A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers.

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.

Hypocitraturia as a biomarker of renal tubular acidosis in patients with Sjögren's disease.

INTRODUCTION: Sjögren's disease (SD) is an immune-mediated chronic inflammatory disease that affects epithelial tissues, mainly salivary and lacrimal glands. It also presents extraglandular manifestations. The main renal manifestation is tubulointerstitial nephritis (TIN), which can manifest as renal tubular acidosis (RTA). Urinary citrate may be a biomarker of RTA in these patients. The objective of this study was to evaluate whether hypocitraturia is a predictive biomarker of RTA in a sample of patients with SD in a tertiary hospital in southern Brazil. METHODS: All patients with SD who met the inclusion criteria and who participated in the rheumatology outpatient clinic of the Irmandade Santa Casa de Misericórdia de Porto Alegre were included. Demographic, SD, serological and urinary data were obtained. RTA was considered in those patients who persistently presented urinary pH above 5.5 and serum pH below 7.35. Patients who persistently had urinary pH above 5.5 underwent a urinary acidification test with furosemide and fludrocortisone. These patients received 1 mg of fludrocortisone and 40 mg of furosemide and had their urine samples tested 2, 4 and 6 h after taking the medications. The test was stopped at any urine sample with pH 5.5 or less. The variables were expressed as mean and standard deviation or interquartile range. The association between hypocitraturia and RTA was assessed using the chi-square. RESULTS: Forty-two patients were included, 95.2% female with a median age of 61.73 years. The prevalence of complete distal RTA was 4.88%. Twenty-eight patients underwent urine acidification testing. Five patients had hypocitraturia, and two of them had complete distal RTA. The association between hypocitraturia and RTA was statistically significant (p < 0.012), with a sensitivity of 100%, specificity of 91.2% and accuracy of 91.7%. The negative predictive value was 100%. The global renal assessment of the population demonstrated two patients with RTA, one patient with decreased renal function and six patients with proteinuria greater than 0.5 g/24 h. CONCLUSION: The prevalence of RTA in the studied population was 4.88%. Hypocitraturia had high sensitivity and accuracy for the diagnosis of RTA.

The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.

OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo. Instead, in human immune cells, TLR2 and TLR4 orchestrate the response to OM-85, which binds to both receptors as shown by surface plasmon resonance assay. Ribonucleic acid-sequencing analyses of human monocyte-derived dendritic cells reveal that OM-85 triggers a pro-inflammatory signature and a unique gene set, which is not induced by canonical agonists of TLR2 or TLR4 and comprises tolerogenic genes. A largely overlapping TLR2/4-dependent gene signature was observed in individual subsets of primary human airway myeloid cells, highlighting the robust effects of OM-85. Collectively, our results suggest caution should be taken when relating murine studies on bacterial lysates to humans. Furthermore, our data shed light on how a standardized bacterial lysate shapes the response through TLR2 and TLR4, which are crucial for immune response, trained immunity, and tolerance.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Pediatric kidney transplantation: outcomes with under and over 6-year-old donors.

OBJECTIVE: Kidney shortage for pediatric kidney transplantation (PKT) entails the need to use low-weight and age donors, despite the apprehension. The aim of this study was to analyze the pediatric deceased donor kidney transplantations (pDDKT) outcomes in the first year after the procedure, stratified by donor age. METHOD: Retrospective cohort of pDDKTs carried out between January 2013, and January 2018, at a PKT reference hospital in Southern Brazil. Donors were divided into group 1 (≤ 6 years), and group 2 (> 6 years); the analysis of the outcomes was carried out in the same period. RESULTS: There were 143 pDDKTs; 51 (35.66%) in group 1; and 92 (64.34%) in group 2. In both groups there were 17 graft losses (11.8%), with vascular thrombosis as the main cause (group 1: 5; group 2: 4). Among the complications, renal artery stenosis (RAS) with indication for angioplasty and stenting was more frequent in group 1 (7.8%; group 2: 2.2%). The 1-year Renal Transplant Recipients' and graft survival did not show significant differences between the groups, (p =  = 0.95). However, the Glomerular Filtration Rate analysis was higher in group 2, reaching, in the 12th month, 79.3 mL/min/1,73m2, compared to 69.7 mL/min/1,73m2 in group 1(p =  = 0.033). CONCLUSIONS: Small donors can be considered for pDDKTs, as long as there is an expert team to perform the transplantation.

