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BACKGROUND: Lateral lumbar interbody fusion supplemented with insertion of pedicle screws is a surgical procedure that has gained popularity in the last years, becoming an important tool in the armamentarium of spine surgeons. In recent years, there is a trend to complete both procedures in a single position, thus avoiding flipping the patient prone to insert the pedicle screws. METHODS: We describe a step-by-step workflow of the robotic-assisted technique for multilevel lateral lumbar interbody fusion supplemented with posterior instrumentation. The surgical procedure is performed in a single lateral position. For access to L4-5 or L5-S1, an oblique abdominal incision is performed in the same position, and the desired disc space is approached through an oblique or anterior corridor in the retroperitoneal space. CONCLUSION: Robotic-assisted single-position lateral for multilevel circumferential lumbar interbody fusion is a safe and effective procedure in patients where lumbar stabilization is required. This technique provides patients with a faster recovery and low risk of complications.
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Tornillos Pediculares , Procedimientos Quirúrgicos Robotizados , Fusión Vertebral , Humanos , Columna Vertebral , Fusión Vertebral/métodos , Vértebras Lumbares/cirugíaRESUMEN
Primary intraventricular hemorrhage (PIVH) is a special subtype of intraventricular hemorrhage (IVH) without a hemorrhagic parenchymal component. Different conditions may cause this uncommon hemorrhage including trauma, vascular anomalies, coagulation disorders, and others. Frequently, PIVH is associated with structural vascular anomalies such as aneurysms, arteriovenous malformations, and dural fistulas. Traditionally, hypertension has been considered a predisposing factor for PIVH. A wide variety of studies have been published describing patients with PIVH; however, studies describing exclusively patients with hypertensive PIVH are lacking in the literature. For this reason, the features of PIVH secondary to hypertension are not well described. The purpose of this study is to analyze and describe the characteristics of hypertensive PIVH. A PubMed and Scopus search adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed to include studies reporting patients with hypertensive PIVH. The search yielded 19 articles reporting retrospective case series. The diagnosis of hypertensive PIVH should be established in patients meeting the following criteria: (a) elevation of blood pressure is observed at admission, (b) a cerebral angiography is negative for vascular anomalies, and (c) other causes of intracranial hemorrhage are ruled out. The prognosis is poorer in patients who present with low Glasgow Coma Score (GCS), old age, hydrocephalus, or more extensive intraventricular bleeding. The results of this study show that hypertension is the most common cause of PIVH, followed by hemorrhage caused by vascular anomalies. Hypertension may be a direct cause of PIVH, but also it may be a predisposing factor for bleeding in cases of an associated vascular anomaly.
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Hemorragia Cerebral , Hipertensión , Presión Sanguínea/fisiología , Hemorragia Cerebral/diagnóstico , Ventrículos Cerebrales , Humanos , Hipertensión/complicaciones , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
This paper presents the case of a 68 years old male who was admitted to the hospital after being attacked by another person. The main clinical signs were confusion and severe periorbital edema, findings of gunshot injury were not evident initially. However, a CT scan showed findings compatible with an orbito-cranial perforating gunshot injury. To the best of the author's knowledge, cases like this have not been reported in the literature. This report shows us that an orbito-cranial gunshot injury should be ruled out in cases of severe periorbital edema, especially if the cause of the injury remains unidentified.
