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Edward Ivanov
Edward Ivanov

Ldn Muscle Cutting Guide V3 Pdf 136 UPD



Take a thorough history of substance use and review the Prescription Drug Monitoring Program, currently operational in 49 states and the District of Columbia. The Prescription Drug Monitoring Program is a valuable resource to determine whether patients have received prior opioid prescriptions or other high-risk medications such as benzodiazepines, and should be consulted when patients request opioid pain medication or when opioid misuse is suspected. This resource (available at www.pdmpassist.org/content/state-profiles can guide safe prescribing and help identify patients who suffer from opioid misuse or opioid use disorder and who would benefit from treatment. Several states now require that health care providers use Prescription Drug Monitoring Programs before prescribing certain controlled substances.




ldn muscle cutting guide v3 pdf 136



*Ewing H. A practical guide to intervention in health and social services with pregnant and postpartum addicts and alcoholics: theoretical framework, brief screening tool, key interview questions, and strategies for referral to recovery resources. Martinez (CA): The Born Free Project, Contra Costa County Department of Health Services; 1990.


I began posting this guide to Covid-19 in February 2020, to organize my research into the emerging science and to cut through the deluge of false information on the Internet and the misleading information being repeated in news cycles. I have updated it periodically, as new data and new perspectives emerged. My goal is to help you make informed decisions for protecting your health and the health of those you care about and to be able to critically evaluate breaking news. I have been asked hundreds of questions about Covid-19 over the past year and have attempted to include all the answers in this document.


Ursolic acid is a dietary compound found in many fruits, vegetables, herbs and spices and is used as a muscle-building supplement by body builders. Ursolic acid has anti-inflammatory, anti-viral and cancer-fighting activity[147]. It also inhibits the growth of Enterococcus faecalis[148]. Dietary sources of ursolic acid include apple peel, cranberries, bilberries, blueberries, prunes, peppermint, rosemary, oregano, thyme, sage, and marjoram. Dried cranberries are an especially good source[149].. Human clinical trials of ursolic acid show anti-inflammatory effects at doses of 150 mg taken 1 to 3 times a day[150] [151]. Ursolic acid may also inhibit the SARS-CoV-2 Main Protease[152] [153] (The importance of this enzyme is described above in AFTER ENTRY: THE ROLE OF NSPs).


The cells of origin of neurogenic heterotopic ossifications (NHOs), which develop frequently in the periarticular muscles following spinal cord injuries (SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells (SCs), which are myogenic, and fibroadipogenic progenitors (FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.


Our group previously reported the first mouse model of NHOs in which NHOs spontaneously develop when an SCI is combined with muscle injury without additional nonphysiological manipulations, such as the overexpression of bone morphogenetic protein (BMP) transgenes or the insertion of hyperactive mutants of BMP receptors.19 Our model revealed that SCI causes a further exacerbation of the inflammatory response in injured muscles with exaggerated Ly6Cbright inflammatory monocyte/macrophage infiltration and persistent accumulation of the inflammatory cytokine oncostatin M (OSM), leading to persistent activation of JAK1/2 tyrosine kinases and signal transducer and activator of transduction-3 (STAT3), which in turn promote NHOs instead of muscle repair.19,20,21


How injured skeletal muscles generate heterotopic bones instead of regenerating functional myofibers following severe lesions of the CNS remains a fascinating stem cell biology question and may reveal novel therapeutic strategies to treat NHOs.17,18 Adult skeletal muscles contain two populations of stem/progenitor cells: (1) satellite cells (SCs), residing within the myofiber under the myofiber basal lamina, which regenerate myoblasts and myocytes following injury and are as such true muscle stem cells,22,23,24 and (2) fibroadipogenic progenitors (FAPs) residing in the interstitial space between myofibers.25 Unlike SCs, FAPs are of mesenchymal origin and do not regenerate myoblasts.25 Muscle repair following injury is a highly orchestrated process that involves the coordinated recruitment of both SCs and FAPs as well as macrophages. Upon muscle injury, FAPs proliferate transiently for the first 3 days in mice and then undergo apoptosis under the effect of tumor necrosis factor (TNF) released by infiltrating C-C chemokine receptor-2 (CCR2)+ inflammatory monocytes/macrophages, which also clear apoptotic FAPs.26,27 Both FAPs and macrophages are essential to orchestrate and complete appropriate myogenic repair from SCs, and the critical function of FAPs is thought to involve the secretion of appropriate growth factors and extracellular matrix, which enable SC proliferation, myogenic differentiation and myofiber assembly.25,28,29 As both muscle SCs and FAPs have osteogenic potential in vitro,19,21 the question of the cells of origin of NHOs has not been resolved.


In addition to the high specificity of these lineage tracing strategies, the recombination efficiency was also very high, with over 90% of SCs and FAPs labeled in the muscle of the Pax7ZsG and Prrx1ZsG strains, respectively (Fig. 1f). Importantly, Cre-mediated recombination in the Pax7ZsG and Prrx1ZsG mice did not affect subsequent NHO development compared to that in the C57BL/6 mice, as measured by microcomputerized tomography (µCT) or hematoxylin-eosin staining, which clearly showed the presence of necrotic and fibrotic muscle together with inflammatory infiltrate and sporadic bony nodules 28 days after injury in both strains, as we previously reported in C57BL/6 mice13,20,21,42 (Fig. S2). Altogether, these experiments confirmed that ZsGreen was specifically expressed in the targeted muscle cell populations in both the Pax7ZsG and Prrx1ZsG strains without altering NHO development, thus illustrating their suitability for lineage tracing of SCs and FAPs in vivo.


