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STUDY OBJECTIVES: The objective of this study was to compare the combination of intramuscular (IM) droperidol/midazolam to haloperidol/lorazepam regarding time to sedation in patients with acute undifferentiated agitation in the emergency department (ED). METHODS: This was a prospective, unblinded observational study in the ED of a university teaching hospital. Subjects with acute undifferentiated agitation refractory to verbal de-escalation were assigned to receive a combination of either haloperidol 5 mg/lorazepam 2 mg or droperidol 5 mg/midazolam 5 mg IM. The primary outcome was the proportion of patients adequately sedated at 10 min defined as ED Sedation Assessment Tool (SAT) score of 0 or less. Secondary outcomes included change in ED SAT score at 5, 15, 30, and 60 min, the need for oxygen supplementation, and the need for airway intervention. RESULTS: A total of 86 patients were enrolled in the study, with 43 patients receiving droperidol/midazolam and 43 patients receiving haloperidol/lorazepam. Ten minutes after receiving medication, 51.2% of patients in the droperidol/midazolam group were adequately sedated compared to 7% of patients in the haloperidol/lorazepam group (OR: 14; 95% CI: 3.7, 52.1). Median time to adequate sedation was 10 min for the droperidol/midazolam group and 30 min for the haloperidol/lorazepam group. Eleven patients (25.6%) in the droperidol/midazolam group received oxygen supplementation compared to four patients (9.3%) in the haloperidol/lorazepam group. No study patients experienced extrapyramidal symptoms or required endotracheal intubation. CONCLUSION: Intramuscular droperidol/midazolam was superior to intramuscular haloperidol/lorazepam in achieving adequate sedation at 10 min. Patients in the droperidol/midazolam arm may be more likely to receive oxygen supplementation than those in the haloperidol/lorazepam arm.
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Droperidol , Haloperidol , Lorazepam , Midazolam , Agitação Psicomotora , Antipsicóticos/uso terapêutico , Droperidol/uso terapêutico , Serviço Hospitalar de Emergência , Haloperidol/uso terapêutico , Humanos , Lorazepam/uso terapêutico , Midazolam/uso terapêutico , Estudos Prospectivos , Agitação Psicomotora/tratamento farmacológicoRESUMO
Background: Interactions with healthcare workers can provide effective entrance into treatment, ensuring retention and lifelong recovery for individuals with Substance Use Disorder (SUD). Healthcare providers approach the challenges of patient management with different skills, comfort levels, and viewpoints. Individuals in recovery also provide crucial perspectives relevant to the complex aspects of the drug epidemic. The purpose of this study was to determine if perceptions of SUD diverge among individuals in recovery, physicians, nurses and medical students. Methods: A survey consisting of 29 Likert statements was deployed to physicians, nurses, medical students, and persons with SUD in recovery. Respondents were asked to rate their level of agreement on statements about SUD such as treatment, stigma, medications for opioid use disorder (MOUD), naloxone kits, safe injection sites, and methamphetamine usage. Separate Welch's analysis of variances (ANOVAs) were conducted to determine differences between the respondent groups and each statement. For any statistically significant findings, Games-Howell post-hoc analyses were employed. Results: A total of 523 individuals provided survey responses: individuals in recovery (n = 111), physicians (n = 113), nurses (n = 206), and medical students (n = 93). Survey results revealed the majority of items had statistically significant differences in respondent groups. Perceptions diverged on items related to treatment, stigma, MOUD, take-home naloxone kits, safe injection sites, needle exchange programs, and methamphetamine. Conclusion: As healthcare providers and policymakers develop treatment strategies to engage those with SUD in quality treatment, they will benefit from understanding how different viewpoints on SUD affect treatment for these individuals. These attitudes impact stigma, willingness to prescribe new treatments, and development of clinical relationships. The insight from this study allows for important discussions on the substance use health crisis and further inquiry on why these differences exist and how the diverging viewpoints may impact the lives of persons with SUD.