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Heridas por Arma de Fuego , Anciano , Edema , Humanos , Masculino , Cráneo , Tomografía Computarizada por Rayos X , Heridas por Arma de Fuego/complicaciones , Heridas por Arma de Fuego/diagnóstico por imagen , Heridas por Arma de Fuego/cirugíaRESUMEN
PURPOSE: Germline pathogenic variants are estimated to affect 3-5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non-clear cell RCC (non-ccRCC) and advanced disease has been suggested. METHODS: To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases. RESULTS: Germline variants in RCC predisposition genes (FH, VHL) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients (P = 0.036). Among the 315 studied patients, 14% of non-type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2) occurred in 5.1% of the unselected series, with unclear significance for RCC. CONCLUSION: Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genética , Células Germinativas , Mutación de Línea Germinal , Humanos , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Mutación , PrevalenciaRESUMEN
The case of a 70-year-old male presenting an ischemic stroke related to COVID-19 infection is described. He was initially admitted to the hospital with respiratory insufficiency syndrome secondary to pneumonia caused by SARS Co2. In the next days, he developed rapid neurological deterioration characterized by drowsiness which progressed to deep coma. D-dimer was elevated. Brain CT scan showed bilateral massive ischemic stroke located in the anterior circulation, CT angiogram showed occlusion in the left internal carotid artery and the right middle cerebral artery. The deterioration of the patient continued and he subsequently died. Large vessel occlusion has been reported in COVID-19 patients, but this clinical presentation is usually unilateral. Cases of bilateral occlusion of large vessels have not been previously reported in COVID-19 patients. This report shows that bilateral massive stroke may occur in COVID-19 cases and it should be suspected in patients who show rapid neurological deterioration without focal deficits.
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Arteriopatías Oclusivas/etiología , COVID-19/complicaciones , Accidente Cerebrovascular Isquémico/etiología , Anciano , Encéfalo/diagnóstico por imagen , COVID-19/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/etiología , Coma/etiología , Angiografía por Tomografía Computarizada , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/etiología , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Masculino , Enfermedades del Sistema Nervioso/etiología , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , TrombectomíaRESUMEN
Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.
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Neoplasias Colorrectales/tratamiento farmacológico , Irinotecán/efectos adversos , Inhibidores de Topoisomerasa I/efectos adversos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/genética , Femenino , Genotipo , Glucuronosiltransferasa/genética , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Glioependymal cysts (GECs) are benign intracranial cysts that have been rarely reported in the literature. The exact pathogenesis of these developmental anomalies is controversial. Moreover, the terminology used to name GECs and other intracranial cysts is confusing because they are undistinguishably reported under a variety of names. The available information in the literature about GECs is scarce, and for this reason, a detailed description about these uncommon lesions is necessary. METHODS: An illustrative case is presented; in addition, a PubMed and Scopus search adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed to include studies reporting patients with GECs. Different information was analyzed in these patients to describe the characteristics of this condition. In addition, different sources of literature were analyzed to complete the description of this clinical entity. RESULTS: The literature review yielded 26 cases of patients with intracranial GECs showing a diversity of clinical manifestations. All studies were case reports or small case series. Different characteristics of GECs are described. Moreover, the authors suggest an updated classification of intracranial benign cysts. CONCLUSIONS: The data collected from this review shows that GECs are rare and very often are erroneously named. They are congenital benign lesions with a neuroectodermal origin that share many radiological characteristics with a variety of intracranial benign cysts. The definite diagnosis of GECs is confirmed by the presence of a glial layer in the cyst wall at histological examination. The appropriate surgical technique should be selected according to the location of the cyst and its proximity to the ventricles or subarachnoid space.
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Encefalopatías/diagnóstico por imagen , Quistes/diagnóstico por imagen , Neuroglía/patología , Anciano , Encefalopatías/patología , Ventrículos Cerebrales/diagnóstico por imagen , Ventrículos Cerebrales/patología , Quistes/patología , Femenino , Humanos , Espacio Subaracnoideo/diagnóstico por imagen , Espacio Subaracnoideo/patologíaRESUMEN
Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.