Pediatric kidney transplantation: outcomes with under and over 6-year-old donors

Abstract Objective Kidney shortage for pediatric kidney transplantation (PKT) entails the need to use low-weight and age donors, despite the apprehension. The aim of this study was to analyze the pediatric deceased donor kidney transplantations (pDDKT) outcomes in the first year after the procedure, stratified by donor age. Method Retrospective cohort of pDDKTs carried out between January 2013, and January 2018, at a PKT reference hospital in Southern Brazil. Donors were divided into group 1 (≤ 6 years), and group 2 (> 6 years); the analysis of the outcomes was carried out in the same period. Results There were 143 pDDKTs; 51 (35.66%) in group 1; and 92 (64.34%) in group 2. In both groups there were 17 graft losses (11.8%), with vascular thrombosis as the main cause (group 1: 5; group 2: 4). Among the complications, renal artery stenosis (RAS) with indication for angioplasty and stenting was more frequent in group 1 (7.8%; group 2: 2.2%). The 1-year Renal Transplant Recipients' and graft survival did not show significant differences between the groups, (p= = 0.95). However, the Glomerular Filtration Rate analysis was higher in group 2, reaching, in the 12th month, 79.3 mL/min/1,73m2, compared to 69.7 mL/min/1,73m2 in group 1(p= = 0.033). Conclusions Small donors can be considered for pDDKTs, as long as there is an expert team to perform the transplantation.

Real-world effectiveness and safety of direct-acting antivirals for the treatment of hepatitis C virus in kidney and liver transplant recipients: experience of a large transplant center in Brazil.

Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.

Candida: The Ruthless Opportunist.

Spondylodiscitis is a pathology with a devastating potential for functional limitation in patients, which may involve immobilization for months due to the risk of compression or even spinal cord section. It is a rare type of infection occurring in the vertebrae and discs of the spine, and most are bacterial. Fungal cases are rare. We present the clinical case of a 52-year-old female patient with a past medical history of vesicular lithiasis and degenerative disc disease of the cervical spine and no home medication. The patient was hospitalized in the surgery service for about 3.5 months due to necro-hemorrhagic lithiasic pancreatitis that evolved into septic shock and needed organ support in intensive care for 2.5 weeks. Several cycles of antibiotics and endoscopic retrograde cholangiopancreatography (ERCP) with stent placement were performed. She was readmitted for urgent care to the hospital of residence with fever, sweating, and low back pain with sciatica five days after discharge. Lumbar CT and MRI evidence showed the destruction of about two-thirds of the vertebral bodies L3-L4, L5-S1, and adjacent discs, pointing to the diagnosis of infectious spondylodiscitis. Candida albicans was found in blood cultures and lumbar biopsies. The patient was treated with oral fluconazole 400 mg/day for eight months, and the control MRIs showed slow but favorable bone sclerosis over time. She spent a total of 13.5 months in the hospital, including five months in bedbound status. The patient left the hospital walking without any assistance, with an upright mood and disposition. The most likely main fungal infectious factors were the manipulation of the bile ducts, immunosuppression associated with corticosteroid therapy, and multiorgan septic failure. The authors highlight this clinical case for its rarity, complications leading to candidemia, diagnostic and therapeutic delay, complexity, and risk of irreversible injuries to which the patient was subjected. The total recuperation of the patient after such a long physical and emotional struggle was very gratifying.

Myc controls NK cell development, IL-15-driven expansion, and translational machinery.

MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells' ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.

