Mechanisms behind articular cartilage healing after injury

 Understanding how the knee joint environment affects cartilage cells is crucial for joint health. Knowledge of cell-driven cartilage degeneration mechanisms can support the development of effective pharmaceutical interventions for osteoarthritis.

The burden of musculoskeletal diseases, such as osteoarthritis, is increasingly affecting patients' quality of life and bringing enormous costs to health care. In efforts to reduce the burden of the disease, computational models have been developed to predict cartilage degeneration onset and progression.

Current knee joint models have shed light on the development of biomechanical joint forces during walking, and on the severity of joint inflammation. However, cell-tissue-level computational models have gained much less attention, even though cells contribute remarkably to tissue changes in cartilage.

Thus, a better understanding of early osteoarthritis mechanisms at the cell- and tissue-levels is needed to enable the prediction of early disease progression. In addition, these models could also open new avenues for model-guided pharmaceutical research aiming to mitigate osteoarthritis progression.

As a collaborative work between the University of Eastern Finland (UEF), Lund University (LU), the University of Iowa (UIOWA), and Massachusetts Institute of Technology (MIT), researchers have now incorporated the influence of cells in a new numerical model to discover degeneration processes in mechanically loaded and inflamed cartilage.

This model considers different forms of cell death, oxidative stress, and pro-inflammatory biomolecules. As in previous biological experiments, the model predicted that injurious loading causes aggressive cell damage and cartilage degeneration near cartilage lesions, whereas inflammation induces widespread degeneration also in the intact regions.

Interestingly, mitigation of inflammation led to a partial recovery of the cartilage composition consistent with previous literature. This result suggests that the approach could help in pinpointing potential targets for new early intervention strategies and it has great potential to serve as a computational "test track" for different anti-inflammatory or anti-oxidative drug treatments, for example.

"After thorough calibration, the model could provide valuable information to assess drug delivery and effects of therapeutic treatments in cartilage. Thus, in our ongoing work with the University of Iowa, we will utilize the model to study the effectiveness of their antioxidative drug candidate. The model could help in assessing when the drug should be injected into the joint to get the greatest benefit, and what dosage should be used for a certain patient.

"These factors in a knee joint, for example, may depend on the mechanical and inflammatory aspects of each patient, both of which can be considered with our computational model," says the study's lead author, Doctoral Researcher Joonas Kosonen of the University of Eastern Finland.

The research is published in the journal PLOS Computational Biology.

More information: Joonas P. Kosonen et al, Injury-related cell death and proteoglycan loss in articular cartilage: Numerical model combining necrosis, reactive oxygen species, and inflammatory cytokines, PLOS Computational Biology (2023). DOI: 10.1371/journal.pcbi.1010337

https://medicalxpress.com/news/2023-03-unravel-mechanisms-articular-cartilage-injury.html

Study details inflammation in early stages of Parkinson's

 New research by investigators at the University of Alabama at Birmingham supports the premise that inflammation is associated with Parkinson's disease early in the disease's progression. The findings, published online in Movement Disorders, support the conclusion that central inflammation is observed early in the disease process of Parkinson's, is independent of treatment for the disease, and correlates with cognitive features and certain peripheral markers of inflammation.

"An association between inflammation and Parkinson's is well known, but a fundamental question remains unanswered," said Talene Yacoubian, M.D., Ph.D., professor in the Department of Neurology in the Marnix E. Heersink School of Medicine. "Does inflammation play a role in the onset of Parkinson's, or is it a byproduct of the disease itself? Our findings show that inflammation is present in the early stages of the disease."

Yacoubian's team enrolled 58 people with newly diagnosed Parkinson's disease and 62 healthy controls.

"Enrolling study subjects early in their disease progression was significant," said Yacoubian, who holds the John A. and Ruth R. Jurenko Endowed Professorship at UAB. "We wanted to see if inflammation was present early on in the disease, before patients had even begun on Parkinson's medications."

The team used PET imaging to target translocator protein, or TSPO, a protein found primarily in microglial cells and other immune cells in the brain. Increased TSPO has been shown to be associated with inflammation. Yacoubian and colleagues were the first United States research team to employ a radioligand developed in Europe called 18F-DPA-714. Once injected into the bloodstream, this radioactive molecule binds to TSPO, causing it to light up on PET imaging.

"We found elevations in TSPO binding in untreated subjects at early stages of Parkinson's, indicating the presence of inflammation," Yacoubian said. "Our data clearly demonstrate that increased TSPO binding is present in Parkinson's independent of treatment effects. Our multimodal study provides further evidence that TSPO signal as measured by 18F-DPA-714 is a marker of inflammation."