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Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/efectos adversos , Neoplasias Colorrectales/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/toxicidad , Capecitabina/uso terapéutico , Capecitabina/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Estudios Transversales , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) are important indoor contaminants. Their hydrophobic nature hinders the possibility of biological abatement using biofiltration. Our aim was to establish whether the use of a consortium of Fusarium solani and Rhodococcus erythropolis shows an improved performance (in terms of mineralization rate and extent) towards the degradation of formaldehyde, as a slightly polar VOC; toluene, as hydrophobic VOC; and benzo[α]pyrene (BaP) as PAH at low concentrations compared to a single-species biofilm in serum bottles with vermiculite as solid support to mimic a biofilter and to relate the possible improvements with the surface hydrophobicity and partition coefficient of the biomass at three different temperatures. Results showed that the hydrophobicity of the surface of the biofilms was affected by the hydrophobicity of the carbon source in F. solani but it did not change in R. erythropolis. Similarly, the partition coefficients of toluene and BaP in F. solani biomass (both as pure culture and consortium) show a reduction of up to 38 times compared to its value in water, whereas this reduction was only 1.5 times in presence of R. erythropolis. Despite that increments in the accumulated CO2 and its production rate were found when F. solani or the consortium was used, the mineralization extent of toluene was below 25%. Regarding BaP degradation, the higher CO2 production rates and percent yields were obtained when a consortium of F. solani and R. erythropolis was used, despite a pure culture of R. erythropolis exhibits poor mineralization of BaP.
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Benzo(a)pireno/metabolismo , Biodegradación Ambiental , Formaldehído/metabolismo , Fusarium/metabolismo , Rhodococcus/metabolismo , Tolueno/metabolismo , Contaminación del Aire Interior/prevención & control , Biomasa , Filtración/instrumentación , Consorcios Microbianos/fisiología , Hidrocarburos Policíclicos Aromáticos/metabolismo , Compuestos Orgánicos Volátiles/metabolismoRESUMEN
In the diverse mechanosensory systems that animals evolved, the waveform of stimuli can be encoded by phase locking in spike trains of primary afferents. Coding of the fine structure of sounds via phase locking is thought to be critical for hearing. The upper frequency limit of phase locking varies across species and is unknown in humans. We applied a method developed previously, which is based on neural adaptation evoked by forward masking, to analyze mass potentials recorded on the cochlea and auditory nerve in the cat. The method allows us to separate neural phase locking from receptor potentials. We find that the frequency limit of neural phase locking obtained from mass potentials was very similar to that reported for individual auditory nerve fibers. The results suggest that this is a promising approach to examine neural phase locking in humans with normal or impaired hearing or in other species for which direct recordings from primary afferents are not feasible.
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Cóclea/fisiología , Nervio Coclear/fisiología , Potenciales Evocados Auditivos , Enmascaramiento Perceptual , Adaptación Fisiológica , Animales , Gatos , Femenino , MasculinoRESUMEN
There are different etiologies of hemiparkinsonism. A few patients with hemiparkinsonism secondary to infarction in the contralateral substantia nigra have been reported in the literature, and only one of these patients presented with pure hemiparkinsonism. This paper reports the unusual case of a patient presenting with pure hemiparkinsonism secondary to a lacunar stroke in the substania nigra. A 66-year-old man who presented with a 5-year history of left-sided hemiparkinsonism manifested by tremor, rigidity, and bradykinesia located mainly on the upper extremity. Magnetic resonance imaging of the brain revealed a lacunar infarct located in the right substantia nigra. Patients experiencing sudden hemiparkinsonism should be investigated to rule out any abnormality in the contralateral substantia nigra. This case points to the significance of neuroimaging in the evaluation of unilateral parkinsonism.
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Trastornos Parkinsonianos/etiología , Accidente Vascular Cerebral Lacunar/complicaciones , Sustancia Negra/patología , Anciano , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/patología , Accidente Vascular Cerebral Lacunar/patologíaRESUMEN
INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Familia , Glándulas Mamarias Humanas/anomalías , Adulto , Densidad de la Mama , Neoplasias de la Mama/epidemiología , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/patología , Heterocigoto , Humanos , Mamografía , Persona de Mediana Edad , Mutación , Oportunidad Relativa , Factores de RiesgoRESUMEN
BACKGROUND: Autologous cranioplasty has been used for decades and is the gold standard treatment in patients who underwent decompressive craniectomy (DC). One of the most common methods to store the cranial bone flap is cryopreservation at very low temperatures (-70 to -80°). The only way to achieve these low temperatures is by using special freezers which are not always available in all medical facilities, especially in low-resource centers. This paper describes our experience with the storage of cranial bone flaps in freezers of conventional refrigerators. METHODS: This retrospective study included patients treated with autologous cranioplasty, operated between 2015 and 2020. The cranial bone flap was stored at -18°C in the freezer of conventional refrigerators. Complications and outcomes were analyzed and compared with reports of patients in whom ultra-low temperature freezers were used for bone flap preservation. RESULTS: Twenty-five patients were included. The average follow-up period was 33 months. Trauma was the most common cause of DC, followed by stroke. The mean age was 36.7. Aseptic bone flap resorption was observed in 4 cases (16%). No cases of infection were observed. CONCLUSIONS: The use of freezers from conventional refrigerators may be an acceptable alternative for the preservation of the cranial bone flap in facilities where special freezers are not available. The rate of aseptic bone necrosis and infections observed in this paper was similar to the incidence of these complications reported in studies where ultra-low temperatures were used.