Real-world effectiveness and safety of direct-acting antivirals for the treatment of hepatitis C virus in kidney and liver transplant recipients: experience of a large transplant center in Brazil

ABSTRACT Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.

Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

Latent tuberculosis screening before kidney transplantation in the South of Brazil / Rastreamento de tuberculose latente antes do transplante renal no Sul do Brasil

Abstract Background: Tuberculosis (TB) is a prevalent infection after kidney transplantation (KT) in high-burden countries. Latent tuberculosis infection (LTBI) screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) and/or interferon-gamma release assays (IGRAs) results. We aimed to compare our routine LTBI screening of KT candidates and living donors (LD) with their IGRA results, and evaluate if this would improve isoniazid (INH) treatment referral. Methods: We evaluated adult KT candidates and LD with complete routine LTBI screening and QuantiFERON-TB® Gold In-Tube (QFT) testing. Blood samples were collected from April 4th, 2014 to October 31st, 2018, with follow-up until October 31st, 2019. Results: There were 116 KT recipients, with 30% QFT-positive results. Positive QFT was associated with past TB history (p=0.007), positive TST (p<0.0001), residual radiographic lesions (p=0.003), and diabetes (p=0.035). There were 25 LD, 40% had positive QFT. Positive QFT was associated with a positive TST (p=0.002). Positive QFT results increased INH referral in 80%. Post-transplant TB incidence was 2.6% in a median follow-up of 2 (1-33) months. No variables were associated with post-transplant TB. TB patients had inferior, although non-significant, 5-year graft survival (66.7% vs. 76.5%) (p = 0.402). Conclusion: In the present study, the association of QFT to our routine LTBI screening incremented INH treatment referral, but there was still a high incidence of post-transplant TB, possibly related to other forms of infection, such as new exposure and donor transmission.

Resumo Histórico: Tuberculose (TB) é uma infecção relativamente comum pós-transplante renal (TR) em países com alta prevalência da doença. O rastreamento de infecção latente por tuberculose (ILTB) inclui histórico prévio de TB, achados de radiografia do tórax, resultados do teste tuberculínico (TT) e/ou de ensaio de liberação de interferon-gama (IGRAs). Nosso objetivo foi comparar nossa avaliação de rotina de candidatos ao TR e doadores vivos (DV) com seus resultados de IGRA, avaliando se aumentaria o encaminhamento para tratamento com isoniazida (INH). Métodos: Avaliamos candidatos adultos ao TR e DV com rastreamento para ILTB de rotina completo e coleta de testes QuantiFERON-TB® Gold In-Tube (QFT). Coletamos amostras sanguíneas de 4 de Abril, 2014 - 31 de Outubro, 2018, com acompanhamento até 31 de Outubro, 2019. Resultados: Avaliamos 116 receptores de TR, 30% sendo QFT-positivo. QFT positivo foi associado ao histórico prévio de TB (p=0,007), TT positivo (p<0,0001), lesões radiográficas residuais (p=0,003), diabetes (p=0,035). Avaliamos 25 DV, 40% apresentaram QFT positivo. QFT positivo foi associado a TT positivo (p=0,002). Resultados positivos do QFT aumentaram o encaminhamento para INH em 80%. A incidência de TB pós-transplante foi 2,6% em uma mediana de acompanhamento de 2 (1-33) meses. Nenhuma variável foi associada à TB pós-transplante. Pacientes com TB tiveram sobrevida do enxerto em 5 anos inferior, embora não-significativa (66,7% vs. 76,5%) (p = 0,402). Conclusão: Neste estudo, a associação do QFT à nossa avaliação de ILTB de rotina aumentou o encaminhamento para tratamento com INH, mas ainda houve alta incidência de TB pós-transplante, possivelmente relacionada a outras formas de infecção, como nova exposição e transmissão pelos doadores.

The Isolated Mucosa of the Rat Colon Decellularization, Microscopy and Cell Cultures.