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Transtornos Relacionados ao Uso de Opioides , Médicos , Estudantes de Medicina , Humanos , Naloxona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estigma SocialRESUMO
INTRODUCTION: As the opioid epidemic continues, state legislatures and clinicians increasingly utilize Prescription Drug Monitoring Programs (PDMPs). These programs record dates prescribed and filled for all controlled substances, attempting to identify high-risk prescribing. The aims of this study were to (i) examine data from individuals who died of accidental opioid overdose and (ii) compare differences between those with prescriptions documented in Kentucky's PDMP with individuals without recorded prescriptions. METHODS: This was a retrospective, observational cohort study conducted in Jefferson County, Kentucky. We reviewed records for all opioid overdose death subjects from 2017 and 2018, cross-referencing with prescriptions in Kentucky's PDMP (Kentucky All Schedule Prescription Electronic Reporting System [KASPER]) back to 2014. We performed χ2 analyses for categorical variable comparisons and a separate univariate analysis for age. RESULTS: Of the 575 individuals who died of accidental opioid overdose in Jefferson County during the study period, 379 (65.9%) had prescriptions documented in KASPER. Individuals had a high prevalence of fentanyl on postmortem toxicology. Only one individual had postmortem toxicology positive for buprenorphine, a medication for opioid use disorder (MOUD). Several subjects experienced what we termed see-saw MOUD prescribing (prescriptions alternating between MOUD and other controlled substances including full agonists), and multiple prescriptions were apparently written and/or filled for deceased subjects. CONCLUSIONS: Review of PDMP data in deceased patients can prevent unnecessary opioid prescribing and optimize clinical practice. Buprenorphine may have a protective effect in opioid dependence, but access must be consistent. Providers should be aware of see-saw MOUD prescribing and understand the effects on patient care. In response to the prescriptions filled for deceased individuals, legislators could enact a policy such as Void All Prescriptions or VAP alerts to cancel all prescriptions for individuals who have died, reducing drug diversion. It is vital that providers routinely use PDMP data along with counseling and other treatment strategies to optimize patient care.
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Overdose de Opiáceos , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/efeitos adversos , Estudos de Coortes , Prescrições de Medicamentos , Humanos , Morfolinas , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Padrões de Prática MédicaRESUMO
BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.
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Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Relaxina/farmacologia , Relaxina/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Fluxo Sanguíneo Regional/efeitos dos fármacos , Escócia , Adulto JovemRESUMO
Pericytes, perivascular cells embedded in the microvascular wall, are crucial for vascular homeostasis. These cells also play diverse roles in tissue development and regeneration as multi-lineage progenitors, immunomodulatory cells and as sources of trophic factors. Here, we establish that pericytes are renin producing cells in the human kidney. Renin was localized by immunohistochemistry in CD146 and NG2 expressing pericytes, surrounding juxtaglomerular and afferent arterioles. Similar to pericytes from other organs, CD146+CD34-CD45-CD56- renal fetal pericytes, sorted by flow cytometry, exhibited tri-lineage mesodermal differentiation potential in vitro. Additionally, renin expression was triggered in cultured kidney pericytes by cyclic AMP as confirmed by immuno-electron microscopy, and secretion of enzymatically functional renin, capable of generating angiotensin I. Pericytes derived from second trimester human placenta also expressed renin in an inducible fashion although the renin activity was much lower than in renal pericytes. Thus, our results confirm and extend the recently discovered developmental plasticity of microvascular pericytes, and may open new perspectives to the therapeutic regulation of the renin-angiotensin system.
