Category Archives: Louisiana Stem Cells

What if, in people with blinding retinal disorders, one could simply introduce into the retina healthy photoreceptor cells derived in a dish from stem cells, and restore sight?

Its a tantalizingly straightforward strategy to curing blindness, yet the approach has been met with a number of scientific roadblocks, including introduced cells dying rapidly or failing to integrate with the retina.

A new study, published in Stem Cell Reports, overcomes these challenges and marks significant progress toward a cell-based therapy. The work, led by a team at the University of Pennsylvania School of Veterinary Medicine, in collaboration with researchers at the University of Wisconsin-Madison, Childrens Hospital of Philadelphia, and the National Institutes of Healths National Eye Institute (NEI), introduced precursors of human photoreceptor cells into the retinas of dogs. A cocktail of immunosuppressive drugs enabled the cells to survive in the recipients retinas for months, where they began forming connections with existing retinal cells.

In this study, we wanted to know if we could, one, improve the surgical delivery of these cells to the subretinal space; two, image the cells in vivo; three, improve their survival; and four, see them migrate to the layer of the retina where they should be and start integrating, says William Beltran, a professor of ophthalmology at Penn Vet and senior author on the study. The answer to all those questions was yes.

Beltran and Gustavo Aguirre at Penn Vet have long been interested in addressing retinal blinding disorders and they have had great successes to date at producing corrective gene therapies for conditions with known causative genes. But for many cases of inherited retinal degeneration, a gene has not been identified. In other patients, the disease has progressed so far that no photoreceptor cells remain intact enough for gene therapy. In either scenario, a regenerative medicine approach, in which photoreceptors could be regrown outright, would be extremely valuable.

To develop a cell therapy, Beltrans team joined with groups led by John Wolfe of CHOP and Penn Vet; David Gamm at the University of Wisconsin-Madison; and Kapil Bharti at the NEI, in a consortium supported by the NEIs Audacious Goals Initiative for Regenerative Medicine. The partnership combined Beltrans teams expertise in canine models of retinal degeneration and vast experience in cell-based therapy approaches from the Wolfe, Gamm, and Bharti labs.

Photoreceptor cells, which are made up of rods and cones, constitute a layer of the outer retina critical to initiating the process of vision, whereby the energy of light transforms into an electrical signal. To function properly, they must form a connection, or synapse, with cells of the inner retina to pass along the visual information. Thus, the goal of this cell therapy is to recreate this layer and enable it to integrate with the retinas other cell types in order to relay signals from one layer to the next.

In the current work, the team used stem cellderived precursors of human photoreceptor cells developed in the Gamm lab to serve as the basis of the cell therapy. In collaboration with the Bharti lab, they developed a new surgical approach to inject the cells, which were labeled with fluorescent markers, into the retinas of seven dogs with normal vision and three with a form of inherited retinal degeneration, then used a variety of non-invasive imaging techniques to track the cells over time.

The use of a large animal model that undergoes a naturally occurring form of retinal degeneration and has a human-size eye was instrumental to optimize a safe and efficient surgical procedure to deliver doses of cells that could be used in patients, says Gamm.

The researchers observed that cell uptake was significantly better in the animals with retinal degeneration compared to those with normal retinas.

What we showed was that, if you inject the cells into a normal retina that has its own photoreceptor cells, the retina is pretty much intact and serves as a physical barrier, so the introduced cells dont connect with the second-order neurons in the retina, the bipolar cells, Beltran says. But in three dogs that were at an advanced stage of retinal degeneration, the retinal barrier was more permeable. In that environment, cells had a better ability to start moving into the correct layer of the retina.

Because the transplanted human cells could be interpreted by the dogs immune system as foreign entities, the researchers did what would be done in other tissue transplant procedures: They gave the dogs immunosuppressive drugs. The trio of medications had been tested previously by Oliver Garden, a veterinary immunologist with Penn Vet at the time of the study, who is now dean of Louisiana State University School of Veterinary Medicine.

Indeed, while the injected cell populations declined substantially in dogs that did not receive the immune-suppressing drugs, the cell numbers dipped but then sustained in the dogs that received the cocktail.

Further characterization of the introduced cells revealed evidence of potential synapses. We saw that yes, some are appearing to shake hands with those second-order neurons, Beltran says. There appeared to be contact.

The next stage for this project will be to continue optimizing the therapy, and then test whether there is a functional responsein other words, improved visionin its recipients.

William Beltran is a professor of ophthalmology and director of the Division of Experimental Retinal Therapies at the University of Pennsylvania School of Veterinary Medicine.

Beltrans coauthors on the work were Penn Vets Ana Ripolles-Garcia, Natalia Dolgova, Svetlana Savina, John H. Wolfe, Oliver A. Garden, and Gustavo D. Aguirre; the University of Wisconsin-Madison's M. Joseph Phillips, Allison L. Ludwig, Sara A. Stuedemann, Uchenna Nlebedum, and David M. Gamm; and the National Eye Institutes Arvydas Maminishkis, Juan Amaral, and Kapil Bharti.

This study was supported by the National Institutes of Health (grants EY029890, EY06855, and EY031230), Fighting Blindness Canada, Foundation Fighting Blindness, Research to Prevent Blindness, the Van Sloun Fund for Canine Genetic Research, Retina Research Foundation, Emmett A. Humble Distinguished Directorship of the McPherson Eye Research Institute, the Sanford and Susan Greenberg End Blindness Outstanding Achievement Prize, and the Sandra Lemke Trout Chair in Eye Research.

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Progress toward a stem cellbased therapy for blindness

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The U.S. Supreme Court's June 24 ruling ending federal abortion rights under Roe v. Wade could inspire groups that seek to protect embryos to urge greater restrictions on in vitro fertilization (IVF) and embryonic stem cell research, according to Henry T. (Hank) Greely, director of the Stanford Law School Center for Biomedical Ethics.

Assisted reproductive technologies such as IVF aren't constitutionally protected and neither is preimplantation genetic testing, which screens for certain traits and DNA-caused conditions in embryos that haven't yet been implanted in the uterus, he said in a recent interview prior to the landmark ruling.

The court's ruling doesn't ban these technologies, which assist people seeking to have children, but it is likely to inspire some groups and states to seek to preserve unused embryos or ban embryonic stem cell research, Greely said.

His paper about the potential short- and long-term impacts of the decision is in preprint publication and is expected to be published in the Journal of Law and Biosciences in the coming weeks. In the short term, the technologies that embryo-protection groups might seek to ban or limit might be an alternative for women who can no longer receive an abortion in their home state.

Prenatal testing currently can determine if the fetus has a serious DNA defect that would cause disease or disability; a woman can then decide whether to continue with or terminate the pregnancy. That choice would likely disappear in states that restrict abortions, Greely said.

But a genetic testing technique that is used during in vitro fertilization could be utilized to prevent IVF pregnancies with fetal abnormalities. Preimplantation genetic testing, or PGT, screens out embryos with DNA-causing birth defects before the embryos are transferred to the uterus. The procedure can determine with a high degree of accuracy whether an embryo would develop into a baby who might have one of a large number of conditions. The decision not to transfer an embryo with genes that could cause a disability, condition or trait isn't illegal in the U.S., he said.

In states where abortion is illegal, it's likely there would be an increased interest in using PGT. The embryos are screened while outside the womb and prior to implantation and pregnancy.

"I think some people, some couples will say, well, if we have an embryo for the pregnancy that would have a severe disability as a child, our state wouldn't allow us to abort it. So let's go through preimplantation," he said.

But Greely doesn't think using PGT will skyrocket after the court's abortion decision. The technique requires that prospective parents use IVF, which is unpleasant and risky due to egg harvesting, he said.

IVF is also expensive. Most couples seeking the technique do so due to infertility and the decision isn't made lightly. Anyone with enough money to afford IVF would likely be able to afford to travel to another state for an abortion, he said.

Greely thinks it is unlikely embryo-protection groups would advocate for any kind of legislation that has a negative effect on IVF, however.

"Americans like IVF; almost everybody knows somebody or will know somebody who's either gone through IVF or who's actually the product of IVF. Two percent of the babies born every year in the U.S. with the product of IVF, and particularly the wealthier people are, the more likely they are to have either used IVF or know somebody who uses IVF, and also, the more likely they are to be politically powerful," he said.