This project presents the most important findings of the studies, which we carried out in our laboratory on the decellularization of the rat isolated colonic mucosa. We have also included some details of the experiences gathered with the muscle layer as well as the whole wall of the colon. The question of the cytocompatibility of this new substrate has been addressed with the application of primary cultures of human cells and well-established cell lines. The possible applications in experimental and medical settings will be discussed.

BK Virus and Cytomegalovirus Coinfections in Kidney Transplantation and Their Impact on Allograft Loss.

We aimed to ascertain the interaction and effects of combined reactivations of BK virus and cytomegalovirus on kidney graft function. All consecutive kidney transplant recipients (KTR) between 2003 and 2016 were included. Of 1976 patients who received a kidney transplant, 23 (1.2%) presented BKV-associated nephropathy (BKVAN). Factors independently associated with BKVAN were diabetes mellitus (odds ratios (OR) 3.895%, confidence intervals (CI) (1.4-10.5)), acute allograft rejection (OR 2.8 95%, CI (1.1-7.6)) and nephrostomy requirement (OR 4.195%, CI (1.3-13)). Cytomegalovirus infection was diagnosed in 19% of KTR patients. Recipients with BKVAN presented more frequently with cytomegalovirus (CMV) infection compared to patients without BKVAN (39% vs. 19%, p = 0.02). Acute allograft rejection (OR 2.95%, CI (1.4-2.4)) and nephrostomy requirement (OR 2.95%, CI (1.2-3)) were independently associated with CMV infection. Sixteen patients (69%) with BKVAN had graft dysfunction at one-year post-transplant and eight of them (35%) lost their graft. Patients presenting with BKVAN and graft loss presented more frequently a cytomegalovirus infection (OR 2.295%, CI (1.3-4.3)). In conclusion, we found a relation between CMV infection and graft loss in patients presenting BKVAN, suggesting that patients with CMV reactivation should be actively screened for BKV.

Latent tuberculosis screening before kidney transplantation in the South of Brazil.

BACKGROUND: Tuberculosis (TB) is a prevalent infection after kidney transplantation (KT) in high-burden countries. Latent tuberculosis infection (LTBI) screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) and/or interferon-gamma release assays (IGRAs) results. We aimed to compare our routine LTBI screening of KT candidates and living donors (LD) with their IGRA results, and evaluate if this would improve isoniazid (INH) treatment referral. METHODS: We evaluated adult KT candidates and LD with complete routine LTBI screening and QuantiFERON-TB® Gold In-Tube (QFT) testing. Blood samples were collected from April 4th, 2014 to October 31st, 2018, with follow-up until October 31st, 2019. RESULTS: There were 116 KT recipients, with 30% QFT-positive results. Positive QFT was associated with past TB history (p=0.007), positive TST (p<0.0001), residual radiographic lesions (p=0.003), and diabetes (p=0.035). There were 25 LD, 40% had positive QFT. Positive QFT was associated with a positive TST (p=0.002). Positive QFT results increased INH referral in 80%. Post-transplant TB incidence was 2.6% in a median follow-up of 2 (1-33) months. No variables were associated with post-transplant TB. TB patients had inferior, although non-significant, 5-year graft survival (66.7% vs. 76.5%) (p = 0.402). CONCLUSION: In the present study, the association of QFT to our routine LTBI screening incremented INH treatment referral, but there was still a high incidence of post-transplant TB, possibly related to other forms of infection, such as new exposure and donor transmission.

Commentaries on the publication entitled: "Structure and distribution of an unrecognized interstitium in human tissues" by Benias et al. (2018)

The claim made in this publication of the existence of a hitherto unknown interstitial space is based on studies with sample-based confocal laser endo-microscopy (pCLM). Due to postings on various web portals (New Cellvizio, EurekAlert, Google Scholar,...) the alleged discovery has found great resonance. Nevertheless, there are several critical issues in this publication, the most important being that this is not the discovery of an "unrecognized" interstitium as it has, in fact, been known for a long time

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Reabsorción Condilar como Complicación Postoperatoria en Pacientes Sometidos a Cirugía Ortognática. Revisión Narrativa / Condylar Resorption as a Postoperative Complication in Patients Undergoing Orthognathic Surgery. Narrative Review