Yacoubian says several key gaps still remain as to the role of inflammation in Parkinson's disease, including the potential effects of Parkinson's treatments on inflammation, whether inflammation changes over time and whether pro-inflammatory signals predict more rapid progression of the disease.

The study subjects were enrolled over three years, and each has been involved in the study long enough to have had at least a one-year follow-up, with some subjects now followed for as long as four years. The goal is to repeat the imaging at five years for study participants.

"Follow-up of these study subjects will be critical to determine the significance of early inflammatory changes and to observe whether certain inflammatory changes predict clinical progression," Yacoubian said. "We will continue to collect biospecimens annually to determine whether the inflammatory measures change over time in Parkinson's disease. Future studies will need to examine the potential causal relationship between inflammation and neurodegeneration."

More information: Talene A. Yacoubian et al, Brain and Systemic Inflammation in De Novo Parkinson's Disease, Movement Disorders (2023). DOI: 10.1002/mds.29363

https://medicalxpress.com/news/2023-03-inflammation-early-stages-parkinson-disease.html

'Pregnant patients with anxiety shown to have altered immune systems'

 The immune system of pregnant women with anxiety is biologically different from that of pregnant women without anxiety, according to new research from Weill Cornell Medicine, Johns Hopkins University School of Medicine and Columbia University Irving Medical Center investigators.

The study, published Sept. 14, 2022 in Brain, Behavior and Immunity, demonstrates that pregnant women with anxiety have higher levels of certain immune cells known as cytotoxic T cells; these cells attack infected or otherwise compromised cells within the body. Women with anxiety also showed differences in the activity of immune markers that circulate in the blood. This is the first known study to evaluate the relationship of anxiety to the trajectory of immune changes over the course of pregnancy and the postpartum period.

"Women with anxiety appear to have an immune system that behaves differently from that of healthy women during pregnancy and after delivery," said principal investigator Dr. Lauren M. Osborne, vice chair for clinical research for the Department of Obstetrics and Gynecology at Weill Cornell Medicine, who conducted the research while on Johns Hopkins University School of Medicine's faculty. "During pregnancy, a delicate dance is supposed to occur, in which the immune system changes so that it does not reject the fetus but is still strong enough to keep out foreign pathogens."

This study could encourage better treatment of anxiety in pregnant patients, said Dr. Osborne, who is also a reproductive psychiatrist at New York-Presbyterian/Weill Cornell Medical Center. As a clinician, she finds that women with anxiety may resist taking antianxiety medications because they fear the drugs will hurt the baby, despite evidence that they are compatible with pregnancy.

Anxiety during pregnancy, which is self-reported by more than 20 percent of people, according to the researchers, is already known to be detrimental to the parent and child. For example, it can increase the risk of preterm birth and a lower newborn birth weight.

For this study, Dr. Osborne and her colleagues assessed a group of 107 pregnant women, 56 with anxiety and 51 without anxiety, during their second and third trimesters and at six weeks postpartum. The researchers evaluated blood samples for immune activity and conducted psychological evaluations to detect clinical anxiety.

They found that in the women with anxiety, levels of cytotoxic T cells were elevated during pregnancy and then decreased in the weeks following childbirth. In women without anxiety, the activity of these cells declined in pregnancy and continued to decline after birth.

The researchers also observed that the activity of largely pro-inflammatory cytokines, or substances secreted by cells as part of the immune system response, was suppressed during pregnancy in women with anxiety and then rose after childbirth, while healthy women exhibited the opposite pattern.

"The takeaway is that this is the first clear evidence that immune activity differs for pregnant women depending on their anxiety status. Knowing that there is immune system involvement is a first step toward understanding the biological factors related to anxiety in pregnancy, and a first step toward developing new treatments," said Dr. Osborne. "We know that anxiety needs to be treated to ensure healthy outcomes for both mother and child."

More information: Morgan L. Sherer et al, The immune phenotype of perinatal anxiety, Brain, Behavior, and Immunity (2022). DOI: 10.1016/j.bbi.2022.09.005

https://medicalxpress.com/news/2023-03-pregnant-patients-anxiety-shown-immune.html

Inflation data pushed 10-year Treasury yield above 4%. How much higher can rates go?