There's a certain sort of law Greely thinks might be politically viable: limiting the selection or deselection of an embryo for IVF for a specific reason such as race, gender or disability.

"We've already seen it in abortion state statutes. A lot of abortion laws ban abortion for the purpose of discriminating on race, sex or disability status. And some of them explicitly say Down syndrome status.

"I can imagine the disability community coming together with protection groups to try to pass laws banning using PGT to select against embryos based on race, sex or disability. The important part of that would probably be disability and maybe even with the focus just on Down syndrome, which has a very strong support group and has some political sympathy," he said.

There isn't much political support for eliminating embryos that would have a fatal disease, however, he said.

"There's a more attractive case for protecting embryos that might become people with Down syndrome compared to protecting embryos that might become babies who would die within a year from Tay-Sachs disease," he said.

The court's decision on Roe v. Wade could invigorate efforts to pass new legislation to protect embryos outside the uterus among people who believe embryos are viable far earlier than at the 15 weeks in the Mississippi case that challenged Roe v. Wade. Some groups have claimed that human life starts far earlier and even at fertilization, which would make, in their view, all embryos for IVF "viable" regardless of whether they are implanted in the womb.

In the normal medical standard of care, no more than two embryos should be transferred into a woman's uterus at a time to minimize the chances of multiple pregnancies, Greely noted in his paper.

Most IVF cycles produce more than two eggs. Prospective parents can choose to have the extra embryos frozen for possible later use, donated to other couples, designated for research or destroyed and discarded.

Some legislation advocated by embryo-protection groups could limit or change the practice, he said. With the exception of Louisiana, there are no limitations on destroying embryos that aren't implanted, he said, though some other states have considered the legislation.

"The only limitation that I know of is the Louisiana law where you're not allowed to destroy embryos. So leftover embryos are kept frozen indefinitely in IVF clinics there," he said.

Legislation could lead clinics to build facilities to freeze and store unused embryos in perpetuity, he said, adding that the Louisiana law hasn't caused IVF clinics to close.

Embryo-protection groups might also try to get a law passed that's similar to a 2004 Italian law, which was subsequently limited by a court decision, Greely noted.

"They said you have to transfer for possible implantation every viable embryo you make, which means in Italy they typically only make one or two embryos at a time.

The embryo-protection groups "might try that, but all that would do is make IVF more difficult or expensive, and I don't think there's going to be political support for it. I don't think there'll be enough political support for it for people to adopt it," he said.

Greely noted that there could potentially be a significant change in embryo research as opposed to clinical treatments in an IVF clinic.

"Actually, embryo research in particular has really nothing to do with Roe v. Wade. As a matter of law, Roe v. Wade never protected embryo research, but I think it's connected in terms of the political dynamics after the death of Roe v. Wade," Greely said.

There's a good chance that at some stage, states will pass laws that eliminate human embryo research, in part because it is a huge issue, he said. Embryonic stem cells are taken from embryos created and then not used for pregnancy at IVF clinics.

"Twenty years ago, a number of states banned it; a number of states like California encouraged that research. But research into Type 1 diabetes and other major diseases has been disappointing.

"I think it has been useful, but there have been no miracles from it so far," he said.

The discovery in 2007 of a method to turn regular body cells into cells that can become any cell type in the human body makes the argument for using embryonic stem cells less compelling, he noted in his paper. Called induced pluripotent stem cells or iPSCs, these cells take away some of the urgency about using embryonic stem cells.

But iPSCs aren't exactly like human embryonic stem cells, Greely noted. Researchers would likely argue that human embryos are still required for research on embryonic development that would lead to ways for couples to succeed in having babies.

iPSCs might also play a role in the same types of research, since scientists have been creating "embryo-like things" or "embryo models" that provide more information about human embryonic development, he wrote.

How these laws might affect funding for embryonic research is also unknown.

The federal government has had little appetite for funding embryonic research and has refused to fund research that "destroys, discards, or knowingly subject(s) to risk of injury of death" embryos, Greely noted in his paper.

Yet, the federal government doesn't limit or ban the research itself; its actions have solely been about research it funds. Federal funds can be used for research on cells created from embryos that were destroyed somewhere else, he noted.

At least 11 states, however, have banned (or effectively banned) human embryo research on cells created from destroyed embryos that came from somewhere else, he wrote.

Some states allow such research, including California, Connecticut, Michigan, Montana and New York, Greely noted. California in particular continues to support stem cell research without a ban on the use of embryonic cells. In 2020, the state's voters passed Proposition 14 for $5.5 billion in bonds to advance the research.

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How abortion ruling could affect IVF and embryonic research - The Almanac Online

Introduction

Canine elbow osteoarthritis (OA) is a common sequela from elbow dysplasia.1 Elbow OA is a progressive joint disease characterized by decreased joint range of motion, pain, cartilage destruction, and osteophyte formation.1,2 Treatment is mainly palliative and current strategies often consist of medical management including NSAIDs, analgesics, nutraceuticals, weight control, physical rehabilitation, and changes in activity level.13 Although daily use of NSAIDs may reduce OA pain, these agents have the potential to cause or exacerbate renal, gastrointestinal, and hepatobiliary disorders.4 In addition, it may not be practical for some owners to administer daily medications. Surgery often fails to prevent progression of OA and may not provide superior outcomes to medical management.5,6 Salvage procedures such as elbow replacement have inconsistent outcomes and a high complication rate.1,7,8

Nonsurgical management will likely remain a viable treatment option for dogs with elbow OA; therefore, optimization of current nonsurgical options and development of new innovative nonsurgical treatments are important. The use of intra-articular (IA) injections including platelet-rich plasma, dextrose prolotherapy, autologous protein solution, or stem cells has been reported for OA treatment with mixed results.912 Larger clinical studies are needed to fully understand the effects of these therapies on dogs with OA.

Synovitis precedes development of radiographic OA changes in humans and dogs.2,13,14 It is characterized by marked hyperplasia and permeability of the synovial lining, overexpression of proinflammatory cytokines, infiltration of inflammatory cells, production of degradative enzymes, and synovial neovascularization and proliferation.15 Inflammation sensitizes peripheral neurons in synovial tissue, resulting in joint pain.16 Marked synovitis precedes structural changes in the progression of OA and early intervention targeting joint inflammation, prior to radiographic changes, can delay or prevent chronic arthritic changes.15 Low-dose radiation therapy has direct anti-inflammatory effects on the synovium.17 A small study of 5 dogs with elbow OA concluded that use of single-low-dose radiotherapy may have short-term clinical benefits.18

As synovitis is strongly implicated in OA pathogenesis, surgical and nonsurgical synovectomy (synoviorthesis) have been used to alleviate human synovitis symptoms.19 Another reported method to relieve synovitis is via radiosynoviorthesis (RSO), which involves IA injection of low-energy ionizing radiation to induce apoptosis and ablate inflamed synovial cells.20 Use of this therapy has been reported in humans to treat synovitis in an effort to prevent, delay, or limit arthritic changes.20 Radiosynoviorthesis, primarily involving yttrium-90 (90Y), erbium-169 (169Er), and rhenium-186 (186Re), is an accepted outpatient therapy for treatment of early-stage chronic synovitis in humans with rheumatoid arthritis, psoriatic arthritis, hemophilic arthritis or OA.20,21 The success rate of RSO reported by Zuderman et al was 89% for rheumatoid arthritis and 79% for OA in humans.22 Tin 117m (117mSn) homogeneous colloid was specifically developed to avoid the serious outcomes following treatment with high-energy beta emitters.23 Tin 117m colloid is a non-beta emitter with lower energy from which the conversion electrons have a therapeutic distance of activity of only 300 microns (0.3 mm).

