndrome (PCOS) have a twofold increased risk to develop obesity, according to a study published in Cell Reports Medicine. The findings highlight a previously unknown risk of passing PCOS-related health problems across generations through the male side of a family, say the the researchers from Karolinska Institutet.

PCOS is caused by overproduction of testosterone by the ovaries and affects around 15% of women of childbearing age worldwide, impacting fertility. In addition, the disease is associated with various health problems such as diabetes, obesity, and mental illness. 

Daughters of women with PCOS have a fivefold risk of developing the same disease. Although it is not yet clear how sons of women with PCOS are affected, research suggests that they are more likely to have weight and hormone problems

The researchers used both registry data and mouse models in the newly published study to determine if and how PCOS-like traits are passed from mothers to their sons. Just over 460 000 sons born in Sweden between July 2006 and December 2015 were included in the registry study. Of these, roughly 9000 had mothers with PCOS. The researchers then identified which of the children were obese. 

“We discovered that sons of women with PCOS have a twofold increased risk of obesity and of having high levels of “bad” cholesterol, which increases the risk of developing insulin resistance and type 2 diabetes later in life”, says study leader Elisabet Stener-Victorin, professor at Karolinska Institutet. 

These findings were confirmed in the mouse study, where the researchers examined male offspring of female mice that before and during pregnancy were fed either a standard diet or a diet rich in fat and sugar, and were exposed to high levels of the male sex hormone dihydrotestosterone during pregnancy to mimic the pregnancy of normal weight individuals and obese women with PCOS. 

The male mice were then fed a standard diet until adulthood when their fat distribution and metabolism were examined. 

“We could see that these male mice had more fat tissue, larger fat cells, and a disordered basal metabolism, despite eating a healthy diet”, says Elisabet Stener-Victorin.

To investigate the reproductive function of the offspring and whether physiological characteristics can be passed on from generation to generation, the first-generation male mice were mated with healthy female mice that were not exposed to male sex hormones or a diet rich in fat and sugar. The whole process was repeated in the second generation to reach the third generation which is the first generation that was not affected by the mother condition.  
 
“Through these experiments, we can show that obesity and high levels of male hormones in the woman during pregnancy can cause long-term health problems in the male offspring. Their fat tissue function, metabolism, and reproductive function deteriorate, which in turn affects future generations”, says Qiaolin Deng, associate professor at the same department and one of the researchers behind the study.
 
“These findings are important because they highlight the risk of passing health problems down through the male side of a family, highlight the risk of passing this kind of health problem, and they may help us in the future to find ways to identify, treat and prevent reproductive and metabolic diseases at an early stage,” says Elisabet Stener-Victorin.

Source: Karolinska Institutet

Categories : Cardiovascular Disease ExerciseTags :

For Stroke Recovery, Physical Activity is Crucial

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A University of Gothenburg study shows that after a stroke, physical activity can be pivotal to successful recovery. People who spend four hours a week exercising after their stroke achieve better functional recovery within six months than those who do not.

The study, published in JAMA Network Open, analysed data from 1500 stroke patients who were grouped according to their post-stroke patterns of physical activity.

The results show that increased or maintained physical activity, with four hours’ exercise weekly, doubled the patients’ chances of recovering well by six months after a stroke. Men and people with normal cognition kept up an active life relatively more often, with better recovery as a result.

Positive programming from exercise

The researchers have previously succeeded in demonstrating a clear inverse association between physical activity and the severity of stroke symptoms at the actual onset of the condition. These new findings highlight the importance of maintaining a healthy, active lifestyle after a stroke.

The first and corresponding author of the study, Dongni Buvarp, is a researcher in clinical neuroscience at Sahlgrenska Academy, University of Gothenburg. Besides her research internship, she is a resident doctor at an initial stage of specialist training at Sahlgrenska University Hospital.

“Physical activity reprograms both the brain and the body favourably after a stroke. Exercise improves the body’s recovery at the cellular level, boosts muscle strength and well-being, and reduces the risk of falls, depression, and cardiovascular disease. Regardless of how severe the stroke has been, those affected can derive benefits from exercising more,” she says.

Knowledge and support vital

“Being physically active is hugely important, especially after a stroke. That’s a message that health professionals, stroke victims and their loved ones should all know. Women and people with impaired cognition seem to become less active after stroke. The study results indicate that these groups need more support to get going with physical activity,” Buvarp says.

One weakness of the study is that, with a few exceptions, the researchers were unable to study the participants’ degree of activity before the stroke. The patients included were treated in Sweden in the period from 2014 to 2019.

