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Endodontics has made significant progress in regenerative approaches in recent years, thanks to advances in biologically based procedures or regenerative endodontic therapy (RET). In recent years, our profession has witnessed a clear conceptual shift in this therapy. RET was initially based on a blood clot induced by apical bleeding without harvesting the patient's cells or cell-free RET. Later, the RET encompassed the three principles of tissue engineering, stromal/stem cells, scaffolds, and growth factors, aiming for the regeneration of a functional dentin pulp complex. The regenerated dental pulp will recover the protective mechanisms including innate immunity, tertiary dentin formation, and pain sensitivity. This comprehensive review covers the basic knowledge and practical information for translational applications of stem cell-based RET and tissue engineering procedures for the regeneration of dental pulp. It will also provide overall information on the emerging technologies in biological and synthetic matrices, biomaterials, and signaling molecules, recent advances in stem cell therapy, and updated experimental results. This review brings useful and timely clinical evidence for practitioners to understand the challenges faced for a successful cell-based RET and the importance of preserving or reestablishing tooth vitality. The clinical translation of these current bioengineering approaches will undoubtedly be beneficial to the future practice of endodontics.

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Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARß/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARß/δ on MSC metabolic activity and the relevance of PPARß/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARß/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARß/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARß/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

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A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher's exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

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Mesenchymal stem cells (MSCs) are known to display important regenerative properties through the secretion of proangiogenic factors. Recent evidence pointed at the key role played by exosomes released from MSCs in this paracrine mechanism. Exosomes are key mediators of intercellular communication and contain a cargo that includes a modifiable content of microRNA (miRNA), mRNA, and proteins. Since the biogenesis of the MSCs-derived exosomes is regulated by the cross talk between MSCs and their niche, the content of the exosomes and consequently their biological function are dependent on the cell of origin and the physiologic or pathologic status of their microenvironment. Recent preclinical studies revealed that MSCs-derived exosomes have a critical implication in the angiogenic process since the use of exosomes-depleted conditioned medium impaired the MSCs angiogenesis response. In this review, we discuss the current knowledge related to the angiogenic potential of MSCs-exosomes and methods to enhance their biological activities for improved vascular regeneration. The current gain of insight in exosomes studies highlights the power of combining cell based therapies and their secreted products in therapeutic angiogenesis.

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Mesenchymal stem cells (MSCs) obtained from bone marrow (BM) have been shown to promote neuronal growth and survival. However, the comparative effects of MSCs of different sources, including menstrual MSCs (MenSCs), BM, umbilical cord and chorion stem cells on neurite outgrowth have not yet been explored. Moreover, the modulatory effects of MSCs may be mediated by paracrine mechanisms, i.e. by molecules contained in the MSC secretome that includes soluble factors and extracellular vesicles such as microvesicles and/or exosomes. The biogenesis of microvesicles, characterized by a vesicle diameter of 50 to 1000 nm, involves membrane shedding while exosomes, of 30 to 100 nm in diameter, originate in the multivesicular bodies within cells. Both vesicle types, which can be harvested from the conditioned media of cell cultures by differential centrifugation steps, regulate the function of target cells due to their molecular content of microRNA, mRNA, proteins and lipids. Here, we compared the effect of human menstrual MSCs (MenSCs) mediated by cell-cell contact, by their total secretome or by secretome-derived extracellular vesicles on neuritic outgrowth in primary neuronal cultures. The contact of MenSCs with cortical neurons inhibited neurite outgrowth while their total secretome enhanced it. The extracellular vesicle fractions showed a distinctive effect: while the exosome-enriched fraction enhanced neurite outgrowth, the microvesicle-enriched fraction displayed an inhibitory effect. When we compared exosome fractions of different human MSC sources, MenSC exosomes showed superior effects on the growth of the longest neurite in cortical neurons and had a comparable effect to BM-SC exosomes on neurite outgrowth in dorsal root ganglia neurons. Thus, the growth-stimulating effects of exosomes derived from MenSCs as well as the opposing effects of both extracellular vesicle fractions provide important information regarding the potential use of MenSCs as therapeutic conveyors in neurodegenerative pathologies.