Despite its many advantages, RSO is seldom performed in veterinary medicine, with limited reports including use of 177lutetium-labeled zirconia in dogs and 117mSn homogeneous colloid in rats.2426 In a recent prospective safety study of 5 dogs, blood, urine, feces, and organ scintigraphy counts showed that >99% of 117mSn activity was retained in the elbow joint for approximately 67 weeks.23 There were no adverse effects, and post-mortem evaluation revealed no joint damage. These findings, combined with the potential for protracted clinical improvement after a single IA injection, justify further evaluation of 117mSn for the management of canine OA. The authors designed the current study to assess the value of IA 117mSn for pain management in dogs with naturally occurring elbow OA. Specifically, the authors aimed to quantify changes in peak vertical force (PVF) from force plate gait analysis as the primary outcome measure and canine brief pain inventory (CBPI) scores and elbow goniometry as secondary outcome measures, at multiple time-points for one year after a single unilateral IA injection of 117mSn in dogs with grade 1 or 2 elbow OA. By limiting the study to unilateral elbow injection, the opposite leg is a source of comparison data. The hypothesis was that IA 117mSn-colloid treatment is associated with clinically relevant beneficial effects in dogs with elbow OA.

The study was designed as a long-term longitudinal and prospective study using serial measurements in dogs. The study protocol was approved by the Institutional Animal Care and Use Committee and informed client consent was obtained prior to study enrollment.

A convenience sample of 23 dogs was used in this study. No sample size calculation was performed. Dogs were eligible if they were, 8kg, at least 1 year of age, had a visible forelimb lameness or pain localizable to one or both elbows, had radiographic evidence of grade 1 or 2 OA in one or both elbows based on international elbow working group (IEWG) classification,27 had no clinically detectable abnormalities including pain in any other joint in the forelimbs, had no comorbid condition likely to preclude a 1-year survival, and had no surgical procedure on any leg in the past 4 months or received any joint injections previously. Elbow OA grading was performed by a single board-certified radiologist. All images were calibrated, and osteophyte size was prioritized over trabecular pattern. Dogs with orthopedic disease affecting either hind limb were considered eligible as long as there was no visible lameness present in any of the hind limbs. Dogs being treated with nutraceuticals and/or medications such as NSAIDs were eligible provided they still had lameness or pain localizable to one or both elbow/s.

Initially, information was collected from dog owners including signalment, duration of OA, and type and duration of current medications/supplements. Owners also completed the CBPI.28,29 After meeting initial evaluation requirements, all dogs received a baseline assessment within 30 days of treatment prior to study participation. Dogs had a physical examination, and the following variables were obtained: CBC, serum biochemistry, urinalysis (UA), bilateral elbow radiographs, bilateral elbow goniometry and PVF using force plate gait analysis. These parameters were also collected post-treatment at 1, 3, 6, 9, and 12 months. Bilateral elbow radiographs were performed at the 12-month follow-up exam. Treatment included a unilateral IA injection of 117mSn in the elbow that was determined to be the source of observable lameness or was more painful when observable lameness was not noted. Dogs were randomly assigned to one of the three 117mSn dose groups (normalized based on body surface area, Supplementary Table 1): low dose (LD): 1.0 mCi (millicuries) or 37 MBq (MegaBequerel), medium dose (MD): 1.75mCi or 64.75 MBq and high dose (HD): 2.5mCi or 92.5 MBq, using a computer-generated randomized table. Observers and owners were masked to the dose group except the radiologist who injected the colloid.

Both sites used the same model force-plate (OR6-WP-1000, Advanced Medical Technology Inc, Newton, MA) and commercially available force-plate analysis software. Data logging (100Hz, Acquire version 7.3, Sharon Software Inc, Dewitt, MI) was triggered by a force of 5N on the force plate. Five successful trials at a velocity of 1.52.5m/sec and acceleration of 0.9 to 0.9m/sec2 were recorded for each leg. Dogs were acclimated and trained to walk across the force plate during the pretreatment gait trial. Trained handlers walked the dogs for all testing. PVF (N/kg) was recorded and normalized to body weight and the mean value of five trials was used for statistical analyses. Body weight distribution % (BW-D%) between the forelimbs was calculated according to the formula: BW-D% = PVFT/(PVFUT + PVFT) 100%, where PVFT = mean PVF of the treated leg, and PVFUT = mean PVF of the contralateral untreated leg.

A positive response was defined as 5% increase in mean PVF at a single time point in the treated leg2934 at months 1, 3, 6, 9, and/or 12 compared with baseline (0 month) for each individual dog evaluated on the force plate.

Owners completed the CBPI28,35 scores at initial evaluation and then monthly from 1 through 12 months except for the 2nd month post treatment. The same individual was required to complete the survey each time. Owners did not have access to their previous scores at each follow-up visit.

A single boarded surgeon from each site performed a physical/orthopedic examination. Elbow goniometry was performed using a standard two-arm plastic goniometer as previously described.36

Dogs were anesthetized, positioned in dorsal recumbency, and the medial aspect of the elbow to be injected was aseptically prepped. The homogeneous 117mSn-colloid (Synovetin OA, Exubrion Therapeutics, Buford, GA) was injected into the joint as previously described.23 After completion of the injection, dogs were recovered from anesthesia and discharged the following morning. Instructions for care and handling with regards to the radioisotope were provided to the owners. All disposables coming in contact with 117Sn were disposed of following all State Regulatory Commission guidelines. Tin 117m is a non-beta emitter in which radiation burns do not occur. The low-energy characteristics of the therapeutic conversion electrons are very different from the higher energy beta emitters (90Y, 169Er, 186Re) commonly used in human RSO.20 As mentioned, elbow injection doses of Tin 117m were based on a chart based on body surface area (Supplementary Table 1) to allow clinicians to adhere to the ALARA (as low as reasonably achievable) principle. Previous studies in both laboratory rats and dogs in which histologic sections were obtained have shown that even with higher doses of homogeneous Tin 117m colloid, beta burns did not occur.23,25 Standard industry precautions were taken when handling homogeneous tin colloid as with any unsealed radiation source as prescribed by the Nuclear Regulatory Commission.

Data analyses were performed using JMP Pro 15.0 (SAS Institute Inc., Cary, NC). All continuous parameters were presented as mean SD and assessed with a repeated measure ANOVA with a mixed effect model was used with time as the fixed effect and each dog as the random effects with the variance compounds covariance structure within each dose group and within treated or untreated elbow. Kenward-Roger approximation was used to determine the degrees of freedom in the model. A contrast hypothesis was performed at each time point against baseline. Assumptions of these models (linearity, normality of residuals, and homoscedasticity of residuals) and influential data points were assessed by examining standardized residual and quantile plots, and the normality of residual was confirmed with the ShapiroWilk test. Ordinal subjective variables at each time point were presented as median (range). Due to small sample size, the data was combined and compared with baseline and untreated elbow using a Wilcoxon signed-rank test. The outcomes of positive response among 3 groups were evaluated with Fishers exact test. Significance was set at P <0.05.

Demographic characteristics of the study population are shown in Table 1. One dog in the LD-group received a much lower dose, about 40% lower than the prescribed dose of 117mSn-colloid, so that dog was excluded from the study. Another dog (female intact) from the HD-group was excluded because the owner reported the dog had rough play with two other large housemate dogs and was very sore in the front limbs especially on the treated limb at the one-month recheck and the same dog was bred later during the three-month recheck. The exclusion of these 2 dogs resulted in a total of 21 dogs in our study population. Duration of arthritis and type of medical management are shown in Supplementary Table 2. All dogs had visible unilateral lameness except 3 dogs (2 had bilateral grade 1 OA and 3rd one had bilateral grade 2 OA). No adverse effects were observed on physical/orthopedic examination or reported by owners, and no clinically significant laboratory findings were noted related to the IA injection of 117mSn at regularly scheduled re-evaluations.

Table 1 Demographic Characteristics for 21 Dogs with Naturally Occurring Elbow OA Based on 117mSn Dose Group

Both PSS and PIS significantly improved at all time-points except for the 10-month (PSS) and the 10- and 11-month (PIS) (Table 2) scores compared to baseline. No significant differences were noted in QoL scores.