Source: University of Gothenburg

Categories : Cardiovascular DiseaseTags :

Novel Ablation Strategy for Arrhythmia Treatment

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Credit: CC0

An innovative three-step ablation approach including ethanol infusion of the vein of Marshall improves freedom from arrhythmias in patients with persistent atrial fibrillation compared to pulmonary vein isolation (PVI) alone, according to late breaking science presented at EHRA 2023, a scientific congress of the European Society of Cardiology (ESC). Preliminary results at 10 months are presented, with follow up ongoing until 12 months. The results are discussed in an accompanying editorial.

The cornerstone of catheter ablation of atrial fibrillation is complete isolation of the pulmonary veins. However, only 50–60% of patients remain in sinus rhythm at two years. Numerous trials of different ablation strategies have failed to demonstrate superiority over PVI.

The Marshall-Plan ablation strategy consists of 1) PVI; 2) ethanol infusion of the vein of Marshall; and 3) a linear ablation set to block the three main anatomical isthmuses to the pulmonary veins (dome, mitral and cavotricuspid isthmus lines). The technique focuses on anatomical targets that have been individually recognised as important for the initiation or maintenance of atrial fibrillation but have not been collectively targeted in a systematic manner. The current investigators previously reported encouraging results using this strategy in non-randomised studies.

The present study compared 12-month arrhythmia-free survival with the Marshall-Plan ablation strategy versus PVI only. This was a prospective, randomised, parallel group trial of superiority. The trial included 120 patients with symptomatic persistent atrial fibrillation for more than one month. The average age of participants was 67 years and 21 (18%) were women.

Participants were randomised to receive the Marshall-Plan or PVI alone. Follow up occurred at 3, 6, 9 and 12 months during which patients underwent a number of tests including an electrocardiogram (ECG), echocardiography, stress test and 24-hour Holter monitoring. Recurrence of arrhythmias was identified using ECG teletransmission, with findings sent to the hospital once a week plus any time the patient had symptoms. The primary endpoint was recurrence of atrial fibrillation or atrial tachycardia lasting more than 30 seconds at 12 months (including a 3-month blanking period) after a single ablation procedure.

The total radiofrequency time was significantly longer in the PVI group (29 minutes) compared with  the Marshall-Plan group (23 minutes; p<0.001). The full lesion set was successfully completed in 53 patients (88%) receiving the Marshall-Plan strategy and 59 patients (98%) receiving PVI only. In an intention-to-treat analysis, the recurrence of arrhythmias after an average follow up of 10 months was significantly higher in the PVI group compared with the Marshall-Plan group (18 vs. 8 patients; p=0.026). Follow up will continue until 12 months.

Principal investigator Dr Nicolas Derval said: “After 10 months of follow up, the success rate in the Marshall-Plan group was significantly better (87%) compared to the PVI only group (70%). However, the results are still preliminary as follow up is not completed for all patients. While the findings indicate that the Marshall-Plan strategy holds promise for patients with persistent atrial fibrillation, they need to be confirmed in a multicentre trial.”

Source: European Society of Cardiology

Categories : Cardiovascular DiseaseTags :

Aggressive BP Control may Help Prevent Left Ventricular Conduction

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Electrical problems in the heart such as left ventricular conduction disease can often lead to serious and fatal complications. Treatment to lessen its effects involves implanting a permanent pacemaker, but there are no proven preventive strategies at present.

In a study published in JAMA Cardiology, researchers took advantage of a prospective trial in which individuals with hypertension were randomly assigned to standard and aggressive blood pressure (BP) control. They found that intensive BP control is associated with lower risk of left ventricular conduction disease, indicating left ventricular conduction disease may be preventable.

“This research was motivated by patients who came in with complete heart block where I put in a pacemaker and they asked, ‘Why did this happen to me?’” said senior author Gregory Marcus, cardiologist and UCSF professor of medicine. “The answer to this question has not been clear, so we wanted to look at the impact that blood pressure might have on the development of their conduction disease.”

The authors performed a statistical analysis of the previously completed Systolic Blood Pressure Intervention Trial (SPRINT) to determine the association between targeting intensive BP control and the risk of developing left ventricular conduction disease. Participants included in the five year long SPRINT trial were adults 50 years and older with hypertension and at least one other cardiovascular risk factor. Participants with early signs of left ventricular conduction disease, ventricular pacing or ventricular pre-excitation were excluded from the analysis.