 Rates across the entire Treasury market all go above 4%

Signs of continued U.S. labor market strength plus persistent inflation out of Europe were all it took on Thursday for bond investors to push yields up toward new milestones on rising interest-rate expectations.The 10-year Treasury yield rose meaningfully above 4%, the highest level since November and one of the highest in more than a decade. BMO Capital Markets strategists Ian Lyngen and Ben Jeffery said the benchmark rate is near the top of what they see as a 100-125 basis point trading range centered around 3.5% -- meaning the rate could go as high as 4.5% or 4.75% at some point if bond-selling momentum continues. Yields and debt prices move opposite each other.

For now, Lyngen and Jeffery are putting the 10-year yield's 4.241%-4.335% intraday peaks reached late last year back on the map.

March marks the first anniversary of the first Federal Reserve rate hike of the current tightening cycle, and the outlook for inflation across developed markets has only gotten murkier since.

U.S. data on Thursday showed that weekly initial jobless claims stayed below 200,000 for the seventh week in a row at the end of February, a sign of continued labor-market strength. Meanwhile, inflation hasn't come off nearly as much as expected in either the U.S. or the eurozone, with the latter recording an annual CPI inflation rate of 8.5% for last month. Together, that's adding up to rising yields and interest-rate expectations, which continue to pressure stocks. Yields across the entire Treasury market, including the 30-year rate BX:TMUBMUSD30Y, are all now above 4%.As with almost everything in financial markets, bond trading is a two-way street: Yields tend to back up each time inflation fears prompt investors to sell off bonds. Those rates then start to ease down again as a fresh pool of investors, attracted by higher yields, jump back in to buy fixed income at more appealing returns than they might get elsewhere, such as in stocks. "We don't believe the 10-year can stay over 4% for a long period of time without affecting the economy, and we expect to see an increase in unemployment as we move through the year," said Rhys Williams, chief strategist at Spouting Rock Asset Management, which oversees $2.3 billion in assets from Bryn Mawr, Pa.

"We wouldn't get too negative on stocks and bonds, because we think both stocks and bonds will rally hard at the first sign that PCE inflation is slowing and unemployment is increasing, and we think that is likely in the next three months," Williams said.

The 10-year yield, which hovered around 4.07% in New York trading, hasn't ended the New York session above 4% since Nov. 9, 2022, though it came within less than 1 basis point of doing so on Wednesday. Prior to October to November of last year, the yield hasn't consistently traded above 4% since 2007-2008.Fed policy makers have delivered 450 basis points worth of tightening in the past year -- taking their benchmark rate target to 4.5% and 4.75% from almost zero. On Thursday, fed funds futures traders briefly boosted their expectations for a 5.5%-plus interest rate by November, and the policy-sensitive 2-year rate BX:TMUBMUSD02Y inched closer to 5% or the highest level in more than a decade. Meanwhile, U.S. stocks turned mostly higher Thursday afternoon, a reversal from the pattern seen during the first trading session of March. Over the last month, "inflation expectations have spiked back and 2yr and 5yr U.S. breakevens are now at 7-month and 4-month highs, respectively," said Deutsche Bank's Jim Reid, in a note. "To be frank, the inflation call is now tougher than it was in 2020-2022," describing it as a "sticky and messy outlook." "Further ahead, structural forces are becoming inflationary, including those relating to deglobalisation and demographics," Reid wrote. "But in the near term, inflation will likely be sticky until the monetary overhang has been eradicated and the U.S. recession we expect hits later this year. After that, we could fall sharply given current monetary trends and the lag of policy, before the structural forces re-emerge again in the next cycle."

https://www.morningstar.com/news/marketwatch/20230302656/inflation-data-pushed-the-10-year-treasury-yield-above-4-how-much-higher-can-interest-rates-go

Childhood Obesity: What You’re Not Hearing In The News

 by Sally Fallon Morell via The Epoch Times (emphasis ours),

New guidelines on treating childhood obesity from the American Academy of Pediatrics call for early and aggressive treatment—including weight loss drugs for children as young as 6 and bariatric surgery for youths as young as 13—instead of what they call “watchful waiting or unnecessary delay of appropriate treatment of children.”

The guidelines immediately stirred controversy, with critics on the left concerned about unequal access to treatment and conservative commentators suggesting that the guidelines offer an easy out for poor lifestyle choices. Critics from across the spectrum have noted the potential long-term consequences of putting children on drugs and performing irreversible surgery on teenagers.

“Lifestyle choices” typically mean more exercise—along with less processed food and more fruits and vegetables in the diet—but no one in the mainstream is suggesting that the solution is to allow children to eat more natural saturated fat.