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Rim/ultraestrutura , Pericitos/metabolismo , Renina/metabolismo , Humanos , Rim/embriologia , Células-Tronco Mesenquimais , Cultura Primária de CélulasAssuntos
Agendamento de Consultas , Sistemas de Apoio a Decisões Clínicas , Registros Eletrônicos de Saúde , Serviço Hospitalar de Emergência , Linhas Diretas , Transtornos Relacionados ao Uso de Opioides/terapia , Encaminhamento e Consulta/organização & administração , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Force-sensing insoles are wearable technology that offer an innovative way to measure loading outside of laboratory settings. Few studies, however, have utilized insoles to measure daily loading in real-world settings. This is an ancillary study of a randomized controlled trial examining the effect of weight loss alone, weight loss plus weighted vest, or weight loss plus resistance training on bone health in older adults. The purpose of this ancillary study was to determine the feasibility of using force-sensing insoles to collect daily limb loading metrics, including peak force, impulse, and loading rate. Forty-four participants completed a baseline visit of three, 2-minute walking trials while wearing force-sensing insoles. During month two of the intervention, 37 participants wore insoles for 4 days for 8 waking hours each day. At 6-month follow-up, participants completed three, two-minute walking trials and a satisfaction questionnaire. Criteria for success in feasibility was defined as: a) > 60 % recruitment rate; b) > 80 % adherence rate; c) > 75 % of usable data, and d) > 75 % participant satisfaction. A 77.3 % recruitment rate was achieved, with 44 participants enrolled. Participants wore their insoles an average of 7.4 hours per day, and insoles recorded an average of 5.5 hours per day. Peak force, impulse, and loading rate collected at baseline and follow-up were 100 % usable. During the real-world settings, 87.8 % of data was deemed usable with an average of 1200 min/participant. Lastly, average satisfaction was 80.5 %. These results suggest that force-sensing insoles appears to be feasible to capture real-world limb loading in older adults.
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Fenômenos Mecânicos , Caminhada , Idoso , Humanos , Extremidades , Estudos de Viabilidade , Sapatos , Redução de Peso , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
There are two closely related hik31 operons involved in signal transduction on the chromosome and the pSYSX plasmid in the cyanobacterium Synechocystis sp. strain PCC 6803. We studied the growth, cell morphology, and gene expression in operon and hik mutants for both copies, under different growth conditions, to examine whether the duplicated copies have the same or different functions and gene targets and whether they are similarly regulated. Phenotype analysis suggested that both operons regulated common and separate targets in the light and the dark. The chromosomal operon was involved in the negative control of autotrophic events, whereas the plasmid operon was involved in the positive control of heterotrophic events. Both the plasmid and double operon mutant cells were larger and had division defects. The growth data also showed a regulatory role for the chromosomal hik gene under high-CO(2) conditions and the plasmid operon under low-O(2) conditions. Metal stress experiments indicated a role for the chromosomal hik gene and operon in mediating Zn and Cd tolerance, the plasmid operon in Co tolerance, and the chromosomal operon and plasmid hik gene in Ni tolerance. We conclude that both operons are differentially and temporally regulated. We suggest that the chromosomal operon is the primarily expressed copy and the plasmid operon acts as a backup to maintain appropriate gene dosages. Both operons share an integrated regulatory relationship and are induced in high light, in glucose, and in active cell growth. Additionally, the plasmid operon is induced in the dark with or without glucose.
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Proteínas de Bactérias/metabolismo , Carbono/metabolismo , Luz , Óperon/fisiologia , Synechocystis/metabolismo , Proteínas de Bactérias/genética , Cromossomos Bacterianos , Meios de Cultura , Metabolismo Energético/fisiologia , Deleção de Genes , Regulação Bacteriana da Expressão Gênica/fisiologia , Modelos Biológicos , Pigmentos Biológicos , Transdução de Sinais/fisiologia , Synechocystis/genéticaRESUMO
OBJECTIVE: Peer support specialists (PSSs) can effectively link patients with substance use disorders (SUD) to treatment. These specialists can engage patients in treatment after emergency department (ED) visits or inpatient hospitalization, crucial points in time when these patients have contact with the health care system. We describe success of PSSs in recruiting SUD patients into treatment, with attention to racial disparities in linkage to care. METHODS: This is a retrospective, observational cohort study performed at an urban, academic medical center. Patients with SUD who indicated interest in pursuing addiction treatment were linked with PSSs by staff at discharge from the ED or inpatient hospitalization. PSSs then transported willing patients to a partnering addiction treatment facility. The treatment facility provided data on successful linkage to care, defined as enrolling in an inpatient or outpatient treatment program. Our primary outcome was successful enrollment in treatment after engagement. The secondary outcome was patients' agreement to transport to the treatment facility after engagement by a PSS. We performed subgroup analysis of patients by self-described race. RESULTS: A total of 785 patients met inclusion criteria for the study: 168 Black patients and 617 White patients. White patients were more likely than Black patients to be enrolled in treatment by PSSs (adjusted odds ratio [aOR; 95% confidence interval {CI}] = 1.61 [1.11 to 2.34]), after adjusting for the effects of age, sex, insurance, and marital status, p = 0.012. We found no statistically significant differences between races in agreeing to be transported for the total sample or inpatient subjects. For ED patients, White individuals were more likely to be transported to treatment compared to Black or African American patients (adjusted odds ratio [aOR; 95% confidence interval {CI}] = 1.50 [1.00 to 2.23]). CONCLUSION: Our results provide evidence of racial disparities in successful linkage to care by PSSs among patients with SUD. Fewer Black patients were successfully linked to care when approached in the ED, where the majority of these patients were engaged, and after controlling age, sex, insurance, and marital status. Future research should study factors that drive these disparities, and how to successfully link all patients to care.