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Nuestro objetivo fue describir la frecuencia de úlceras digitales en una población de pacientes con Esclerosis Sistémica y comparar las características clínicas de los que desarrollaron úlceras de los que no lo hicieron. Se incluyeron en forma retrospectiva pacientes que cumplían criterios ACR para Esclerosis Sistémica. Se recolectaron datos demográficos, clínicos y serológicos de las historias clínicas. Se clasificó a los pacientes en dos grupos: un Grupo A con úlceras digitales y Grupo B aquellos pacientes sin antecedentes de úlceras digitales. Se compararon ambos grupos. Se estudiaron 60 pacientes con diagnóstico de Esclerosis Sistémica, 33% subtipo difuso, edad promedio al diagnóstico de 50,75 ± 14,75 años, el 15% (9 pacientes) eran de sexo masculino. La frecuencia de úlceras digitales fue de 33,33% (n=20). Los pacientes del grupo A eran más jóvenes al momento del diagnóstico (p=0,03) y tenían más tiempo de evolución de la enfermedad (pNS). En este grupo, fue más frecuente la forma difusa (p=0,002) y el fenómeno de Raynaud se inició a edades más precoces (p=0,006). Los pacientes del grupo A presentaron menor capacidad funcional, medida por HAQ score, y mayor frecuencia de patente tardía en la capilaroscopia, aunque no fue estadísticamente significativo. La totalidad de los pacientes de género masculino (n=9) tuvieron úlceras digitales (p <0,0001).Conclusión: El desarrollo de úlceras digitales en nuestro estudio se asoció a inicio más precoz de la enfermedad, a sexo masculino, a la forma difusa y a inicio más temprano de fenómeno de Raynaud.

The aim of this study was to describe digital ulcer frequency ina patient population with Systemic Sclerosis and to compare theclinical features of those who developed ulcers with those who didnot. Retrospectively, patients meeting ACR criteria for SystemicSclerosis were included. Demographic, clinical, and serologicalinformation was obtained from medical records. Patients wereclassified into two groups: Group A comprised patients with digitalulcers, while Group B included patients with no digital ulcers ontheir records. Findings for both groups were compared. We studied60 patients diagnosed with Systemic Sclerosis, 33% with diffusecutaneous subset, the mean age at the time of diagnosis was 50.75± 14.75 years, 15% (9 patients) were males. The frequency of digitalulcers was 33.33% (n=20). Group A patients were younger at thetime of diagnosis (p=0.03) and had longer time of evolution (pNS).The diffuse variant was more frequent in this group (p=0.002) andRaynaud’s phenomenon onset occurred at earlier ages (p=0.006).All male patients (n=9) entered into the study had digital ulcers (p<0.0001).Conclusions: In our study, development of digital ulcers wasassociated with an earlier onset of disease, males, diffuse subsetand an earlier onset of Raynaud’s phenomenon.

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Objetivo: Evaluar cumplimiento, y así mismo concordancia y discordancia de los criterios de clasificación de Esclerosis Sistémica (ES) ACR/EULAR 2013 y ACR 1980 en pacientes con diagnóstico clínico de la enfermedad. Método: Se incluyeron 169 pacientes con diagnóstico de Esclerosis Sistémica. Resultados: El 72,2 por ciento cumplía los criterios ACR 1980, y el 99,4 por ciento (168 pacientes) cumplía los criterios ACR/EULAR 2013. La concordancia absoluta de toda la muestra fue 72,7 por ciento, para el subtipo limitado 35,2 por ciento, y 100 por ciento el difuso. Se subanalizaron los pacientes con limitada que sólo cumplían criterios ACR/EULAR 2013, y se comparó con el resto de las limitadas. Los primeros presentaron en forma estadísticamente significativa menor esclerodactilia distal a MCF, menor presencia de úlceras digitales y pitting scars, menor afectación intersticial pulmonar, y mayor daño microvascular en la capilaroscopia. Conclusión: Los nuevos criterios de clasificación de Esclerosis Sistémica serían más adecuados para detectar esclerodermias limitadas, siendo dicho hallazgo estadísticamente significativo.

Objective: To evaluate the performance, and likewise concordance and discordance of the classification criteria of Systemic Sclerosis ACR/EULAR 2013 and ACR 1980 in a group of patients with clinical diagnosis of SSc. Methods: We enrolled 169 patients with diagnosis of Systemic Sclerosis. Results: 72.2 percent met the 1980 ACR criteria, and 99.4 percent met the ACR/EULAR 2013 criteria. The absolute agreement of the entire sample was 72.7 percent, 35.2 percent for the limited subtype, and 100 percent for the diffuse. Those patients with limited subtype who only met the ACR/EULAR 2013 criteria were compared with the rest of limited patients. The first group had statistically significantly lower sclerodactyly distal to MCF, lower presence of digital ulcers and pitting scars, less interstitial lung involvement, and greater abnormal nail fold capillaries. Conclusion: The new classification criteria for systemic sclerosis seem to be more suitable for detecting limited scleroderma. In the present study, statistically significant discrepancy was found in the limited subtype.