Participants were randomly assigned to either normal blood pressure control (targeting a systolic blood pressure less than 140) or a more aggressive BP control (targeting a BP less than 120). As part of the analysis, the authors reviewed the serial ECGs that the participants received over the course of the trial and found that those randomly assigned to the more aggressive BP control experienced significantly less conduction disease on the left side of the heart.

“This analysis suggests that more aggressive BP control might be a way to prevent this sort of common disease,” said Marcus. “More broadly, the use of randomised controlled trial data provided compelling evidence that this common disease is not an immutable fate, but that the risk can be modified.”

By contrast, the researchers saw no differences in right-sided conduction disease (manifested by right bundle branch blocks). The authors considered right bundle branch blocks as a “negative control” since the right side of the heart is not directly affected by BP control and as such bundle branch blocks are not generally associated with the same severe outcomes as left bundle branch blocks.  

The authors note that SPRINT did not examine the role of anti-hypertensive drugs, suggesting further research into associations between specific medications and conduction disease rates may be warranted.

Source: University of California, San Francisco

Categories : Mental Health New Compounds and TreatmentsTags :

Scientists Create Antidepressant Drug Candidates from Traditional African Plant Medicine

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Scientists have developed two new drug candidates for potentially treating addiction and depression, modelled on the pharmacology of a traditional African psychedelic plant medicine called ibogaine. At very low doses, these new compounds were able to blunt symptoms of both conditions in mice.

The study, published in Cell, took inspiration from ibogaine’s impact on the serotonin transporter (SERT), which is also the target of selective serotonin reuptake inhibitor (SSRI) drugs, such as fluoxetine. A team of scientists from UC San Francisco and Yale and Duke universities virtually screened 200 million molecular structures to find ones that blocked SERT in the same way as ibogaine.

“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the US,” said Brian Shoichet, PhD, co-senior author and professor in the UCSF School of Pharmacy. “Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behaviour, at least in mice.”

Dozens of scientists from the laboratories of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD, (UCSF); Gary Rudnick, PhD, (Yale); and Bill Wetsel, PhD, (Duke) helped demonstrate the real-world promise of these novel molecules, which were initially identified using Shoichet’s computational docking methods.

Docking involves systematically testing virtual chemical structures for binding with a protein, enabling scientists to identify new drug leads without having to synthesise them in the lab. “This kind of project begins with visualizing what kinds of molecules will fit into a protein, docking the library, optimising and then relying on a team to show the molecules work,” said Isha Singh, PhD, a co-first author of the paper who did the work as a postdoc in Shoichet’s lab. “Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”

Optimising a shaman’s cure

Ibogaine is found in the roots of the iboga plant, which is native to central Africa, and has been used for millennia during shamanistic rituals. In the 19th and 20th centuries, doctors in Europe and the US experimented with its use in treating a variety of ailments, but the drug never gained widespread acceptance and was ultimately made illegal in many countries.

Part of the problem, Shoichet explained, is that ibogaine interferes with many aspects of human biology.

“Ibogaine binds to hERG, which can cause heart arrhythmias, and from a scientific standpoint, it’s a ‘dirty’ drug, binding to lots of targets beyond SERT,” Shoichet said. “Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”

Shoichet, who has used docking on brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Rudnick, an expert on SERT at Yale, spent a sabbatical in his lab. Singh picked up the project in 2018, hoping to turn the buzz around ibogaine into a better understanding of SERT.

It was the Shoichet lab’s first docking experiment on a transporter – a protein that moves molecules into and out of cells – rather than a receptor. One round of docking whittled the virtual library from 200 million to just 49 molecules, 36 of which could be synthesised. Rudnick’s lab tested them and found that 13 inhibited SERT.

The team then held virtual-reality-guided “docking parties,” to help Singh prioritise five molecules for optimization. The two most potent SERT inhibitors were shared with Basbaum and Wetsel’s teams for rigorous testing on animal models of addiction, depression and anxiety.

“All of a sudden, they popped – that’s when these drugs looked a lot more potent than even paroxetine [Paxil],” Shoichet said.

Manglik, an expert with cryo-electron microscopy (cryo-EM), confirmed that one of the two drugs, dubbed ‘8090,’ fit into SERT at the atomic level in a way that closely resembled Singh and Shoichet’s computational predictions. The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover impacts on a panel of hundreds of other receptors and transporters.

“With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum said. “Dropping the dose almost 200-fold could make a big difference for patients.”

Source: University of California – San Francisco