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Negro ou Afro-Americano , Transtornos Relacionados ao Uso de Substâncias , População Negra , Estudos de Coortes , Serviço Hospitalar de Emergência , Disparidades em Assistência à Saúde , Humanos , Transtornos Relacionados ao Uso de Substâncias/terapiaRESUMO
The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study, we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the endometrium. Using scRNAseq, we identified a novel population of PDGFRb + mesenchymal stromal cells that developed a unique transcriptomic signature in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they were stromal fibroblasts in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2/CSPG4+). We demonstrated that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to the rapid restoration of an intact luminal epithelium during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Asherman's syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.
The human uterus is a formidable organ. From puberty to menopause, it completely sheds off its internal lining every 28 days or so, creating what is in effect a large open wound. Unlike the skin or other parts of the body, however, this tissue can quickly repair itself without scarring. This fascinating process remains poorly understood, partly because human samples and animal models that mimic human menstruation are still lacking. This makes it difficult to grasp how various types of uterine cells get mobilised for healing. To fill this gap, Kirkwood et al. focused on fibroblasts, a heterogenous cell population which helps to support the epithelial cells lining the inside of the uterus. How these cells responded to the advent of menstruation was examined in female mice genetically manipulated to have human-like periods. A method known as single-cell RNAseq was used to track which genes were active in each of these cells before, one day and two days after period onset. This revealed the existence of a subpopulation of cells which only appeared when wound healing was most needed. These 'repair-specific' fibroblasts expressed a mixture of genes; those typical of fibroblasts but also some known to be active in the epithelial cells lining the uterus. This suggests that the cells were in the process of changing their identity so they could remake the uterine layer lost during a period. And indeed, labelling these fibroblasts with a fluorescent tag showed that, during healing, they had migrated from within the uterine tissue to become part of its newly restored internal surface. These results represent the first evidence that fibroblasts play a direct role in repairing the uterus during menstruation. From endometriosis to infertility, the lives of millions of people around the world are impacted by disorders which affect the uterine lining. A better understanding of how the uterus can fix itself month after month could help to find new treatments for these conditions. This knowledge could also be useful for to address abnormal wound healing in the skin and other tissues, as this process often involves fibroblasts.
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Endometriose , Células-Tronco Mesenquimais , Feminino , Camundongos , Humanos , Animais , Menstruação/metabolismo , Endométrio , Células-Tronco Mesenquimais/metabolismo , Células Epiteliais/metabolismo , Análise de Sequência de RNARESUMO
Decidualization is the hormone-dependent process of endometrial remodeling that is essential for fertility and reproductive health. It is characterized by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodeling. Deficits in decidualization are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-eclampsia. Androgens are key regulators of decidualization that promote optimal differentiation of stromal fibroblasts and activation of downstream signaling pathways required for endometrial remodeling. We have shown that androgen biosynthesis, via 5α-reductase-dependent production of dihydrotestosterone, is required for optimal decidualization of human stromal fibroblasts in vitro, but whether this is required for decidualization in vivo has not been tested. In the current study we used steroid 5α-reductase type 1 (SRD5A1) deficient mice (Srd5a1-/- mice) and a validated model of induced decidualization to investigate the role of SRD5A1 and intracrine androgen signaling in endometrial decidualization. We measured decidualization response (weight/proportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5α-reductase deficiency on the decidualization response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signaling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5α-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualization restored decidualization responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signaling is required for optimal decidualization in vivo and confirm a major role for androgens in the development of the vasculature during decidualization through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signaling in the endometrium.