Years ago, my co-author and colleague Mary Enig, who held a doctorate in nutritional sciences, had an interesting conversation with an official at the U.S. Department of Agriculture. The agency had researched the best way to fatten pigs—research that was never published. When they fed pigs whole milk or coconut oil, the pigs stayed lean—they found that the best way to fatten pigs was to feed them skim milk.

The Department’s dietary guidelines stipulate reduced fat milk for all Americans above the age of 2. Could this policy—initiated in the 1990s—explain the increase in obesity among American children? A couple of studies indicate that this could be the case.

The first, published in 2006 in the American Journal of Clinical Nutrition, looked at diet and metabolic markers in 4-year-old children in Sweden. “High body mass index was associated with a low percentage of energy from fat,” and greater weight was related to greater insulin resistance, especially in girls. In other words, children on low-fat diets tended to be overweight and had markers that presage diabetes later in life.

The second study, published in 2013 in the Archives of Diseases of Children, looked specifically at children consuming reduced-fat milk, comparing the body mass index of those drinking 1 percent skim milk and 2 percent “whole milk” drinkers. (I put “whole milk” in quotation marks because commercial whole milk contains 3.5 percent fat, and whole milk obtained from the farm can contain up to 5 percent fat.)

Across all racial, ethnic, and socio-economic status subgroups, those drinking 1 percent skim milk “had an increased adjusted odds of being overweight … or obese … In longitudinal analysis, children drinking 1 percent skim milk at both 2 and 4 years were more likely to become overweight/obese between these time points …” In other words—children on skim milk are more likely to become fat—just like pigs do!

https://www.zerohedge.com/medical/childhood-obesity-what-youre-not-hearing-news

End of England's Long-Term National Cancer Plan: Costing Lives?

 Hello. I'm David Kerr, professor of cancer medicine at University of Oxford.

There was an interesting article I picked up recently in The BMJ , which was authored and led by a dear friend of mine, Professor Richard Sullivan, from King's College in London. Richard has been a friend for more than two decades and has played a great role nationally and internationally in cancer control in the most general sense.

He and some very senior oncologists in the UK have prepared this publication for The BMJ in which they called the government's decision to merge cancer with other chronic diseases — cardiovascular, respiratory, dementia, and mental health — putting it all into one basket of chronic diseases, a catastrophe for cancer services in the United Kingdom.

Their argument, which I think is entirely reasonable, is that if you look around the world, the World Health Organization has taken a lead in developing a framework for cancer control. Indeed, many of you who listen to Medscape have heard me talk about the work that we've done in sub-Saharan Africa, Iraq, other areas of the Middle East, and India in supporting cancer control.

I was, in the late nineties, one of the architects of the British National Cancer Plan. We have made great strides — there's no question about that. We had a government that was prepared to invest in cancer and that was prepared to understand the depth and the extent of the problem. The fact that our cancer survival figures internationally are lagging behind many of our European neighbors' set the scene for a significant investment in cancer services.

Despite almost two decades of investment, planning, and delivery by the health policymakers and the community of oncologists and cancer healthcare professionals, I still think that this plan is a bad idea.

Cancer stands alone in terms of the complexity of treatment, the multiple modalities involved, and the referral journey from primary care to secondary care, which of course is still not done in a timely fashion. There was some evidence to suggest that cancer patients in the United Kingdom present with somewhat later-stage disease than those of our neighbors, their cousins, and their brothers and sisters in the continent of Europe. There is work to be done there.

Despite the investment in cancer care, we have some worrying statistics suggesting a significant degree of unwarranted variation. We have talked about this in the past. All of us understand biological variation. We're genetically different; therefore, our response to treatments and drugs, and the phenotype and behavior of cancer, can depend on the genetics that we inherit from our parents and the environment in which we choose, or are forced, to live.

Unwarranted variation has to do with variations in access to the appropriate screening, treatment, and follow-up. There are some quite stark statistics that, despite successive cancer plans, unwarranted variation still looms large in the United Kingdom. If it looms large here, it will loom large even further elsewhere. This health equity gap, I think, dishonors us all.

One might say I would say that because I'm a cancer lobbyist, but I think that we have compelling evidence that, given its complexity, this policy seems to be swimming against the tide and against the general global direction of singling cancer out as a complex set of many diseases that require specific attention.

I'd be very interested in comments from your own experience, from your own country, and from those of us who work with me within the National Health Service. Do we think this is a good idea? Do we think we've had it too good for too long, as some of our colleagues might say from these other — one would argue — chronically underfunded chronic conditions?

