blood‑brain barrier spinal cord

(4):420-2. doi: 10.1038/nn2073. [1] The BSCB is involved in many disorders affecting the central nervous system, including neurodegenerative diseases, pain disorders, and traumatic spinal cord injury. Epub 2016 Dec 21. Cerebrospinal fluid (CSF) is a clear fluid present in the ventricles (core cavities) of the brain, in the central canal that runs through the core of the spinal cord, and in the subarachnoid space that surrounds the entire outer surface of the brain and spinal cord (Figure 15-1). The Anatomical Record. In adsorption-mediated transport, the nanoparticle is covered in positive charges that interact with the negative charges found on the endothelium. Human brain endothelial cells used to generate lab models of the human blood-brain barrier were missing several key proteins found in natural endothelial cells. Wang, D., Wang, C., Wang, L., & Chen, Y. Immediately deep to the periosteum is the periosteal and meningeal which create the dura mater. The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. There are two major pharmacological goals regarding drug delivery to the CNS: the first is finding ways to repair CNS tissue (including the BBB and BSCB) after it has been damaged, and the second is creating methods of drug delivery that improve therapy. The blood-brain barrier (BBB) is the cellular interface between the blood and the central nervous system (CNS; brain and spinal cord) It serves to maintain the interstitial fluid environment to ensure optimal functionality of the neurons. Tong M, He Z, Lin X, Zhou Y, Wang Q, Zheng Z, Chen J, Xu H, Tian N (January 2018). Until now, we have had to use viral vectors to deliver genes and subsequently control expression. Even if intuitively the BSCB could be considered as the morphological extension of the BBB int … Therapeutic efficacy of nanoparticles and routes of administration. Impairment. It was his student, Edwin Goldman, who did the other half of the experiment and realized the truth of wha… Because of its function as a protective barrier for the spinal cord, disruption of the BSCB exposes spinal cord tissue to inflammatory signals, pathogens, and toxins. 2017 Feb 3;639:103-113. doi: 10.1016/j.neulet.2016.12.049. 8(1):1688‐1702. Let’s talk about the blood-brain barrier, the BBB, or as it is sometimes called, the blood-brain-spinal cord barrier. The special properties of the blood-brain barrier were first observed in the late 19th century by the German bacteriologist Paul Ehrlich. Thus, nervous tissue needs extra safety & protection. Levels of the soluble form rise in cerebrospinal fluid when the blood-brain barrier is compromised. These long nerve fibres are called peripheral nerves. [29], Nanoparticles are composed of nano-sized particles that have widespread medical application. Cytokines are also able to pass through the BSCB with more ease, making it more vulnerable to disruption and inflammation relative to the BBB. Only a selected part of the endothelial cells exhibits lanthanum infiltration within the cytoplasm or in the basal lamina in the rat brain (a: A–E, arrows). As you may recall from Biology 101, this is the physical structure, a kind of wall, that separates blood and the cerebrospinal fluid that surrounds the brain and spinal cord. An established method of accomplishing this is through osmotic disruption. Electron microscope examination of brainstem, cervical and lumbar spinal cords was performed in ALS mice at early and late stages of disease. Mannitol-enhanced delivery of stem cells and their growth factors across the blood-brain barrier. Drug delivery, 26(1), 551–565. "Biologic therapeutics, such as proteins or nucleic acids, are notoriously difficult to get into the central nervous system," said Pun, Professor of Bioengineering at the University of Washington and co-senior author of the work. The brain and spinal cord are restricted; the blood-brain barrier keeps cerebrospinal fluid extra pure and offers the central nervous system an additional layer of protection from the general flotsam and jetsum in the bloodstream. Blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) impairment is an additional accident occurring during the amyotrophic lateral sclerosis (ALS) progression. [25][26], The BBB/BSCB can be deliberately disrupted to increase paracellular transport of drugs to the CNS. [11], With the endothelium compromised, proteins and antibodies can infiltrate the cerebrospinal fluid (CSF). [16], Neuropathy is a type of severe chronic pain that is caused by disease and dysfunction of the somatosensory system that allows for perception of touch, pain, vibration, and other sensations. The blood brain barrier [the microvessels] consists of two main cell types 1. Proteins like albumin and antibodies like IgG are too large to pass through the BSCB on their own, so their presence in CSF indicates a leaky endothelium. Hence, TAxI-based peptide:protein chimeras offer a potential replacement of the viral methods used currently for protein delivery to the spinal cord. DOI: Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN (February 2017). 