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Introducción: los pacientes lúpicos presentan un riesgo incrementado de deterioro cognitivo (DC) comparado con individuos sanos, el cual puede ser debido a múltiples causas. Objetivo: Describir la frecuencia y características del deterioro cognitivo en pacientes con lupus sin manifestaciones neuropsiquiátricas conocidas. Materiales y método: Se incluyeron pacientes de 16 a 55 años con diagnóstico de LES según criterios del Colegio Americano de Reumatología (ACR) de 1997. Se incluyeron test neuropsicológicos acordes a la propuesta del ACR y el cuestionario de Beck para evaluar depresión. Se definió DC a valores de <2 o más desvíos estándar comparada con la media de población normal en al menos un test. Se consideró focal cuando afectó una o más medidas de un dominio y multifocal en 2 o más dominios. Para comparar proporciones se utilizó prueba exacta de Fisher y para comparar variables numéricas se usó prueba de Kruskal-Wallis. Se consideró significativo un valor de p <0,05. Resultados: Se estudiaron 86 pacientes con lupus, el 90% de origen caucásico, 8% mestizos y 1% amerindio. El 82% alcanzó nivel secundario. La frecuencia de DC fue del 65% (56/86). Los dominios afectados: memoria 45%, funciones ejecutivas 30%, atención 29%, lenguaje 4,6%. Se detectó depresión en un 48% de los pacientes. Se analizaron diferentes factores de riesgo, sin hallar diferencias estadísticamente significativas a excepción de la etnia (p=0,02). Conclusión: Se halló una frecuencia elevada de deterioro cognitivo en pacientes con LES, los pacientes no caucásicos tuvieron mayor DC con diferencias significativas en comparación con los pacientes caucásicos.

Background: patients with systemic lupus erythematosus (SLE)have an increased risk of cognitive impairment (CI) compared tohealthy individuals and it may be due to multiple causes. Objective: To determine the frequency and characteristics of CI inlupus patients without known previous neuropsychiatric events. Methods: Patients aged 16 to 55 fulfilling the 1997 ACR criteria forSLE were included. The neuropsychological test battery proposedby the ACR was used to determine CI and Beck depression werealso assessed. CI was defined as values of ≤2 standard deviationscompared to the mean of the general population in at least one test. It was considered focal involvement if it affected one or more measuresof a single domain and multifocal if 2 or more domains wasaffected. To compare proportions, Fisher’s exact test was used andto compare numerical variables, Kruskal-Wallis. A value of p <0.05was considered significant. Results: 86 patients were evaluated, 90% were Caucasian, 8%mestizos and 1% Amerindian. 82% had high school. CI was foundin 65% of patients (56/86). The affected domains were: memory45%, executive functions 30%, attention 29% and language 4.6%. Depression was detected in 48% of patients. Different risk factorswere analyzed and found no statistically significant differences exceptfor ethnicity (p=0.02). Conclusion: A high frequency of CI was found in patients with SLE,non-Caucasian had higher CI with significant differences in comparisonwith Caucasian patients.

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We report a case of botfly myiasis presenting as an ankle cellulitis in a teenager returning from Guyana. Main clinical features and therapeutic approaches are described.

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We used a preoperative evaluation model based on the clinical history in order to determine the clinical characteristics of the patients. We also estimated the prevalence of asymptomatic disease in ASA1 patients and described the frequency of diagnosis that motivated suspension of the surgery during the preoperative time. Another purpose was to establish the perioperative complications according to the risk index and to detect the medical reasons for suspension of surgery during hospitalization. A total of 777 patients having an indication of surgery were evaluated in this program. Only 507 completed the preoperative evaluation. Of these, 57.79%, had at least one known disease or were diagnosed by their clinical history. Preoperative tests were indicated according to age in ASA1 patients. Complementary studies were indicated in relationship to the history and physical examination in ASA2 and ASA3 patients. After the evaluation, 27 surgeries were suspended: 21 were considered high risk, 2 suffered unknown active infections, and 4 ASA1 patients had severe asymptomatic anemia. A total of 328 patients were admitted for surgery. In 5 of these patients the anesthesiologist stopped the procedure in the operating room. The causes were acute decompensations of known pathologies. There were no complications or deaths related to unknown diseases and no patients died from cardiopulmonary or metabolic complications. In ASA1 patients, there were no complications related to this evaluation. This study allowed us to determine the clinical status of the patients and in consequence high-risk surgeries were canceled. In admitted patients a few surgeries were canceled for clinical reasons. This program probably decreased patient morbimortality, unnecessary hospitalization and costs.