Table 2 Canine Brief Pain Inventory (CBPI) Scores for 21 Dogs with Elbow OA at Pretreatment and at Each Time-Point Post Treatment. Values are Presented as Median (Range)

In the HD group for elbow extension there was a trend in improvement (approaching significance) in the treated leg at 6, and 9 months, respectively, compared to baseline (Table 3). Elbow extension also increased in the untreated leg at 9-month in the HD group and at 6-month in the MD group. In 1 dog from the MD-group, baseline force-plate data for the treated leg was missing and this dog died secondary to GDV after its 3-month evaluation. In 1 dog from the LD-group, five successful repeatable trials during force-plate data collection could not be obtained at the baseline evaluation. These 2 dogs were not included in the force plate data analysis. This resulted in a total of 19 dogs for force plate data analysis. The mean peak vertical force improved in the treated leg in the HD group by 5.4%, 12.0%, 10.1% and 12.3% at 1, 3, 6, and 9 months, respectively, compared to baseline. This increase was statistically significant at the 3- and 9-month time points. The mean PVF was significantly lower (by 9%) in the untreated leg at the12-month time point compared to baseline (Table 4). In the HD group, the mean BW-D% for the treated leg improved compared to baseline and this improvement approached significance at 3- and 9-month time points (Table 4).

Table 3 Evolution of Elbow Extension, Flexion and Range of Motion from Baseline to Month-12 in Treated and Untreated Elbows in 21 Dogs with Elbow OA for All Three 117mSn Dose Groups. The Means of Three Values for Elbow Extension and Flexion Were Recorded Bilaterally. The Data is Summarized as Mean Standard Deviation (SD)

Table 4 Evolution of PVF and BW-D% from Baseline to Month-12 in Nineteen Dogs with Elbow OA for All Three 117Sn Dose Groups. The Data is Summarized as Mean Standard Deviation (SD)

Based on the criteria mentioned above for a positive response, 17 of 19 dogs (89.5%) had a positive response (Table 5). There was no significant difference between the three dose groups for positive responses.

Table 5 Dog Number, 117mSn Dose Group, and Treatment Outcome in 19 Dogs Undergoing Force-Plate Analysis

The radiographic OA scores significantly increased both in treated elbows and untreated elbows at 12-month recheck compared to pretreatment scores (Table 6). There was no significant difference in OA score change from baseline between treated and untreated elbows at the time of the 12-month evaluation for all dose groups (Table 6).

Table 6 Radiographic OA Scores for Treated and Untreated Elbows for Study Dogs with Elbow OA at Pretreatment and at 12-Month Recheck. The 12-Month Radiographs Were Available for 18 Dogs

The ability to use RSO as a localized treatment with lasting results and no systemic adverse effects could make it a valuable therapeutic option for veterinary patients with OA. In our study, the use of IA 117mSn in dogs with elbow OA resulted in clinically relevant beneficial effects lasting for up to 9 months-based on force plate data with statistically significant improvement at 3 and 9 months post-injection and trending towards improvement (approaching significance) at 6 months post injection. The beneficial effects lasted for 1-year post injection based on CBPI data. This duration of RSO response is similar to what has been reported in humans where the response can last for a few months to several years.17

Radiosynoviorthesis (RSO) has been successfully used in human medicine for more than 60 years in many countries, particularly in Europe where it was first described and where its use conforms to guidelines published by the European Association of Nuclear Medicine.22,3739 RSO has been an accepted outpatient therapy for treatment of early stage chronic synovitis in rheumatoid arthritis, psoriatic arthritis, hemophilic arthritis and OA patients for decades.3941 Current standards in human clinical practice generally take a conservative approach by recommending initial treatment with front-line therapies including systemic NSAIDs, glucocorticoids, and local joint therapies such as corticosteroid and hyaluronic acid injections prior to RSO.37 However, in patients that either respond poorly or have adverse side effects following these traditional therapies, RSO is a useful option that should now be considered in veterinary medicine. Traditional veterinary arthritis therapies when successful are oftentimes less costly than RSO using homogeneous tin colloid (117mSn). It can become costly when these initial traditional therapies cannot successfully manage elbow osteoarthritis and alternatives such as stem cell or platelet-rich plasma therapies are considered. The treatment in our study was evaluated specifically to manage canine arthritic elbows because oftentimes traditional veterinary arthritis therapies are not successful in dogs with elbow OA.1,2,4,912

The patients in this study were treated with homogeneous tin colloid (117mSn) containing microparticles (diameter 1.5 to 20.0 microns) of the radioisotope tin 117m (117mSn). These microparticles when injected into a joint are engulfed by intra-articular macrophages, which are killed by apoptosis due to the tin 117m conversion electron (CE) radiation.41 Admittedly, we had limited short-term evaluation for any adverse effects related to 117mSn injection. The absence of any adverse effects in the present study and in a previous experimental study, is most likely due to unique characteristics of 117mSn.23,25,26 Tin 117m emits abundant conversion electrons, low-energy particles with a short, non-diminishing penetration range of approximately 300m in tissue. Other radionuclides that emit beta particles result in variable tissue penetration and can result in damaging irradiation of adjacent non-target tissues.20 117mSn has a life of nearly 14 days, providing an ideal duration of effect spanning several lives to achieve therapeutic results and to enable short-term stability during storage and handling. Studies in rats and colony bred dogs have confirmed the safety of structures within the joint (cartilage, bone) and adnexal structures following IA injection with homogeneous tin colloid (117mSn).23,26 In addition to conversion electrons, 117mSn emits radiation, which is non-therapeutic but readily detectable by scintigraphy. In humans, the risk of infection after IA RSO is very small (1:35,000) and septic arthritis is uncommon.20 Similarly, none of the dogs in our study developed any infection related to 117mSn IA injection. Overall, in humans RSO has very low rate of adverse effects.41 Joint flare ie more pain and joint effusion due to intensification of inflammation (radiosynovitis) within 24 weeks after RSO is the most common adverse effect.20 This may be considered a natural course of the treatment due to rapid and extensive synovial necrosis when using higher energy beta-emitters. In humans, the joint flare from radiosynovitis is the main reason to consider co-injection of steroids. Routinely steroids are co-injected into large joints (shoulder, knee, and hip) because radiosynovitis is common in these joints.20 Even though canine joints are much smaller than human joint but this should be taken into consideration in dogs also in future studies involving RSO of these large joints.

Both PSS and PIS significantly improved at all time points except for PSS at 10 months and for PIS at 10 and 11 months which were not statistically significant compared to baseline, but these scores were still improved compared with baseline. A caregiver placebo effect may have played a role in improvement of CBPI as this effect has been shown to occur approximately 57% of the time for pet owners evaluating their dogs with lameness from osteoarthritis.34 In addition to this a lack to control group makes this measure less ideal compared to force plate gait analysis to determine outcome. However, it would be implausible to expect a placebo effect to persist for the 1-year duration of the study. In addition, the CBPI has been shown to allow reliable quantification of the owners assessment of the severity and impact of clinically relevant chronic pain-related behaviors with the dog in its normal environment.28,29 The QoL item (poor, fair, good, very good, excellent) is a stand-alone item and is used initially as a criterion validity assessment in the validation of the severity and interference scores.35 It takes very large changes in pain scores to elicit a change in the QoL category, which could be a potential reason why we did not see any significant improvement in this category.35 In future studies, QoL as an outcome measure should be better approached with a global assessment of change over time (ie, much worse, worse, same, better, much better).

Goniometry is an economic and simple measurement of joint angles used to objectively assess joint function.42 Mean elbow extension improved by 7 degrees at 6-month and by 10 degrees at 9-month follow-up time point in the treated elbow in the HD-group. However, mean elbow extension also increased in the untreated leg by 7 degrees at 9 months in the HD group and by 8 degrees at 6 months in the MD group. Therefore, our results indicate that there was no significant difference in this outcome measure between treated and untreated elbows.

The force-plate gait analysis is an established objective gold standard for quantification of leg function and pain in dogs with appendicular joint OA.29 It is considered to provide an accurate and unbiased assessment. However, without a placebo treatment group, we are unable to know if other external factors influenced the dogs in a way that may have resulted in improved leg function. A caregiver placebo effect as mentioned above does not exist for appropriately acquired force plate gait analysis. In addition, in a randomized, blinded, placebo-controlled crossover study where every dog received tramadol or carprofen or placebo during the study period, the authors found no change in PVF over a 10-day period in the placebo group.33 Additionally, in our study the untreated opposite leg served as a source of comparison data. The improvement noted in PVF in our study is larger than what has been previously reported.29,32,33

One of the limitations of this pilot study was a small sample size. Another limitation was the lack of a placebo or control group; however, OA is a progressive disease. The lack of any therapy for osteoarthritis would not have been acceptable for an ethical committee for running a control group for up to 1 year. While using client-owned dogs is a strength of the study, it is also a limitation. Studies of naturally occurring OA in dogs are associated with potential confounding factors, such as the potential for owner errors in study compliance and variations in the home environment. However, this is the environment in which the agent will be used and assessed by veterinarians and owners. Dogs were allowed to continue previous medical management (NSAIDs or other analgesics) during the study. It is possible that use of these medications could have biased our results. Ideally, dogs would have all been taken off of medical management and undergone a washout period before enrollment. The authors elected to allow dogs to be continued on any previous medications for multiple reasons: to avoid increasing pain should the IA injection fail to control pain, to provide pain control in the untreated leg, to allow the study to be clinically relevant, and for the study to be reflective of the general canine population with OA. Future studies might include more stringent exclusion criteria. We focused on the elbow joint for consistency; it would be interesting to know the effects of this treatment on other arthritic joints.