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Resorción Ósea , Craniectomía Descompresiva , Procedimientos de Cirugía Plástica , Humanos , Adulto , Estudios Retrospectivos , Configuración de Recursos Limitados , Craniectomía Descompresiva/métodos , Colgajos Quirúrgicos/cirugía , Cráneo/cirugía , Resorción Ósea/etiología , Complicaciones Posoperatorias/etiologíaRESUMEN
Periodontoid pannus formation is a pathologic condition caused by a multitude of different etiologies, however, it is most commonly due to rheumatoid arthritis. In these cases, the pannus is typically located in the retro-odontoid space ventral to the spinal cord, leading to progressive neural compression. We describe in this report, a patient who presented with progressive high cervical myelopathy, who on imaging revealed both a retro-odontoid pannus and a posterior C1-C2 mass causing severe circumferential compression of the spinal cord. The patient was successfully treated with a C1-C2 laminectomy and occipitocervical fusion. Periodontoid pannus is a common entity; however, the presence of a C1-C2 posterior pannus is a unique finding. To our knowledge, circumferential pannus at C1-C2 causing neural compression is a clinical entity that has not been previously reported.
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This study explores the Hydrothermal Carbonization (HTC) treatment of lignocellulosic biomass blends, delving into the influence of several key parameters: temperature, additive nature and dosage, residence time, and biomass composition. Rapeseeds, Pinus radiata sawdust, oat husks, and pressed olive served as the studied biomasses. One hundred twenty-eight experiments were conducted to assess the effects on mass yield (MY), energy yield (EY), higher heating value (HHV), and final ash content (ASH) by a Factorial Experimental Design. The derived model equations demonstrated a robust fit to the experimental data, averaging an R2 exceeding 0.94, affirming their predictive accuracy. The observed energy yield ranged between 65% and 80%, notably with sawdust and olive blends securing EY levels surpassing 70%, while rapeseed blends exhibited the highest HHV at 25 MJ/kg. Temperature emerged as the most influential factor, resulting in an 11% decrease in MY and a substantial 2.20 MJ/kg increase in HHV. Contrastingly, blend composition and additive presence significantly impacted ASH and EY, with all blends exhibiting increased ASH in the presence of additives. Higher initial hemicellulose and aqueous extractive content in raw biomass correlated proportionally with heightened HHV.
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Biocombustibles , Biomasa , Biocombustibles/análisis , Lignina/química , Temperatura , Pinus/química , Olea/química , Brassica rapa/química , CalorRESUMEN
BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. RESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. CONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.
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Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Femenino , Humanos , Leiomiomatosis/genética , Leiomiomatosis/patología , Neoplasias Renales/genética , Neoplasias Cutáneas/patología , Mutación/genética , SíndromeRESUMEN
Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.
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Quinasas Asociadas a Receptores de Interleucina-1 , Ratones Noqueados , Estrés Oxidativo , Degeneración Retiniana , Epitelio Pigmentado de la Retina , Animales , Humanos , Masculino , Ratones , Senescencia Celular , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Degeneración Macular/metabolismo , Degeneración Macular/patología , Degeneración Macular/genética , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Degeneración Retiniana/genética , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patologíaRESUMEN
BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.