2019 Nov 21;23:20. doi: 10.1186/s40824-019-0166-x. “Neuropathic pain.” Nature Reviews Disease Primers. The blood-brain barrier (BBB) is a highly selective membrane barrier at the brain microvessel level that facilitates transport between the systemic circulation and the central nervous system. Furthermore, studies with rat models have shown that the initial phases of ALS result in a loss of 10-15% of the BSCB capillary length, edema, and collapsed capillary beds. “Blood–spinal cord barrier breakdown and pericyte deficiency in peripheral neuropathy”. Fluids and barriers of the CNS, 13(1), 19. Nature Neuroscience. At its core, neuropathy occurs when the central excitatory and inhibitory nerves in the somatosensory system are altered in some way, as this leads to dysfunctional sensory signaling. Fig. DOI: 10.1097/01.CCM.0000050287.68977.84. Candidates could be optogenetic channels so that we can activate muscle groups that lack descending control. “Lithium chloride contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux.” Biochemical and Biophysical Research Communications. 13(6):3163-3166. doi: 10.3892/etm.2017.4410. 56(3):2039-2056. doi: 10.1007/s12035-018-1207-5. Why blood-brain barrier important? [8] Additionally, widening of the tight junctions adhering endothelial cells and oxidative stress are both associated with a long-term increase in BSCB permeability. In this context the abluminal side is the brain side. It encloses and protects the vessels that supply the brain and contains CSF between the pia mater and arachnoid maters. Widened paracellular gaps can facilitate passage of larger molecules that otherwise would be unable to cross the BBB/BSCB. Takigawa T, Yonezawa T, Yoshitaka T, et al. Similar to the BBB, the majority of small molecule drugs and virtually all large molecule and biological drugs cannot penetrate the BSCB, making treatment of spinal cord diseases difficult. Amyotrophic lateral sclerosis (ALS) is a chronic, progressive, and ultimately fatal neurodegenerative disease that is caused by the death of motor neurons in the brain and spinal cord. Pericytes play a key role in maintaining blood-CNS barriers. Points of view or opinions do not, therefore, necessarily represent official Administration for Community Living policy. Impressively, a single injection of TAxI-Cre into the gastrocnemius led to efficient transfer of functional protein to motor neurons in the spinal cord. “Multiple sclerosis: Pathology, diagnosis and treatments.” Experiments in Therapeutic Medicine. For example, if the initial injury includes excessive separation of the basement membrane from the blood vessels, a space is created that can accommodate more immune cells and thus propagate damaging inflammation. 8. Endothelial cells that form the wall of the blood vessels [Luminal cells] 2. We further use this peptide ... to deliver an active enzyme into spinal cord neurons after peripheral muscle injection in mice. [1] The lack of fenestrations and endocytic vesicles reflects the restricted transcellular flow, while the increased number of mitochondria contributes to a high metabolic rate in these endothelial cells. 1-800-225-0292, Reeve Summit 2021: Where Care, Cure and Community Connect | Virtual Conference | April 27-29, 2021. In this work, we aimed to decipher if BBB/BSCB leakage appeared before critical detrimental events and could serve as a marker preceding clinical symptoms. 