The safe use of any radioisotope requires documented training by veterinarians and support staff. There is a recommended licensing, treatment and post-treatment caretaker instruction process published by the US Nuclear Regulatory Commission for the safe use of 117mSn in the US.43 Unlike I-131 and Tc 99m radiation quarantine is not indicated for 117mSn as it is not excreted in any appreciable amount. Instead, 117mSn is retained within the joint and is eventually cleared by the lymphatics to the liver as microparticles of inert (nonradioactive) tin.23,25,26 However, there are gamma emissions that must be measured at 1 meter post treatment to determine the amount of interaction with a patient by household members. All household members are to monitor and follow their interactions within 3 feet (from treated joint(s) to center of torso) prescribed by written instructions for 2 weeks. For dogs in which there is an extended close association (sleeping in the same bed, sitting beneath an occupied office chair or in ones lap > 4 hrs daily) there could be a longer period of abstaining from these behaviors for up to 46 weeks following 117mSn radiosynoviorthesis.43,44 All patients can return to normal activities and interactions with anyone beyond 3 feet immediately post treatment.43,44

Clinical response to RSO is usually expected to have some lag phase that can last from weeks to months.20 In humans, the effect in the knee is seen as soon as 4 weeks.20 In the current study, improvement was noted in dogs at 1-month evaluation, similar to humans. In humans, the full therapeutic impact of RSO can take 46 months and duration of response depends on already existing joint damage.20 Similarly in our study full therapeutic effect as shown by significantly improved objective measurements such as PVF (and improvement in BW-D% approaching significance) was achieved at 3 months post treatment. Advanced-stage OA and pre-existing joint damage are negative outcome predictors of RSO in humans.45 Thus, the best responders would be patients with limited joint damage or the patients with large amounts of inflammation/effusion rather than advanced degenerative changes. Our study population included dogs with mild to moderate (grade 1 to 2) degree of OA and, as in human studies, a good clinical response was noted. Future studies in dogs with advanced OA are indicated to evaluate the effects of IA 117mSn in those cases.

In conclusion, IA injection of 117mSn improved CBPI scores and increased weight-bearing associated with elbow OA, providing preliminary evidence that 17mSn is beneficial in the management of elbow OA in dogs. This localized therapy with protracted results can be considered as an adjunct to other nonsurgical or surgical treatments or as a stand-alone therapy for elbow OA and might be useful for patients that cannot tolerate traditional OA medications such as NSAIDs. Although 17mSn appeared to be effective for the treatment of elbow OA, this pilot study has inherent limitations; therefore, future studies with larger numbers of dogs and with placebo group are needed.

The study protocol was approved by Institutional Animal Care and Use Committee (Protocol #16-008) and the Radiation Safety Office of the Louisiana State University (site A) and Medical Director Board and Radiation Safety Committee of Gulf Coast Veterinary Specialists (site B). All dogs were client-owned and written consent was obtained before study enrollment. This study adhered to veterinary care best practice guidelines.

The authors thank the LSU and GCVS force-plate teams and Sarah Keeton, PhD for her invaluable assistance in managing all data records.

Dr Andrews reports grants from Exubrion Therapeutics, during the conduct of the study. Dr Lattimer reports grants from Exubrion Therapeutics, during the conduct of the study. Dr Lattimer, however, had a career long interest in therapeutics of this type and has participated in privately and publicly funded work that employs radiopharmaceuticals and devices. None of this work has been done in the last several years except that associated with the parent project to this work. The study was funded by Exubrion Therapeutics, Buford, GA, USA. Drs. Aulakh, Hudson, and Fabiani are advisory board members for Exubrion Therapeutics and receive a small honorarium for consultation. All authors declare no other conflicts of interest related to this report.

1. Krotscheck U, Bottcher P. Surgical diseases of the elbow. In: Veterinary Surgery: Small Animal. Vol. 1. 2nd ed. St. Louis, MS: Elsevier; 2018.

2. Coppieters E, Gielen I, Verhoeven G, et al. Erosion of the medial compartment of the canine elbow: occurrence, diagnosis and currently available treatment options. Vet Comp Orthop Traumatol. 2015;28:918. doi:10.3415/VCOT-13-12-0147

3. Sanderson RO, Beata C, Flipo RM, et al. Systematic review of the management of canine osteoarthritis. Vet Rec. 2009;164:418424. doi:10.1136/vr.164.14.418

4. Innes JF, Clayton J, Lascelles BD. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec. 2010;166:226230. doi:10.1136/vr.c97

5. Burton NJ, Owen MR, Kirk LS, et al. Conservative versus arthroscopic management for medial coronoid process disease in dogs: a prospective gait evaluation. Vet Surg. 2011;40:972980. doi:10.1111/j.1532-950X.2011.00900.x

6. Dempsey LM, Maddox TW, Comerford EJ, et al. A comparison of owner-assessed long-term outcome of arthroscopic intervention versus conservative managemento f dogs with medial coronoid process disease. Vet Comp Orthop Traumatol. 2019;32:19. doi:10.1055/s-0038-1676293

7. Dejardin L, Guillou R. Total elbow replacement in dogs. In: Johnston S, Tobias K, editors. Veterinary Surgery: Small Animal. Vol. 1. 2nd ed. St. Louis, MS: Elsevier;2018:885896

8. Conzemius MG, Aper RL, Corti LB. Short-term outcome after total elbow arthroplasty in dogs with severe, naturally occurring osteoarthritis. Vet Surg. 2003;32:545552. doi:10.1111/j.1532-950X.2003.00545.x

9. Franklin SP, Cook JL. Prospective trial of autologous conditioned plasma versus hyaluronan plus corticosteroid for elbow osteoarthritis in dogs. Can Vet J. 2013;54:881884.

10. Guercio A, Di Marco P, Casella S, et al. Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int. 2012;36:189194. doi:10.1042/CBI20110304

11. Wanstrath AW, Hettlich BF, Su L, et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in a canine population. Vet Surg. 2016;45:764774. doi:10.1111/vsu.12512

12. Sherwood JM, Roush JK, Armbrust LJ, et al. Prospective evaluation of intra-articular dextrose prolotherapy for treatment of osteoarthritis in dogs. J Am Anim Hosp Assoc. 2017;53:135142. doi:10.5326/JAAHA-MS-6508

13. Quinn R, Preston C. Arthroscopic assessment of osteochondrosis of the medial humeral condyle treated with debridement and sliding humeral osteotomy. Vet Surg. 2014;43:814818. doi:10.1111/j.1532-950X.2014.12260.x

14. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625635. doi:10.1038/nrrheum.2010.159

15. de Lange-brokaar BJ, Ioan-Facsinay A, van Osch GJ, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage. 2012;20:14841499. doi:10.1016/j.joca.2012.08.027

16. McDougall JJ. Arthritis and pain. Neurogenic origin of joint pain. Arthritis Res Ther. 2006;8:220. doi:10.1186/ar2069

17. Kresnik E, Mikosch P, Gallowitsch HJ, et al. Clinical outcome of radiosynoviorthesis: a meta-analysis including 2190 treated joints. Nucl Med Commun. 2002;23:683688. doi:10.1097/00006231-200207000-00013

18. Kapatkin AS, Nordquist B, Garcia TC, et al. Effect of single dose radiation therapy on weight-bearing lameness in dogs with elbow osteoarthritis. Vet Comp Orthop Traumatol. 2016;29:338343. doi:10.3415/VCOT-15-11-0183