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We used a preoperative evaluation model based on the clinical history in order to determine the clinical characteristics of the patients. We also estimated the prevalence of asymptomatic disease in ASA1 patients and described the frequency of diagnosis that motivated suspension of the surgery during the preoperative time. Another purpose was to establish the perioperative complications according to the risk index and to detect the medical reasons for suspension of surgery during hospitalization. A total of 777 patients having an indication of surgery were evaluated in this program. Only 507 completed the preoperative evaluation. Of these, 57.79

, had at least one known disease or were diagnosed by their clinical history. Preoperative tests were indicated according to age in ASA1 patients. Complementary studies were indicated in relationship to the history and physical examination in ASA2 and ASA3 patients. After the evaluation, 27 surgeries were suspended: 21 were considered high risk, 2 suffered unknown active infections, and 4 ASA1 patients had severe asymptomatic anemia. A total of 328 patients were admitted for surgery. In 5 of these patients the anesthesiologist stopped the procedure in the operating room. The causes were acute decompensations of known pathologies. There were no complications or deaths related to unknown diseases and no patients died from cardiopulmonary or metabolic complications. In ASA1 patients, there were no complications related to this evaluation. This study allowed us to determine the clinical status of the patients and in consequence high-risk surgeries were canceled. In admitted patients a few surgeries were canceled for clinical reasons. This program probably decreased patient morbimortality, unnecessary hospitalization and costs.

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We evaluated retrospectively 96 patients older than 64 years admitted with the diagnosis of Community Acquired Pneumonia (CAP) in order to describe the clinical features, evaluate severity and assess prognostic factors. During an 18-month period 100 cases of CAP were included. Average age was 82.3 years +/- 8.3 (+/- SD). By the time of admission, cough and fever were found in 35% of cases and 48% had altered mental status. Fourteen per cent needed mechanical ventilation. Etiology was determined in 21% of cases. Most common pathogens were S. pneumoniae (38.1%), S. aureus (19%) and H. infuenzae (14.3%). Overall mortality was 29%. The most commonly present criteria of severity were tachypnea (respiratory rate > 30) and a PaO2/FIO2 ratio < 250. Severe pneumonia was found in 60% of patients and mortality in that group was 40%. Multivariate analysis demonstrated that some independent prognostic factors were associated with higher mortality: requirement of vasopressors (Odds Ratio [OR] = 22.0; 95% confidence interval [CI] = 1.9-249.5), oliguria (OR = 9.9; CI = 1.5-66.2), previous neurologic disease (OR = 8.2; CI = 1.8-36.6), PaCO2 > 44 mm/Hg (OR = 6.9; CI = 1.1-43.2), and creatinine > 1.4 mg/dl (OR = 4.7; CI = 1.2-19.1). We conclude that CAP features in elderly patients requiring hospitalization are atypical, severe presentations are frequent and mortality is high. Prognostic factors as found in this study can help the evaluating physician to identify those who require special care.

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We evaluated retrospectively 96 patients older than 64 years admitted with the diagnosis of Community Acquired Pneumonia (CAP) in order to describe the clinical features, evaluate severity and assess prognostic factors. During an 18-month period 100 cases of CAP were included. Average age was 82.3 years +/- 8.3 (+/- SD). By the time of admission, cough and fever were found in 35

of cases and 48

had altered mental status. Fourteen per cent needed mechanical ventilation. Etiology was determined in 21

of cases. Most common pathogens were S. pneumoniae (38.1

), S. aureus (19

) and H. infuenzae (14.3

). Overall mortality was 29

. The most commonly present criteria of severity were tachypnea (respiratory rate > 30) and a PaO2/FIO2 ratio < 250. Severe pneumonia was found in 60

of patients and mortality in that group was 40

. Multivariate analysis demonstrated that some independent prognostic factors were associated with higher mortality: requirement of vasopressors (Odds Ratio [OR] = 22.0; 95

confidence interval [CI] = 1.9-249.5), oliguria (OR = 9.9; CI = 1.5-66.2), previous neurologic disease (OR = 8.2; CI = 1.8-36.6), PaCO2 > 44 mm/Hg (OR = 6.9; CI = 1.1-43.2), and creatinine > 1.4 mg/dl (OR = 4.7; CI = 1.2-19.1). We conclude that CAP features in elderly patients requiring hospitalization are atypical, severe presentations are frequent and mortality is high. Prognostic factors as found in this study can help the evaluating physician to identify those who require special care.