1157, 126-137. “Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases”. The blood-spinal cord barrier (BSCB) is a semipermeable anatomical interface that consists of the specialized small blood vessels that surround the spinal cord. In the present study we induced a contusive SCI at T9 in the rat and studied the effects of intravenous MSC infusion on BSCB permeability, microvascular architecture and locomotor recovery over a 10 week period. Because of this sudden infiltration of normally absent particles, an inflammatory response is triggered by astrocytes and microglia that extends the initial injury into previously uncompromised segments of cord. Disruption of the blood-spinal cord barrier (BSCB) results in secondary injury and apoptosis of neurons, leading to permanent neurological dysfunction after spinal cord injury. The blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) prevent entry of toxic circulating molecules and cells into the central nervous system (CNS) ().Amyotrophic lateral sclerosis (ALS) is the most prominent adult motor-neuron disorder resulting in progressive motor-neuron loss in the spinal cord, brainstem, and motor cortex (). Traumatic injury can disrupt the barrier dramatically, leading to marked changes in the perineuronal environment. One important consequence of SCI is damage to the microvasculature and disruption of the blood spinal cord barrier (BSCB). Treatment is generally aimed at reducing symptoms and slowing progression of disease. Cell transplantation, 23(4-5), 531–539. In recent years, molecular biology has taken the BBB apart and examined it in living animals. [16][18], While it does not occur in all cases, some people who experience peripheral nerve injury develop neuropathy through the signaling induced by the injury. The basal membrane is formed and maintained by all cell types in the BSCB and contributes to the cytoskeletal morphology of the endothelial cells, which affects the integrity of tight junctions and, by extension, the BSCB. Frontiers in neuroengineering, 6, 7. Blood-Brain Barrier. While this showed that a barrier … 1405(1):71-88. However, for drugs that cannot cross the BBB/BSCB, there must be either a method of bypassing the barriers or the creation of a drug delivery system that allows penetration. They release secretory compounds that influence the phenotype of endothelial cells and express aquaporin and potassium channels that help regulate ion concentration and fluid volume within the spinal cord. A growing body of evidence supports a major role for the BBB in the etiology and pathogenesis of multiple vascular and neurodegenerative disorders. As you may recall from Biology 101, this is the physical structure, a kind of wall, that separates blood and the cerebrospinal fluid that surrounds the brain and spinal cord. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. The BBB is important in spinal cord injury in two ways. Polderman, K. H., van de Kraats, G., Dixon, J. M., Vandertop, W. P., Girbes, A. R. (2003) Increases in spinal fluid osmolarity induced by mannitol. Perhaps the most exciting aspect of our data is the demonstration of targeted delivery of a biologically active protein to the CNS and the demonstrated binding to neurons in human spinal cord. Evidence of compromised blood-brain barrier (BBB) and/or blood-spinal cord barrier (BSCB) integrity was recently identified in ALS patients and in an animal model of ALS. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. [26] There is ongoing issue with nanoparticles as a whole, particularly regarding accumulation in the targeted region and cytotoxicity; however, nanoparticles have been found to be of incredible use to medical research and hold promise as a method of drug delivery to the CNS. This impact disrupts the capillaries around the spinal cord and initiates many pathophysiological cascades by allowing the molecules and cells within the bloodstream to enter nervous tissue. Scientists discovered the BBB about 125 years ago, wondering why when they shot blue dye into the body all cells turned blue – except those in the brain and spinal cord. Bouhassira D, Attal N. (2018) “Emerging therapies for neuropathic pain: new molecules or new indications for old treatments?” Pain. Methods of bypassing the BSCB directly include intrathecal injection (into the spinal canal), intracerebroventricular injection (into the ventricles of the brain, which produce CSF that flows down the CNS), epidural injection (into the epidural space), and depot or implant placement, such as a placement of a catheter. Some anti-cancer drugs, like mitoxantrone and cyclophosphamide, have immunosuppressant effects that slow disease progression. The BBB is more like a neurovascular organ unto itself. So my speculation is that for SCI we may be able to inject select muscles for delivery of active proteins to motor neurons. [1][4], Research shows that the BSCB plays a significant role in the development and progression