19. Ishii K, Inaba Y, Mochida Y, et al. Good long-term outcome of synovectomy in advanced stages of the rheumatoid elbow. Acta Orthop. 2012;83:374378. doi:10.3109/17453674.2012.702391

20. Chojnowski MM, Felis-Giemza A, Kobylecka M. Radionuclide synovectomy - essentials for rheumatologists. Reumatologia. 2016;3:108116. doi:10.5114/reum.2016.61210

21. Szentesi M, Nagy Z, Gher P, et al. A prospective observational study on the long-term results of. Eur J Nucl Med Mol Imaging. 2019;46:16331641. doi:10.1007/s00259-019-04350-3

22. Zuderman L, Liepe K, Zphel K, et al. Radiosynoviorthesis (RSO): influencing factors and therapy monitoring. Ann Nucl Med. 2008;22:735741. doi:10.1007/s12149-008-0167-7

23. Lattimer JC, Selting KA, Lunceford JM, et al. Intraarticular injection of a Tin-117 m radiosynoviorthesis agent in normal canine elbows causes no adverse effects. Vet Radiol Ultrasound. 2019;60:567574. doi:10.1111/vru.12757

24. Polyak A, Nagy LN, Drotar E, et al. Lu-177-labeled zirconia particles for radiation synovectomy. Cancer Biother Radiopharm. 2015;30:433438. doi:10.1089/cbr.2015.1881

25. Doerr C, Stevenson NR, Gonzales G. Homogeneous Sn-117m col- loid radiosynovectomy results in rat models of joint disease [abstract]. J Nucl Med. 2015;1243.

26. Doerr C, Bendele A, Simon J. Validation of the use of homoge- neous Sn-117m colloid radiosynoviorthesis in a GLP osteoarthritis rat model [abstract]. J Nucl Med. 2016;323.

27. Ondreka N, Tellhelm B. Explanation of grading according to IEWG and discussion of cases, Proceedings, 31th annual meeting of the International Elbow Working Group (IEWG), Verona, Italy; 2017. Available from: http://www.vet-iewg.org/wp-content/uploads/2017/03/IEWG-proceedings2016.pdf. Accessed May 5, 2021.

28. Brown DC, Boston RC, Coyne JC, et al. Ability of the canine brief pain inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc. 2008;233:12781283. doi:10.2460/javma.233.8.1278

29. Brown DC, Boston RC, Farrar JT. Comparison of force plate gait analysis and owner assessment of pain using the Canine Brief Pain Inventory in dogs with osteoarthritis. J Vet Intern Med. 2013;27:2230. doi:10.1111/jvim.12004

30. Roush JK, Cross AR, Renberg WC, et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. J Am Vet Med Assoc. 2010;236:6773. doi:10.2460/javma.236.1.67

31. Mirza MH, Bommala P, Richbourg HA, Rademacher N, Kearney MT, Lopez MJ. Gait changes vary among horses with naturally occurring osteoarthritis following intra-articular administration of autologous platelet-rich plasma. Front Veterin Sci. 2016;3. doi:10.3389/fvets.2016.00029

32. Vijarnsorn M, Kwananocha I, Kashemsant N, et al. The effectiveness of marine based fatty acid compound (PCSO-524) and firocoxib in the treatment of canine osteoarthritis. BMC Vet Res. 2019;15:349. doi:10.1186/s12917-019-2110-7

33. Budsberg SC, Torres BT, Kleine SA, et al. Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. J Am Vet Med Assoc. 2018;252:427432. doi:10.2460/javma.252.4.427

34. Conzemius MG, Evans RB. Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc. 2012;241:13141319. doi:10.2460/javma.241.10.1314

35. Brown DC. The canine brief pain inventory; 2021. Available from: http://www.caninebpi.com. Accessed May 5, 2021.

36. Jaegger G, Marcellin-Little DJ, Levine D. Reliability of goniometry in labrador retrievers. Am J Vet Res. 2002;63:979986. doi:10.2460/ajvr.2002.63.979

37. Kampen WU, Voth M, Pinkert J, et al. Therapeutic status of radiosynoviorthesis of the knee with yttrium [90Y] colloid in rheumatoid arthritis and related indications. Rheumatology (Oxford). 2007;46:1624. doi:10.1093/rheumatology/kel352

38. Karavida N, Notopoulos A. Radiation Synovectomy: an effective alternative treatment for inflamed small joints. Hippokratia. 2010;14:2227.

39. Klett R, Lange U, Haas H, et al. Radiosynoviorthesis of medium-sized joints with rhenium-186-sulphide colloid: a review of the literature. Rheumatology (Oxford). 2007;46:15311537. doi:10.1093/rheumatology/kem155

40. Schneider P, Farahati J, Reiners C. Radiosynovectomy in rheumatology, orthopedics, and hemophilia. J Nucl Med. 2005;46(Suppl 1):48S54S.

41. Knut L. Radiosynovectomy in the therapeutic management of arthritis. World J Nucl Med. 2015;14:1015. doi:10.4103/1450-1147.150509

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43. Procedure for use of Synovetin OA [Note: licensee to modify to match specific facility operations]; 2021. Available from: https://www.nrc.gov/docs/ML2028/ML20282A514.pdf. Accessed May 5, 2021.

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Clinical evaluation of intra-articular injection of Tin-117m | VMRR - Dove Medical Press

AVIATIONEthiopian investigators blame March 2019 crash on Boeing 737 Max design flaws

Ethiopian investigators have concluded that the March 2019 crash of an Ethiopian Airlines flight was caused by design flaws in the Boeing 737 Max plane and not by the performance of the airline or its pilots, adding to the scrutiny of the jet model that has been involved in two recent deadly crashes. An interim report released Monday by the Ethiopian Aircraft Accident Investigation Bureau comes almost exactly a year after Ethiopian Airlines Flight 302 went down shortly after departing Addis Ababa, killing all 157 people on board. The crash occurred five months after a similar Max owned by Lion Air of Indonesia crashed minutes after takeoff, killing 189 people. Although several factors have been cited in the two crashes, malfunctions related to automated software known as MCAS were listed as key in both accidents. A Boeing spokesman said Monday that the company continued to extend our heartfelt sympathies to the families and loved ones of Ethiopian Airlines Flight 302. The Indonesian report cited a number of factors, including aircraft design, the flight crews response and a lack documentation on the planes flight and maintenance history. In Ethiopias case, investigators found that the aircraft had a valid certificate of airworthiness, had no known technical problems before departure, and had weight and balance within the operating limits. But they said faulty sensor readings and automatic commands that did not appear on the flight crew operation manual had left the crew unable to control the plane, resulting in the fatal crash. The report also said Boeings reliance on a single sensor for the 737 Max made it vulnerable to undesired activation. NEW YORK TIMES

The worlds wealthiest family moved $48 billion of Walmart Inc. stock to a different holding company in an action that may signal future share sales and bolster their philanthropy. Walton Enterprises LLC, the main investment entity of the retailers founding clan, transferred about 15 percent of Walmarts outstanding shares to the Walton Family Holdings Trust, according to regulatory filings last week. The shift of 415 million shares represented about 29 percent of the shares held by Walton Enterprise. This entity now owns about 1 billion shares. BLOOMBERG NEWS

Facebook Inc. named two new directors, appointing Tracey Travis, chief financial officer of Este Lauder Cos., and longtime McKinsey & Co. executive Nancy Killefer at a time when the boards role at the social media company is under intense scrutiny. The addition of the two women, announced in a statement Monday, makes Facebooks board 40 percent female. The directors are joining the technology giant at a time of turmoil, as regulators and lawmakers question whether the company has monopoly powers and whether its advertising business relies too much on users personal data. BLOOMBERG NEWS

Apple Inc.s iPhone shipments plunged more than 60 percent last month, according to official Chinese data, as the coronavirus forced the technology giant to close stores in the worlds largest smartphone market. Shipments dropped to about 494,600 units from year-earlier levels, according to Bloomberg calculations based on monthly data from the China Academy of Information and Communications Technology, a government think tank. Chinas February overall mobile phone shipments slid 56 percent year-on-year to 6.4 million units, said CAICT. Apple has been reopening its retail stores in China, trying to rebound from a sales hit tied to the coronavirus. Towards the end of last month, 29 of 42 stores in the country had resumed operations. BLOOMBERG NEWS