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3-Oxo-5-alfa-Esteroide 4-Desidrogenase , Decídua , Remodelação Vascular , Animais , Feminino , Camundongos , Gravidez , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Androgênios/farmacologia , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Decídua/efeitos dos fármacos , Decídua/metabolismo , Di-Hidrotestosterona/farmacologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética , Remodelação Vascular/fisiologiaRESUMO
The human endometrium is a remarkable tissue which may experience up to 400 cycles of hormone-driven proliferation, differentiation and breakdown during a woman's reproductive lifetime. During menstruation, when the luminal portion of tissue breaks down, it resembles a bloody wound with piecemeal shedding, exposure of underlying stroma and a strong inflammatory reaction. In the absence of pathology within a few days the integrity of the tissue is restored without formation of a scar and the endometrium is able to respond appropriately to subsequent endocrine signals in preparation for establishment of pregnancy if fertilization occurs. Understanding mechanisms regulating scarless repair of the endometrium is important both for design of therapies which can treat conditions where this is aberrant (heavy menstrual bleeding, fibroids, endometriosis, Asherman's syndrome) as well as to provide new information that might allow us to reduce fibrosis and scar formation in other tissues. Menstruation only occurs naturally in species that exhibit spontaneous stromal cell decidualization during the fertile cycle such as primates (including women) and the Spiny mouse. To take advantage of genetic models and detailed time course analysis, mouse models of endometrial shedding/repair involving hormonal manipulation, artificial induction of decidualization and hormone withdrawal have been developed and refined. These models are useful in modeling dynamic changes across the time course of repair and have recapitulated key features of endometrial repair in women including local hypoxia and immune cell recruitment. In this review we will consider the evidence that scarless repair of endometrial tissue involves changes in stromal cell function including mesenchyme to epithelial transition, epithelial cell proliferation and multiple populations of immune cells. Processes contributing to endometrial fibrosis (Asherman's syndrome) as well as scarless repair of other tissues including skin and oral mucosa are compared to that of menstrual repair.
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The renal mesenchyme contains heterogeneous cells, including interstitial fibroblasts and pericytes, with key roles in wound healing. Although healing is impaired in aged kidneys, the effect of age and injury on the mesenchyme remains poorly understood. We characterized renal mesenchymal cell heterogeneity in young vs old animals and after ischemia-reperfusion-injury (IRI) using multiplex immunolabeling and single cell transcriptomics. Expression patterns of perivascular cell markers (α-SMA, CD146, NG2, PDGFR-α, and PDGFR-ß) correlated with their interstitial location. PDGFR-α and PDGFR-ß co-expression labeled renal myofibroblasts more efficiently than the current standard marker α-SMA, and CD146 was a superior murine renal pericyte marker. Three renal mesenchymal subtypes; pericytes, fibroblasts, and myofibroblasts, were recapitulated with data from two independently performed single cell transcriptomic analyzes of murine kidneys, the first dataset an aging cohort and the second dataset injured kidneys following IRI. Mesenchymal cells segregated into subtypes with distinct patterns of expression with aging and following injury. Baseline uninjured old kidneys resembled post-ischemic young kidneys, with this phenotype further exaggerated following IRI. These studies demonstrate that age modulates renal perivascular/interstitial cell marker expression and transcriptome at baseline and in response to injury and provide tools for the histological and transcriptomic analysis of renal mesenchymal cells, paving the way for more accurate classification of renal mesenchymal cell heterogeneity and identification of age-specific pathways and targets.