RESUMEN: La reabsorción condilar como complicación postoperatoria en cirugía ortognática es una causa frecuente de recidiva de anomalías dentomaxilares, existiendo diversos factores que se relacionan con su aparición. El objetivo de este estudio fue describir mediante una revisión narrativa la reabsorción condilar como complicación postoperatoria en cirugía ortognática. Se realizó una búsqueda electrónica de la literatura en las bases de datos electrónicas PubMed, EBSCO, TripDatabase y Epistemonikos sin límite de años, en idioma inglés y español, incluyendo revisiones sistemáticas, ensayos clínicos y estudios observacionales. Se excluyeron reportes de casos, estudios en animales y aquellos que no relacionaran la complicación con cirugía ortognática. Se evaluaron los estudios según grado de recomendación y calidad de reporte. Veintiún artículos fueron seleccionados según los criterios de selección establecidos en esta revisión. La literatura reportada sugiere que la reabsorción condilar es una patología de frecuencia relativa en pacientes postoperados de cirugía ortognática (1,4-32 % de los casos) y que está asociada a factores de riesgo preoperatorios tales como género, edad, tipo de anomalía dentomaxilar y técnica quirúrgica utilizada. La reabsorción condilar es una complicación postoperatoria a cirugía ortognática que debemos considerar en la planificación del tratamiento e identificar pacientes con factores de riesgo. Luego de la intervención quirúrgica es de vital importancia realizar un seguimiento estricto a este tipo de pacientes e identificar de forma temprana cambios clínicos y radiográficos. Finalmente, es importante seguir investigando sobre esta materia para establecer criterios de prevención y diagnóstico, con mayor claridad.

ABSTRACT: Condylar resorption as a complication following orthognathic surgery is considered to cause dento-facial anomalies, relating to different pre and intra-operative factors. The aim of the research was to describe condylar resorption as a postoperative complication after orthognathic surgery. A review of the literature was made in four databases: PubMed, EBSCO, Trip database and Epistemonikos. The search was carried out without year limiting, articles in English and Spanish, including systematic reviews, observational studies and clinical trials. Exclusion criteria were applied for report cases, animal studies and articles that do not relate condylar resorption with orthognathic surgery. Quality of evidence and strength of the recommendations were assessed for the chosen studies. For this study 21 articles were selected following the inclusion criteria. The literature found reported that condylar resorption is a relatively frequent complication following orthognathic surgery (1.4-32 % of frequency) and that it can be associated with several factors such as genre, age, dento-maxillary anomaly and surgical technique. Condylar resorption is a complication that we must consider in the planning of orthognathic surgery, in order to identify risk factors and patients who are more likely to present this post-surgical complication. Following surgery, strict follow-up is a key factor to determine early clinical and radiographic changes. Finally, further research is needed to establish stronger prevention and diagnostic criteria.

Cambios Faciales y su Estabilidad en el Tiempo en Pacientes con Fisura Labiopalatina no Sindrómica Sometidos a Distracción Osteogénica Maxilar con Distractor Externo Rígido. Revisión Narrativa / Facial Changes and their Stability over Time in Non-Syndromic Cleft Lip and Palate Patients Undergoing Maxillary Distraction Osteogenesis Through Rigid External Distractor. Narrative Review