Aon agreed to buy Willis Towers Watson in an almost $30 billion transaction that combines the worlds second- and third-biggest insurance brokerages. The all-stock deal, the largest ever for the industry, comes almost exactly a year after previous talks between the two companies broke down. Aon chief executive Greg Case and chief financial officer Christa Davies will lead the combined company, according to a statement Monday. Brokerages, which help connect businesses looking for coverage with insurers, have been aggressively merging to diversify, boost commissions, and serve customers who increasingly want to deal with fewer intermediaries. Marsh & McLennan Cos.. the largest broker, bought Jardine Lloyd Thompson Group last year for $5.7 billion. Willis Towers was itself formed in 2016 in an $8.9 billion merger. BLOOMBERG NEWS

A Stanford University professor and stem cell pioneer whose first job in science paid $25 a month is poised to receive a $191 million windfall from the sale of the immunotherapy biotech firm he cofounded. Irv Weissman, 80, owns 4.2 percent of Forty Seven, which Gilead Sciences agreed to buy for about $4.9 billion, a remarkable amount considering the companys market value was less than $250 million just five months ago. Forty Seven is named for a molecule found on healthy and cancerous cells that emits a dont eat me signal that allows cells to go undetected by the immune system. Working in their Stanford lab, Weissman, fellow founder Ravindra Majeti, and Siddhartha Jaiswal identified the role of CD47 proteins in the progression of cancer stem cells into a more malignant form. BLOOMBERG NEWS

US natural gas terminal developer Tellurian Inc. has cut roughly 40 percent of its workforce in a massive restructuring effort aimed at slashing costs and rescuing a struggling, $29 billion export project. The Houston-based company founded by shale gas pioneer Charif Souki laid off as many as 70 workers, according to people familiar with the situation. The company could also put off a final decision on whether to build the Driftwood liquefied natural gas export terminal in Louisiana by 12 to 18 months, said one of the people, who asked to not be identified because the information isnt yet public. BLOOMBERG NEWS

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Target to limit purchases of hand sanitizer, disinfecting wipes - The Boston Globe

It is well understood that eating a healthy, balanced diet is essential to living a long life, with certain foods offering protection against life-threatening health complications. With the spotlight placed firmly on what foods you should embrace and avoid, less attention has been devoted to the frequency of eating and its impact on longevity.

Pearson continues: It's after this period of time that processes such as autophagy and stem cell generation are triggered.

Autophagy is the body's way of cleaning out damaged cells, in order to regenerate newer, healthier cells, according to Priya Khorana, PhD, in nutrition education from Columbia University.

According to Pearson, profound regenerative changes have been shown with periodic water-only fasting but consuming nothing but water for days on end can be challenging for many.

To circumvent this challenge, professor Valter Longo, who has spearheaded much of the research in the field of fasting and longevity, developed the concept of Fasting Mimicking Diets (FMDs).

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Fast Mimicking Diets mimics fasting by tricking your body into a fasted state, while eating specially designed plant-based mini meals, explains Pearson.

FMDs have been shown to promote multi-system regeneration, enhanced cognitive performance, and health span.

Clinical studies on three, five day FMD cycles, spread over three months, show a spike in circulating stem cells that lead to delayed ageing by promoting regeneration in multiple systems.

Body weight, BMI, total body fat, trunk fat, waist circumference, systolic and diastolic blood pressure, cholesterol, insulinlike growth factor 1 (IGF1) and C-Reactive Protein (a marker of inflammation) were significantly reduced, particularly in participants at risk for diseases.

Curiously, scientists from the University of Wisconsin-Madison, and the Pennington Biomedical Research Center, Baton Rouge, Louisiana, reported that health and longevity improved with increased fasting time, regardless of what the mice ate or how many calories they consumed.

According to the study's lead author, Rafael de Cabo, Ph.D., chief of the Translational Gerontology Branch of the NIA Intramural Research Program, scientists have studied the beneficial effects of caloric restriction for more than a century, but the impact of increased fasting times has recently come under closer scrutiny.

"Increasing daily fasting times, without a reduction of calories and regardless of the type of diet consumed, resulted in overall improvements in health and survival in male mice," said de Cabo.

He added: Perhaps this extended daily fasting period enables repair and maintenance mechanisms that would be absent in a continuous exposure to food."

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How to live longer: How does fasting increase your life expectancy? What we know so far - Express

Sean Berman, who earned his MS in Biological Sciences in 2015 from Louisiana Tech, has recently received a grant from the United States Air Force based on his MS research that focuses on traumatic brain injuries and the potential of stem cell therapy in remediating the associated loss in memory and motor coordination.

Berman is hopeful the research will actually aid in repairing the sort of damage to the brain that combat veterans might have experienced as the results of blasts and that football players might have experienced as the result of blows to the head.

His argument is a logical one.

When veterans are coming home from war, theyre being diagnosed with PTSD and treated as though they have a purely psychological problem, said Berman. Zero attention is being paid to the fact theyve had exposure to blasts, both in training and in combat, resulting in many traumatic brain injuries. The structural integrity of their brain is totally disrupted. To not attempt to repair the structural tissue damage and treat it only as a psychological case is like putting a fresh paint job on a high rise thats on the verge of collapse.

Based on work hes been involved with at Tech, along with some clinical work hes done since, we can see that stem cells can help repair this damaged tissue, he said. The goal of this SBIR (Small Business Innovation Research) grant project is to take military personnel diagnosed with severe PTSD, provide stem cell therapy via an IV infusion, and then follow up with typical PSTD verbal tests that are issued at the VA, but also use an advanced assay (test) to measure discrete amounts of neuro-inflammatory markers that can be found in the peripheral blood.

We are partnering with the company, Quanterix, that has equipment that can measure these proteins at a very precise level, so much so that we can correlate it to the severity of the brain injury and hopefully show improvement in that injury over time, Berman said. If successful, we can extend the impact of this research to the public and other groups prone to concussive injury, such as NSF football players.

Earning the grant an Air Force AFWERX SIBR grant is no small accomplishment. The SIBR program is a highly competitive program that encourages domestic small businesses to engage in both Federal Research and Research and Development that has commercialization potential. AFWERX allows the Air Force to engage across industry, academia, and non-traditional contributors to create transformative opportunities and foster an Air Force culture of innovation. The ultimate aim is to solve problems and enhance the effectiveness of the Air Force.

Berman went to Amherst College undergrad and played football there, so he has some experience with head trauma. When he came to Tech with a year of eligibility left, he was given the opportunity to walk on at Tech as a graduate student.

A couple days after I showed up at Tech for Fall Camp, the NFL settled its concussion lawsuit with the NFLPA (National Football League Players Association) for $765 million, a number thats since been upwardly revised to nearly $1 billion, he said. Definitely a hot topic that was all over the news. Everyones initial reaction was, We need to change the game. Make it safer. End football. Take away tackling.

Berman was perplexed, he said, that no one was saying, We need to find a treatment for concussions.

If you roll your ankle in soccer, there are a handful of different treatment options and protocols, Berman said. If you concuss your brain in football, you simply rest until you get better. It didnt make sense to me that the players, trainers, and a medical team would actively work to treat an ankle sprain, but when it came to your brain, the answer was sleep and rest. So I thought itd be a good idea to study concussions while at Tech and hopefully find a solution and viable treatment option. I think we did that.

Bermans research at Tech was conducted under the guidance of Dr. David K. Mills, professor of Biological Sciences and Biomedical Engineering at Tech. Today, he is back in his hometown of Santa Monica, California working with a team of more than 500 doctors across the United States and internationally who are doing stem cell research.

The majority of the work is being done clinically, looking at restoring all kinds of damaged tissue naturally with stem cells, Berman said. We collect and analyze data on thousands of patients, trying to optimize the therapies to figure out which patients are the best candidates, which routes of stem cell administration are most effective, and what complimentary therapies are required, if any.

Its been a lot of fun, he said, and were seeing some life-changing results.