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In our country, patients with congestive heart failure who are treated chronically with digoxin are usually advised by their physicians to stop taking the medication two days a week. This is probably aimed at decreasing digitalis toxicity. Based on digoxin pharmacokinetics we assumed that the drug plasmatic level should diminish by 40 to 50%, below the therapeutic concentration of 0.8 to 2 milligrams, after two days of suspension. The objectives of this study were: a) to analyze the reduction of the plasmatic concentration of digoxin after a two day interruption of treatment, b) to compare the plasmatic levels of the drug between patients who received continuous and discontinuous treatment. A prospective, randomized and simple blind trial was designed. A total of 36 patients with congestive heart failure and systolic dysfunction with atrial fibrillation or sinus rythm were included. Group 1 (19 patients) received continuous treatment and Group 2 (17 patients) took the drug from Monday to Friday. In the continuous treatment group there was no significant difference between the Monday (1.06 +/- 0.55 milligrams) and the Friday (1.1 +/- 0.57 milligrams) digoxin concentrations. In the discontinuous treatment group the Monday digoxin concentration (0.611 +/- 0.396 milligrams) was lower than the Friday one (1.04 +/- 0.58 milligrams). The difference was statistically significant with a p = 0.000002. In conclusion, the two days a week suspension schedule reduces the plasmatic concentration of digoxin to subtherapeutic levels while the continuous regime maintains stable concentrations within the therapeutic range. Adjusting the dose to the creatinine clearance, average concentrations of 1 milligram are obtained. These results suggest that digitalis intoxication could be prevented by adjusting the dose according to renal function rather than interrupting the treatment as it is usually done in our country.

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OBJECTIVE: To evaluate clinically, and with laboratory, tests, women with polycystic ovary syndrome (PCO). PATIENTS: One hundred and twelve women with PCO were studied. METHODS: The following data was recorded: Current age; age at menarche; menstrual irregularity, occurrence of similar cases in the family; fertility, obstetric history; body mass index (BMI); and presence of hirsutism. Serum measurements of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, free testosterone, and dehydroepiandrosterone sulfate were taken. RESULTS: All patients presented either oligomenorrhea (31 percent), periods of secondary amenorrhea (9 percent), or both alterations (60 percent). The majority of the patients were infertile (75.6 percent). The LH/FSH ratio was higher than 2:1 in 55 percent of the patients and higher than 3:1 in 26.2 percent. The ultrasonographic aspect of the ovaries was considered to be normal in 31 percent. CONCLUSION: The main clinical feature of the PCO is the irregularity of menses since menarche, and that the laboratory tests would be important to exclude other disorders such as hyperprolactinemia or hyperandrogenemia caused by late-onset congenital adrenal hyperplasia.

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OBJECTIVE: To determine the serum levels of androstanediol glucuronide (3 alpha-diol G), total T, and free T in hirsute and nonhirsute women. DESIGN: Controlled clinical study. PATIENTS: Hirsute women with oligomenorrhea, hirsute women with regular ovulatory cycles, and nonhirsute women with regular cycles were selected. MAIN OUTCOME MEASURE: Serum levels of 3 alpha-diol G, total T, and free T were measured in 8 hirsute with oligomenorrhea and 11 hirsute women with regular ovulatory cycles and compared with 20 nonhirsute women with regular cycles (control group). Serum 3 alpha-diol G was also measured during the follicular, periovulatory, and luteal phases in hirsute women with regular cycles. RESULTS: Serum levels of 3 alpha-diol G did not change during the menstrual cycle, in addition we observed that there was no difference between the levels of 3 alpha-diol G, total T, and free T in hirsute women with regular cycles when compared with normal women. These three serum androgens were elevated only in the hirsute women with oligomenorrhea. Besides, there was better correlation between total T and free T (r = 0.81) than total T and 3 alpha-diol G (r = 0.49) or free T and 3 alpha-diol G (r = 0.66). CONCLUSION: The findings suggest that serum 3 alpha-diol G does not provide additional benefit as a marker of hirsutism than serum total or free T.

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