RESUMEN: Las fisuras labiopalatinas corresponden a las malformaciones de cabeza y cuello de mayor prevalencia a nivel mundial; dentro de las cuales, aquellas que no están asociadas a síndrome son las más frecuentes. Los pacientes que sufren estas malformaciones presentan en muchos casos hipoplasia maxilar. La distracción osteogénica maxilar mediante distractor externo rígido constituye una alternativa de tratamiento para la corrección de esta deficiencia esqueletal. Describir los cambios faciales y su estabilidad en el tiempo, en pacientes con fisura labio palatina no sindrómica sometidos a distracción osteogénica maxilar con distractor externo rígido. Se realizó una búsqueda estratégica en las bases de datos PubMed, Epistemonikos, EBSCO, BEIC y The Cochrane Library a través de las palabras clave cleft palate; cleft lip and palate; distraction osteogenesis; osteodistraction; callotasis; callotases; callus distraction, maxillary hypoplasia; midface hypoplasia; hypoplastic maxilla; maxillary deficiency; retromaxilla y maxillary retrognatism; con los términos booleanos AND y OR. Se seleccionaron 20 artículos: 2 revisiones sistemáticas, 3 ensayos clínicos, 14 estudios observacionales descriptivos y 1 estudio observacional analítico. La distracción osteogénica maxilar con distractor externo rígido corresponde a una alternativa efectiva en el tratamiento de la retrusión del tercio medio en pacientes con fisura labiopalatina no sindrómica. Esta técnica, sin embargo, no consigue cambios completamente estables, existiendo múltiples factores relacionados con su recidiva.

ABSTRACT: Cleft lip and palate is the world's most prevalent head and neck malformation, within which, nonsyndromic is the most frequent. Patients with this malformation in many cases present maxillary hypoplasia. Maxillary distraction osteogenesis through a rigid external distractor constitutes an alternative to correct this skeletal deficiency. The objective of this study was to describe facial changes and their stability over time in non-syndromic cleft lip and palate patients undergoing distraction osteogenesis through rigid external distractor. An electronic search was carried out in PubMed database, Epistemonikos, EBSCO, BEIC and The Cochrane Library through the keywords cleft palate; cleft lip and palate; distraction osteogenesis; osteodistraction; callotasis; callotases; callus distraction, maxillary hypoplasia; midface hypoplasia; hypoplastic maxilla; maxillary deficiency; retromaxilla and maxillary retrognatism, related to each other with the Boolean terms AND and OR. For this analysis 20 articles were selected: 2 systematic reviews, 3 clinical trials, 14 descriptive observational studies and 1 analytic observational study. Maxillary distraction osteogenesis through rigid external distractor is an effective alternative in the treatment of midface retrusion in non-syndromic cleft lip and palate patients. However, this technique does not completely achieve stable changes, due to multiple factors related to its recurrence.

Albert von Kölliker, Santiago Ramón y Cajal and Camillo Golgi, the main protagonists in the Neuron Theory debate

In the second half of the 19th century Spain was rather isolated from the rest of Europe, although there was remarkable scientific activity. In the midst of this scenario, the figure of Cajal emerged on the scene. During a visit to the laboratory of Luis Simarro in Madrid in 1887, Cajal became acquainted with a paper published by Golgi in 1873 dealing with his famous method. Cajal immediately recognized the value of this method and applied it with much success to the study of the nervous tissue. In the triennium 1887-1889 Cajal's discoveries were so sensational that he decided to attend the meeting of the Anatomische Gesellschaft (Germany Anatomical Society) in Berlin in 1889 in order to present them abroad. The trip proved a great success, and he was able to establish close relations with the president of the society, Alexander von Kölliker, who, in turn, mediated contacts with further renowned scientists such as Retzius, His, Waldeyer, van Gehuchten, etc. Prior to his trip to Berlin, he had already contacted Golgi, but the fact that Cajal's neuronal theory conflicted with Golgi's reticular theory not only prevented a normal relationship between them, but was also -especially on Golgi's part- the source of bitter rivalry between them. Von Kölliker immediately recognized and admired Cajal's stature as a scientist and generously helped him to publicize his ideas throughout the scientific world, and to attain the recognition he deserved. Von Kölliker's relationship with Golgi was of a different nature, and could be described as sincere friendship. Von Kölliker, in fact, proposed both Golgi and Cajal as candidates for the Nobel Prize in 1906, which was subsequently awarded to them jointly. Thanks to Von Kölliker, Cajal's great mentor, the neuronal theory entered the scientific world through the main door and continues to occupy a prevailing position

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