of neurodegenerative diseases, spinal cord injury, pain conditions, and other disorders that affect the CNS. Acta Neuropathology. It’s being shown, for example, that a leaky BBB might be a primary culprit in several maladies, including epilepsy, Alzheimer’s disease and multiple sclerosis. The blood-spinal cord barrier (BSCB) resembles the blood-brain barrier (BBB) in many ways. The main function of the blood–brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in the blood stream. It prevent getting bloodborne pathogens & toxic substance into the brain tissue. Vascular impairment has only recently been recognized as a key factor in ALS, identifying a neurovascular disease signature (Garbuzova-Davis et al., 2011). “Early microvascular reactions and blood-spinal cord barrier disruption are instrumental in pathophysiology of spinal cord injury and repair: novel therapeutic strategies including nanowired drug delivery to enhance neuroprotection.” Journal of Neural Transmission. [1], Spinal cord injuries (SCIs) are debilitating incurable conditions that frequently result in lifelong disability and dysfunction. Sauer R, Kirchner J, Yang D, Hu L, Leinders M, Sommer C, Brack A, Rittner HL (October 2017). [1] As such, the sooner the BSCB is restored, the better the prognosis is for someone after a SCI.[5]. The membranes of endothelial cells have increased permeability, and this may contribute more to pathology than the tight junctions being compromised. If a drug is capable of crossing the BBB or BSCB, then it can be administered orally, rectally, intravenously, etc. The BSCB is more susceptible to immune invasion because tight junctions are weak by default, relative to the BBB. They occur when a mechanical force is applied to the spinal column, most often from motor vehicle accidents and falls. Blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) impairment is an additional accident occurring during the amyotrophic lateral sclerosis (ALS) progression. Triggering changes in the pain signaling pathway occurs the neuroimmune interactions, such as the release of proinflammatory mediators into the spinal cord that are known to promote central sensitization (wherein sensory nerves are activated more easily) and hyperalgesia (increased sensitivity to pain). Antiepileptics are sometimes given off-label for ALS, since hyperexcitability is thought to contribute to motor neuron death; no antiepileptic has been approved for this use, though. [9] Inflammation, compromised tight junctions, and oxidative stress are all contributors to a severe complication of SCI called post-traumatic syringomyelia. Biomater Res. Mural cells on the abluminal side [Abluminal cells] Abluminal side means side not facing the luminal side. In most parts of the body, the smallest blood vessels, called capillaries, are lined with endothelial cells. This project was supported, in part, by grant number 90PRRC0002, from the U.S. Administration for Community Living, Department of Health and Human Services, Washington, D.C. 20201. Engineered viruses and protein chimeras have also been used successfully in animal models to transfer therapeutic genes for conditions such as spinal cord injury, spinal muscular atrophy, chronic pain, and amyotrophic lateral sclerosis. It controls what gets from the bloodstream into the brain, and what does not.. For example, things that the brain needs to survive (water, glucose, and amino acids) can get through the barrier.However, the barrier stops many harmful things, like bacteria and viruses, from getting into the brain. [21] Because of this, the majority of nervous system disorders have limited treatments that may involve invasive means of administration. Relative mean body weight of SOD1 G93A rats. 159(3):576-582. Uchida Y, Sumiya T, Tachikawa M, Yamakawa T, Murata S, Yagi Y, Sato K, Stephan A, Ito K, Ohtsuki S, Couraud PO, Suzuki T, Terasaki T (March 2019). NMR Biomed 2009;22:332–341. 292(2):207-213. Pericytes are microcirculatory cells that, in the BSCB, regulate the proliferation, migration, and differentiation of endothelial cells. Well, our central nervous system (Brain & Spinal cord) is so special & delicate organ. For example, mannitol, an osmotic diuretic, crosses BSCB endothelium more readily than it does BBB endothelium. The blood–brain barrier was discovered in the late 19th century, ... the dye infiltrated all tissues except the brain and spinal cord. These results suggest that intravenously delivered MSCs have important effects on reducing BSCB leakage which could contribute to their therapeutic efficacy. Introduction. Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. To his surprise, the dye infiltrated all tissues except the brain and spinal cord. These vasculature changes preceded motor neuron death, indicating that BSCB breakdown may facilitate tissue damage. Figure 2.3 Blood-Brain bappiepB. “Aquaporin‐4 Overexpression in Rat ALS Model”. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Noble LJ, Wrathall JR. Distribution and time course of protein extravasation in the rat spinal cord after contusive injury. [20] Furthermore, drugs that do pass through the barrier may be subjected to efflux by specialized efflux pumps such as p-glycoprotein and breast-cancer resistance protein, which prevents concentration of therapeutic relevance being reached. The blood-spinal cord barrier (BSCB) is a semipermeable anatomical interface that consists of the specialized small blood vessels that surround the spinal cord. What was surprising to us and unique for this peptide TAxI is that we can deliver active proteins. [14] Many studies support the idea that CNS barrier disruption precedes MS, particularly through altered tight junction protein expression. The team also tracked the integrity of the blood-brain barrier in 73 participants using an MRI-based technique they’d previously developed . [1] Within five minutes following the initial injury, normally impermeable blood components like the large molecule albumin or red blood cells can be detected in spinal cord tissue. Upadhyay RK. Blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced MRI. Grantees undertaking projects under government sponsorship are encouraged to express freely their findings and conclusions. 11:477. doi: 10.3389/fimmu.2020.00477. The goal of nanoparticles in this context are to successfully enter CNS tissue and release its drug cargo safely. Second, by its very nature, the BBB is quite restrictive; very few substances are allowed to cross from blood to CSF. Both drugs have been shown to slow degeneration and improve overall survival time, though it is of utmost importance to begin treatment as early as possible. Wong, A. D., Ye, M., Levy, A. F., Rothstein, J. D., Bergles, D. E., & Searson, P. C. (2013). The primary function of the BSCB is to protect the spinal cord from potentially toxic substances within the blood while still delivering necessary molecules to maintain spinal cord activities. [17] The BSCB is the main anatomical structure that regulates the interaction between the immune system and the nervous system, so its role in neuropathy is of pharmacological interest. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32(11), 1959–1972. 3:17002. doi: 10.1038/nrdp.2017.2. Corticosteroids are a common choice, as they can modulate immune function and decrease symptom severity during an attack. “Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS.” PLoS One. [3] Susceptibility to toxins is already increased in BSCB endothelium through the relative downregulation of the critical efflux protein p-glycoprotein, thus slowing elimination of the toxins that penetrate the barrier. Here, we report the identification of a peptide that is trafficked into the spinal cord after intramuscular (IM) injection. Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M (August 2011). Relative weight means the ratio between the actual weight and the maximum weight in life. Powerful two-photon microscopes allow visualization in real time; it’s much more complicated, of course, than anyone knew. Chenthamara D, Subramaniam S, Ramakrishnan SG, Krishnaswamy S, Essa MM, Lin FH, Qoronfleh MW. As compared with the high fluoride control group, the content of Evans blue increased markedly in spinal cord of the high fluoride group (29.2 ± … In post-traumatic syringomyelia, the structural and function loss of integrity of the BSCB encourages the development of fluid filled cysts within the spinal cord, causing pain and worsening disability. It has been found that blocking the signaling of certain cytokines in cases of neuropathy attenuates the BSCB permeability, decreases the amount of infiltrating immune cells, and ultimately decreases hyperalgesia.