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Rim , Traumatismo por Reperfusão , Idoso , Envelhecimento , Animais , Fibrose , Humanos , Isquemia/metabolismo , Rim/patologia , Camundongos , Microvasos , Miofibroblastos/metabolismo , Pericitos/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
In the dense circulatory system of the kidney, as in all vascularized tissues, pericytes enwrap capillaries and microvessels to regulate angiogenesis, stabilize microvascular networks and control blood flow by vasoconstriction. Specialized renal pericytes known as mesangial cells provide physical support to glomerular capillaries, whereas a subset of juxtaglomerular arteriolar pericytes control the local blood pressure in the glomerulus via contraction and influence systemic blood pressure by secreting renin. Similar to pericytes from many other organs, cultured human renal pericytes give rise to mesenchymal stem/stromal cells, suggesting a role of perivascular cells in renal homeostasis and regeneration. On the other hand, pericytes directly contribute to renal fibrosis, and mesangial cells may have an essential role in the development of glomerulosclerosis and other nephropathies. From their early emergence in the renal embryonic rudiment to their distribution in diverse perivascular niches in the adult organ, we review the anatomy and function of pericytes in the healthy and diseased kidney. Many aspects of the ontogeny, specification and functional specialization of renal pericytes remain elusive. The development of powerful models in the easily accessible and genetically tractable zebrafish will help to uncover the multiple facets of these cells.
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Vasos Sanguíneos/patologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Rim/embriologia , Pericitos/fisiologia , Animais , Pressão Sanguínea , Vasos Sanguíneos/citologia , Linhagem da Célula , Humanos , Rim/irrigação sanguínea , Células-Tronco Mesenquimais , Neovascularização Fisiológica , Peixe-ZebraRESUMO
Autologous adipose tissue is used for tissue repletion and/or regeneration as an intact lipoaspirate or as enzymatically derived stromal vascular fraction (SVF), which may be first cultured into mesenchymal stem cells (MSCs). Alternatively, transplant of autologous adipose tissue mechanically fragmented into submillimeter clusters has recently showed remarkable efficacy in diverse therapeutic indications. To document the biologic basis of the regenerative potential of microfragmented adipose tissue, we first analyzed the distribution of perivascular presumptive MSCs in adipose tissue processed with the Lipogems technology, observing a significant enrichment in pericytes, at the expense of adventitial cells, as compared to isogenic enzymatically processed lipoaspirates. The importance of MSCs as trophic and immunomodulatory cells, due to the secretion of specific factors, has been described. Therefore, we investigated protein secretion by cultured adipose tissue clusters or enzymatically derived SVF using secretome arrays. In culture, microfragmented adipose tissue releases many more growth factors and cytokines involved in tissue repair and regeneration, noticeably via angiogenesis, compared to isogenic SVF. Therefore, we suggest that the efficient tissue repair/regeneration observed after transplantation of microfragmented adipose tissue is due to the secretory ability of the intact perivascular niche. Stem Cells Translational Medicine 2018;7:876-886.
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Tecido Adiposo/metabolismo , Pericitos/metabolismo , Gordura Abdominal/citologia , Gordura Abdominal/metabolismo , Tecido Adiposo/citologia , Adulto , Idoso , Aglutininas/metabolismo , Proteínas Angiogênicas/metabolismo , Colagenases/metabolismo , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pessoa de Meia-Idade , Pericitos/citologia , Proteoma/análiseRESUMO
The World Health Organization (WHO) Field Trials of multidrug therapy (MDT) started at Schieffelin Leprosy Research and Training Centre (SLR & IC), Karigiri, India in December 1981. The patients were treated with two MDT regimens. The first (regimen A) consisted of 600mg rifampicin and 300mg of clofazimine given under supervision on 2 consecutive days monthly, 225mg injection of acedapsone bimonthly and dapsone 100mg daily. The second regimen (regimen B) was the conventional MDT (WHO/MDT), rifampicin 600mg and clofazimine 300mg supervised once a month, dapsone 100mg and clofazimine 50mg daily, unsupervised. Both the regimens were administered for a minimum period of 2 years or until skin smear negativity, whichever occurred later. Thirty-four newly detected previously untreated MB patients, 16 of whom received regimen A and 18 regimen B, were reassessed. Both regimens were well accepted and well tolerated by the patients. Clofazimine discolouration was the only adverse effect of MDT seen in these patients. After completion of treatment with MDT, the patients were followed up for a total duration of 466 person-years with a mean of 13.7 +/- 1.4 years per patient. No relapse was seen.