Are we right to provide evidence and state that still we need to have a separate national cancer plan with milestones and deliverables that we, the community responsible, are held to account to deliver?

Please drop me a note and share your comments. As always, thanks for listening. For the time being, Medscapers, over and out. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of  colorectal cancer  and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

https://www.medscape.com/viewarticle/988551

NP-PA Turf Fights: Where the Relationship Can Improve

 Physician interactions with nurse practitioners (NPs) and physician assistants (PAs) are only going to increase in frequency ― the US Bureau of Labor Statistics forecasts a 40% increase in the NP workforce by 2031, coupled with a 28% rise in PAs.

In recent Medscape reports on the quality of the relationships involving these healthcare professions, survey respondents mostly gave positive accounts of collaboration, using words such as like "comradery," "teamwork," "congenial," and "cohesion." But all was not perfect. Where and how could these important healthcare provider relationships improve?

PAs: "Competition and Collaboration" With RNs

Medscape surveyed more than 770 PAs about their working relationships with other healthcare professionals; 83% of them supported the idea of PAs and NPs practicing more independently from physicians, but sometimes it’s not easy to stay in their individual lanes.

One PA respondent complained that NPs get "more opportunities and preference," another pointed to PA-NP "turf issues," and a third griped about NPs' "strong unions," which have stoked more fighting about practice abilities and available settings.

Robert Blumm, MA, PA-C, a retired surgical and emergency medicine PA who regards himself as an advocate for both PAs and NPs, describes their interaction as a "mixture of competition and collaboration."

On one hand, the two groups typically "cooperate and do an excellent job, incurring patient errors similar to or less than physician colleagues or senior residents." On the other hand, Blumm concedes, there is some jealousy among PAs over NPs' advantage in staffing and hiring decisions, "since they don't need [direct physician] supervision...and there are limits on how many PAs can be supervised by one physician."

Most PA-NP interactions are collaborative, although many people emphasize the relatively few conflicts, says Jennifer Orozco, DMSc, PA-C, president and chair of the American Academy of PAs.

"We see that a lot in this country," she says. "People try to drive a wedge, but it's often a misnomer that there's a lot of arguing and infighting."

NPs: Different Backgrounds, Same Goal

Medscape also heard from 750 NPs on working relationships; 93% of them favored nurses and PAs working more independently from doctors.

NP April Kapu has worked closely with PAs for more than 20 years. "In my experience...they complement one another as health team members, although the education and training are somewhat different," says Kapu, DNP, ARPN, president of the American Association of Nurse Practitioners.

Some respondents to Medscape surveys noted the different educational trajectories for NPs and PAs. "Doctors and PAs are taught using the same model, but NPs are taught under the nursing model," wrote a family medicine PA.

In emergency departments where Blumm has worked, intensive care unit NPs have an edge over PAs in terms of preparation, organization, and the tabulation of formulas. On the other hand, some of Blumm's fellow PAs were also emergency medicine technicians or respiratory therapists, who had "2 years of classroom training, on par with that of medical students."

Must these differences in training and education foment conflict between NPs and PAs? "We all bring something different to the table," says Kapu, who also is associate dean for clinical and community partnerships at the Vanderbilt University School of Nursing. "It is important to respect each person's entry point, education, and training."

Differing Personalities and Environments

Numerous PA respondents told Medscape that individual personalities and work environments are more likely to trigger issues with NPs than are differences in training.

"It depends on the team and situation and who the people are, not the letters behind their names," an emergency medicine PA wrote. A surgical PA noted that "group dynamics and work culture differ from place to place," while a third PA agreed that "it's personality dependent, not title-dependent."

No single formula will resolve areas of NP-PA conflict, Orozco says.

"What works in Chicago might not work in rural Colorado or Texas or California, but we do have to come together. The overall focus should be on greater flexibility for PAs and NPs. Patients will fare better."

Joint Research, Publishing Could Help

About a decade ago, Blumm joined with another PA and an NP to form the American College of Clinicians, the first joint PA-NP national professional organization. Although it disbanded after 6 years, owing to low membership, he hopes a similar collaboration will take off in the future.

"I also recommend that PAs and NPs publish articles together, with research as an excellent place to start," he adds.

"PAs and NPs should stand together and be a source of healing for all our patients. Regardless of our titles, our responsibility is to bring healing together."

https://www.medscape.com/viewarticle/988996