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MS BioSci grad awarded research grant for stem cell therapy for brain injuries - News at Louisiana Tech

I received my PhD in cell biology from Tulane University before attending LSU Medical School, so for many years Ive had a fascination with the clinical use of stem cells to repair the human body. The work were able to do now at Louisiana Regenerative Medicine Center affords me that opportunity, and Ive been able to experience first-hand the benefits to our patients of this exciting new medical technology.

Dr. Chris Trevino joins the Louisiana Regenerative Medical Center bringing vast knowledge and background in clinical medicine, basic sciences and physician leadership. Dr. Trevino received his PhD from Tulane University in cell biology and has published numerous peer reviewed articles

During the past 18 years, in addition to his practice, Dr. Trevino has participated in a variety of community activities including development of a paramedic program for the Gonzales Fire Department and currently is the medical director for Ascension Parish first responders. He was asked to be the Medical Director of the Louisiana Emergency Response Network, which is a statewide trauma network. Dr. Trevino has been involved in physician leadership throughout his career.

University of California, Santa Barbara, B.S. Biology, 1986

Tulane University, Master of Science, Cell and Molecular Biology, 1991

Tulane University, Doctorate of Philosophy, Cell and Molecular Biology, 1991

Louisiana State University School of Medicine, M.D., 1996

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Medical Team Louisiana RMC

Stem cell therapy has actually ended up being a popular dispute in the global medical scene. This extremely questionable therapy has received combined viewpoints from numerous stakeholders in the healthcare market and has also brought in the interest of political leaders, religious leaders and the general population at large. Stem cell treatment is considered a revolutionary treatment for people suffering from a large range of degenerative conditions. Some common questions concerning this therapy are addressed listed below.

Are you a stem cell therapy provider in Baton Rouge LA 70833? Contact us for more information about joining our website.

Stem cells can be referred to as blank state or non-specialized cells that have the ability to become customized cells in the body such as bone, muscle, nerve or organ cells. This suggests that these unique cells can be used to restore or establish a wide variety of broken cells and tissues in the body. Stem cell treatment is for that reason a treatment that focuses on achieving tissue regeneration and can be utilized to treat health conditions and illnesses such as osteoarthritis, degenerative disc disease, spinal cord injury, muscular degeneration, motor nerve cell illness, ALS, Parkinsons, heart problem and much more.

Being a treatment that is still under research, stem cell therapy has not been totally accepted as a viable treatment alternative for the above discussed health conditions and diseases. A great deal of studio is currently being carried out by scientists and medical experts in numerous parts of the world to make this treatment sensible and efficient. There are nevertheless numerous constraints enforced by governments on studio including embryonic stem cells.

Currently, there havent been many case studies performed for this form of treatment. Nevertheless, with the few case studies that have been performed, among the significant issues that has actually been raised is the increase in a clients threat of establishing cancer. Cancer is triggered by the quick reproduction of cells that tend not to pass away so easily. Stem cells have actually been connected with comparable growth aspects that might result in formation of tumors and other malignant cells in clients.

Contact us for more information about stem cell therapy in Baton Rouge LA 70833

Stem cells can be drawn out from a young embryo after conception. These stem cells are commonly referred to as embryonic stem cells. After the stem cells are extracted from the embryo, the embryo is terminated. This is basically one of the significant causes of debate in the field of stem cell research study. Lots of people suggest that termination of an embryo is dishonest and undesirable.

Stem cells can still be gotten through other methods as they can be discovered in the blood, bone marrow and umbilical cords of adult humans. Typical body cells can likewise be reverse-engineered to become stem cells that have actually limited capabilities.

New studio has nevertheless revealed promise as scientists aim at developing stem cells that do not form into tumors in later treatment phases. These stem cells can for that reason successfully transform into other kinds of specialized cells. This therapy is for that reason worth investigating into as numerous clients can gain from this innovative treatment.

Need a stem cell provider close to Baton Rouge LA 70833

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Stem Cell Baton Rouge Louisiana 70833

While pursuing his doctorate degree, he served as an instructor of mathematics at Morehouse College. Following graduation, he joined the faculty at Tulane University, where he pursued research related to heat transfer, fluid dynamics, energy efficiency, and renewable energy. In 2002, he was promoted to Associate Professor with tenure. Mackies eleven-year academic career ended in June 2007, when Tulane University disbanded the engineering school in response to financial hardship induced by Hurricane Katrina. During 2004-2005 academic year, Mackie was a visiting professor in the Department of Chemical Engineering at the University of Michigan, where he performed research on fuel cells. He enjoyed a respected academic career, before refocusing his career on entrepreneurship, consulting and professional speaking.

Following the catastrophic Hurricanes Katrina and Rita in 2005, former Louisiana Governor Kathleen Blanco appointed Dr. Mackie to the thirty-three member board of the Louisiana Recovery Authority (LRA), the guiding agency to lead the state's rebuilding efforts. Possessing instant social, political, cultural, and technical credibility, Mackie was featured prominently in Spike Lees HBO Katrina documentary, When The Levees Broke: A Requiem in Four Parts (HBO 2006) and its successor If God Is Willing and Da Creek Don't Rise (HBO 2010). He has since appeared on numerous national and local news shows including the PBS News Hour with Jim Lehrer, and The Tom Joyner Morning Show. In 2006, Mackie received international acclaim during a visit to Kuwait as an ambassador of the LRA and the guest of the U.S. Embassy in Kuwait, appearing on Good Morning Kuwait and in numerous international Arab newspapers. Mackie accompanied a Louisiana delegation to the Netherlands participating in an information exchange on water management and flow control.

Most recently, Louisiana Governor John Bel Edwards appointed Mackie to the Coastal Protection and Restoration Authority (CPRA). The CPRA was established as the single state entity with authority to articulate a clear statement of priorities and to focus development and implementation efforts to achieve comprehensive coastal protection for Louisiana. Governor Edwards also appointed Mackie to The Louisiana Science, Technology, Engineering, and Mathematics Advisory Council (LaSTEM). LaSTEM was established to coordinate and oversee the creation, delivery, and promotion of STEM education program; to increase student interest and achievement in the fields of STEM; to ensure the alignment of education, economic development, industry, and workforce needs; and to increase the number of women who graduate from a postsecondary institution with a STEM degree or credential.

In 2009, then Louisiana Governor Bobby Jindal appointed Dr. Mackie to the Louisiana Council on the Social Status of Black Boys and Black Men. The board elected Mackie to chair position where he led the states effort to create policy and programs to positively impact the quality of life for black males and families in the state of Louisiana. Committed to community service, Mackie is an active member of the National Speaker Association and the 100 Black Men of Metro New Orleans.

Mackie is formerly a partner and Senior Vice-President of Golden Leaf Energy (GLE). GLE is an innovative, renewable energy company that manufactures lubricants and methyl esters (biodiesel). Utilizing an integrated product development platform and industry leading production technology, GLE manufacturers and distributes renewable lubricants for drilling applications. Golden Leaf Energy also distributes quality methyl esters for a variety of other applications. GLE owns and operates a multi-feedstock biorefinery in located in southeast Louisiana.

Mackie continues in his role as President and CEO of the Channel ZerO Group LLC, an educational and professional development consulting company he co-founded in 1992. He has presented to numerous civic and educational institutions, government entities, professional association, and businesses of every size and industrial focus. Through his travels and online mentoring presence, Mackie reaches millions of students and professionals annually.

Most recently, Dr. Mackie founded STEM NOLA is a non-profit organization founded to expose, inspire and engage communities about the opportunities in Science, Technology, Engineering and Mathematics (STEM). STEM NOLA designs and delivers activities, programs and events that bring inspiration, motivation and training to all STEM stakeholders (especially students) across entire communities. Since December 2013, STEM NOLA has engaged over 11,000 most under-served K-12 New Orleans students in hands-on STEM project based activities. Over 80% of participants receive free or reduce lunch vouchers and thus free admission, and 45% have been females.

Dr. Mackies inspirational memoir A View from the Roof: Lessons for Life and Business has been adopted as educational course material by numerous secondary and college teachers throughout the country. His newest book Grandma's Hands: Cherished Moments of Faith and Wisdom was published in 2012 and recently received a silver medal in the prestigious Living Now Book Awards.

Dr. Mackie is a devoted husband to his wife, Tracy, and father to his two sons, Myles Ahmad and Mason Amir.Please visit calvinmackie.com.

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Meet Dr. Mackie Stem Nola