[17][19]. As we know, neurons doesn't regenerate like other tissue. [5] This secondary injury can contribute heavily to long term loss of function and disability. The blood-brain barrier helps block harmful substances, such as toxins and bacteria from entering the brain. The BBB is semi-permeable; that is, it allows some materials to cross, but prevents others from crossing. Pardridge W. M. (2012). However, hyperosmolarity may also be of use in drug delivery since it causes the membranes of endothelial cells to shrink, resulting in tight junctions stretching and paracellular gaps widening. Huang WJ, Chen WW, Zhang X (June 2017). Epub 2017 Apr 28. He found that when he injected colored dyes into the blood stream they leaked out of capillaries in most regions of the body to stain the surrounding tissues; the brain, however, remained unstained. Physiology. This vulnerability to disruption leaves the spinal cord susceptible to toxins that can inflict tissue damage. Or we may provide proteins that could induce transformative changes in the motor neurons to make them more plastic such as transcription factors that are know to induce dendrite growth. Hladky, S. B., & Barrand, M. A. Certain viruses do travel retrogradely and can be taken up by muscle injection. “Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis”. Let’s talk about the blood-brain barrier, the BBB, or as it is sometimes called, the blood-brain-spinal cord barrier. The blood–brain barrier (BBB) is a highly selective permeability barrier. 1. Sharma HS (January 2011). From a UW press release: A study published Feb. 16 in the Proceedings of the National Academy of Sciences showed that, in mice, a muscle injection of TAxI could transport a recombinant protein into spinal motor neurons. [30] They gain entry in two major ways: adsorption-mediated transport and receptor-mediated transport. Whereas the BBB is adjacent to circumventricular organs in several midline regions, the BSCB is bordered by the filum terminali caudally and the nerve root entry zones laterally. Epub 2012 Sep 1. This barrier ensures that substances entering the brain are tightly regulated. But, scientists knew that the brain also depends upon the delivery of hormones and key nutrients , including glucose and several amino acids, from other organs of the body. 125(1):111-120. doi: 10.1007/s00401-012-1039-8. The blood-spinal cord barrier The spinal cord is highly vascularized, with a complex network of endothelial cell-lined vessels projecting throughout the spinal tissue (Miyasaka et al., 2000). Animals are considered as presymptomatic before weight decline at about 4 month-old. Epub 2008 Mar 16. The demonstration of a nonviral-mediated delivery system demonstrates the clinical potential of this technology to develop powerful therapeutic tools to treat motor neuron diseases. The blood-brain barrier is comprised of layers of the capillary endothelial cells and basement membrane and is maintained by the astrocyte feet which send “signals” to maintain tight junctions in these areas. First, trauma to the cord typically breaks the BBB, thus contributing to inflammation, edema and cellular mayhem at the injury site. For decades, herpes simplex viruses (HSVs) have been known to enter the CNS by retrograde axonal transport, and HSV has been engineered for remote gene transfer in animal models of disease. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis and death. [24], Most pharmaceutical research involving the BSCB aims to find efficient methods of overcoming its barrier mechanism to improve drug delivery. In this study, we evaluate the role of miRNA-125a-5p in the BSCB under hypoxia. [1] In general, the BSCB is more permeable than the BBB, largely due to the relatively low expression of tight junction proteins like ZO-1 and occludin. The purpose of this study was to determine the ultrastructure of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) in G93A SOD1 mice modeling ALS at different stages of disease. Fluids and barriers of the CNS, 15(1), 30. Nicaise C, Soyfoo MS, Authelet M, De Decker R, Bataveljic D, Delporte C, Pochet R (December 2008). Here we report that a group from the University of Washington has developed a way to ferry molecular cargo, including biologic drugs, to brain and spinal cord neurons. PubMed The blood-spinal cord barrier: morphology and clinical implications. Whereas viral delivery can provide high levels of stable expression, TAxI-mediated delivery of proteins offers better control over dosing and would be better tolerated in repeat dosing regimens. Li HL, Huang Y, Zhou YL, Teng RH, Zhou SZ, Lin JP, Yang Y, Zhu SM, Xu H, Yao YX (March 2020). 2014;2014:869269. doi: 10.1155/2014/869269. The blood brain barrier .

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