ZsGreen expression was then examined on frozen longitudinal sections of uninjured muscle, repaired muscle and NHOs from the Pax7ZsG mice (Fig. 2a). In noninjured muscles from the Pax7ZsG mice, ZsGreen was expressed in a discrete population of small cells distributed along myofibers typical of SCs (Fig. 2b). Some myofibers were also ZsGreen+, likely reflecting their natural turnover from ZsGreen+ SCs over a period of 4 weeks after tamoxifen induction. Fourteen days after CDTX-induced muscle injury, in the absence of SCI, all myofibers were ZsGreen+, as anticipated, illustrating muscle regeneration from ZsGreen+ SCs (Fig. 2c).


In the cohort of mice that underwent spinal cord transection (SCI) and CDTX-mediated muscle injury, frozen sections were stained with specific anti-collagen I [Fig. 2d(i-ii)] and anti-osteocalcin antibodies [Fig. 2d(iii-iv)]. An example of a nonimmune IgG negative control for anti-collagen I and anti-osteocalcin antibodies is shown in Fig. 2d(v). Immunohistofluorescence (IHF) confirmed ZsGreen+ cells within areas of regenerating muscle that contained neoformed ZsGreen+ myofibers. Most importantly, ZsGreen+ cells were largely absent among areas of fibrotic muscle and NHO nodules. ZsGreen+ cells were not intercalated among the collagen I+ bone matrix or osteocalcin+ osteoblasts on NHO nodules. Quantification of NHOs through four different Pax7ZsG mice showed that none of the 44 osteocalcin+ NHOs contained ZsGreen+ cells (Fig. 2e). This finding demonstrates that NHOs following SCI are not derived from ZsGreen+ SCs.


ZsGreen expression was also examined on frozen longitudinal sections of uninjured muscle, repaired muscle and NHOs from the Prrx1ZsG mice (Fig. 3a). In the uninjured muscle, reticulated ZsGreen+ cells were scattered in the interstitium along myofibers (Fig. 3b), a typical distribution and morphology of FAPs.25 Importantly, in the regenerating CDTX-injured muscle (without SCI), ZsGreen+ cells were distributed similarly, and most importantly, they did not contribute to neoformation of myofibers (Fig. 3c), in concordance with the literature.25


We then investigated whether cells sorted from muscles surrounding human NHO were able to support in vivo heterotopic bone formation in immunodeficient mice. PDGFRα+ and CD56+ cells were independently seeded into plasma-clotted hydroxyapatite/calcium phosphate scaffolds and implanted subcutaneously into the backs of nude mice (Fig. 7a). Unseeded plasma-clotted scaffolds were used as a negative control, and BM-derived mesenchymal stromal cell (BM-MSC)-seeded plasma-clotted scaffolds were used as positive controls. Fifteen weeks after implantation, scaffolds were collected for histological analysis. As expected, no bone tissue was observed in the control plasma group [Fig. S6a(i)], while all BM-MSC-seeded implants exhibited bone matrix and hematopoietic foci, as detected by hematoxylin, eosin and safranin staining (HES) [Fig. S6a(ii)]. Six of 11 implants (54.5%) with NHO muscle PDGFRα+ cells showed mature bone matrix containing osteocytes together with a hematopoietic marrow, demonstrating the formation of ectopic bone with functional hematopoietic BM [Fig. 7b, c(i)], as evidenced by the presence of numerous mature megakaryocytes (Fig. S6b). In contrast, only 12.5% of scaffolds seeded with CD56+ cells contained bone matrix deposition alone, and 12.5% showed both bone matrix development and hematopoietic colonization [Fig. 7b, c(i)], suggesting a much higher osteogenic potential of PDGFRα+ mesenchymal cells derived from human muscle surrounding NHOs. To analyze the origin of bone-forming cells in these implants, we investigated the expression of human-specific lamin A/C by immunohistochemistry. Figure 7c(ii) highlights that very few human cells were observed within CD56+ cell seeded scaffolds, whereas PDGFRα+ cell seeded implants exhibited numerous human lamin A/C+ osteocytes within the bone matrix [Fig. 7c(ii)], demonstrating that human PDGFRα+ cells actively participate in the formation of heterotopic bone. Of note, no human cells were detected within hematopoietic foci, confirming that hematopoietic cells that colonized these heterotopic bone formations were of murine origin (Fig. S6b). Finally, PDGFRα+ cell implants exhibited numerous osterix+ osteoblasts; most of them were located near hydroxyapatite particles and within the bone matrix (Fig. 7d). Thus, mesenchymal PDGFRα+ cells isolated from muscles surrounding human NHOs have a substantially higher capacity to support mature hemogenic bone formation than myogenic CD56+ cells. These data are concordant with the hypothesis that muscle-resident PDGFRα+ cells are key actors in the onset of NHOs in both humans and mice.


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