Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10-1 mL/h/kg). A precursor-pool PK-PD model (kin = 6.1 × 10-3 mg/h, kp = 8.6 × 10-4 h-1 and kout = 2.7 × 10-2 h-1) with a parallel transit chain (k0 = 1.9 × 10-1 h-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 × 10-1 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

Complement 3a Receptor 1 on Macrophages and Kupffer cells is not required for the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the iver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3aR1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.

Adipsin and adipocyte-derived C3aR1 regulate thermogenic fat in a sex-dependent fashion.

Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and noncanonical effects on nonimmune cells. The adipsin/C3a/C3a receptor 1 (C3aR1) pathway stimulates insulin secretion and sustains pancreatic ß cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd-knockout mice exhibited increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1-knockout mice exhibited enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1-knockout mice displayed decreased brown fat thermogenesis and were cold intolerant. Female mice expressed lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 was also lower in female subcutaneous adipose tissue than in males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis and defense against cold stress. Our findings establish a potentially new role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

Nuevo índice aterogénico para la predicción de aterosclerosis carotídea basado en la ratio proteína C reactiva no ultrasensible/HDL / New atherogenic index for the prediction of carotid atherosclerosis based on the non-ultrasensitive c-reactive protein/HDL ratio

Introducción La valoración del riesgo cardiovascular aparece en las guías clínicas como medida de prevención de enfermedades cardiovasculares, cuya etiología fundamental es la arteriosclerosis. Una de las herramientas que se utiliza para estimar el riesgo en práctica clínica son los índices aterogénicos (IA), cocientes entre fracciones lipídicas con rangos de referencia bien establecidos. A pesar de su uso extendido, existe todavía información limitada sobre su utilidad clínica. En los últimos años, algunas investigaciones han reforzado el papel de la inflamación en la etiología y cronicidad del proceso aterosclerótico. La inclusión de parámetros inflamatorios en el cálculo de IA podría mejorar su rendimiento diagnóstico en la detección de arteriosclerosis. Nos propusimos evaluar un nuevo IA en forma de ratio entre los valores de proteína C reactiva (PCR) no ultrasensible y las cifras de colesterol unido a lipoproteínas de alta densidad (HDL). Métodos Se incluyeron en el estudio 282 pacientes, asintomáticos, y sin historia de enfermedad cardiovascular. Se realizó en todos ellos analítica con perfil lipídico y PCR, y en el plazo inferior a un mes, ecografía carotídea para evaluar la presencia de ateromatosis. El nuevo IA se estableció como el cociente entre el valor de PCR no ultrasensible en mg/dL (multiplicado por 100) y el valor de HDL en mg/dL. Se comparó con los índices de Castelli I y II, y el índice aterogénico del plasma. La curva ROC determinó que el punto de corte óptimo del nuevo IA fue valor=1, con un área bajo la curva de 0,678 (IC 95% 0,60-0,75; p<0,001). ResultadosLa edad media de la muestra fue 60,4±14,5 años. Un total de 118 pacientes (41,8% del total) tenían arteriosclerosis carotídea. Al evaluar el rendimiento diagnóstico de los IA, encontramos que la ratio PCR·100/HDL mostró los valores más elevados de sensibilidad y valor predictivo positivo (0,73 y 0,68, respectivamente) ... Conclusiones... (AU)

Introduction Current guidelines recommend cardiovascular risk assessment as a preventive measure for cardiovascular diseases, whose fundamental etiology is arteriosclerosis. One of the tools used to estimate risk in clinical practice are atherogenic indices (AI), ratios between lipid fractions with well-established reference ranges. Despite its widespread use, there is still limited information on its clinical utility. In recent years, some research has reinforced the role of inflammation in the etiology and chronicity of the atherosclerotic process. The inclusion of inflammatory parameters in the AI calculation could improve its diagnostic performance in the detection of arteriosclerosis. We sought to evaluate a new AI as a ratio between C-reactive protein (CRP) values and high-density lipoprotein cholesterol (HDL) values. Methods A total of 282 asymptomatic patients with no history of cardiovascular disease were included in the study. Laboratory tests with lipid profile and CRP, and carotid ultrasound to assess the presence of atheromatosis were performed in all of them. The new AI is established as the ratio between non-ultrasensitive CRP value in mg/dL (multiplied by 100) and HDL value in mg/dL. It was compared with the Castelli I and II indices, and the plasma atherogenic index. The optimal cut-off point of the new AI was value=1 as determined by ROC curve, with an area under the curve of 0.678 (95% CI 0.60-0.75; p<0.001).Results Mean age of patients was 60.4±14.5 years. A total of 118 patients (41.8% of total) had carotid arteriosclerosis. When evaluating the diagnostic performance of different AIs, we found that CRP·100/HDL ratio showed the highest values of sensitivity and positive predictive value (0.73 and 0.68, respectively) compared to the Castelli I and II indices, and the plasma atherogenic index. ... Conclusions ... (AU)

New atherogenic index for the prediction of carotid atherosclerosis based on the non-ultrasensitive c-reactive protein/HDL ratio. / Nuevo índice aterogénico para la predicción de aterosclerosis carotídea basado en la ratio proteína C reactiva no ultrasensible/HDL.

INTRODUCTION: Current guidelines recommend cardiovascular risk assessment as a preventive measure for cardiovascular diseases, whose fundamental etiology is arteriosclerosis. One of the tools used to estimate risk in clinical practice are atherogenic indices (AI), ratios between lipid fractions with well-established reference ranges. Despite its widespread use, there is still limited information on its clinical utility. In recent years, some research has reinforced the role of inflammation in the etiology and chronicity of the atherosclerotic process. The inclusion of inflammatory parameters in the AI calculation could improve its diagnostic performance in the detection of arteriosclerosis. We sought to evaluate a new AI as a ratio between C-reactive protein (CRP) values and high-density lipoprotein cholesterol (HDL) values. METHODS: A total of 282 asymptomatic patients with no history of cardiovascular disease were included in the study. Laboratory tests with lipid profile and CRP, and carotid ultrasound to assess the presence of atheromatosis were performed in all of them. The new AI is established as the ratio between non-ultrasensitive CRP value in mg/dL (multiplied by 100) and HDL value in mg/dL. It was compared with the Castelli I and II indices, and the plasma atherogenic index. The optimal cut-off point of the new AI was value=1 as determined by ROC curve, with an area under the curve of 0.678 (95% CI 0.60-0.75; p<0.001). RESULTS: Mean age of patients was 60.4±14.5 years. A total of 118 patients (41.8% of total) had carotid arteriosclerosis. When evaluating the diagnostic performance of different AIs, we found that CRP·100/HDL ratio showed the highest values of sensitivity and positive predictive value (0.73 and 0.68, respectively) compared to the Castelli I and II indices, and the plasma atherogenic index. It was also the only predictor of carotid atheromatosis both when considering its values quantitatively (with OR 1.4 [95% CI 1.1-1.7]; p=0.005), and qualitatively (with OR 2.9 [95% CI 1.5-5.5]; p<0.001) in patients with a CRP·100/HDL ratio>1. CONCLUSIONS: The new PCR·100/HDL index showed the best diagnostic performance in the detection of carotid atheromatosis compared to other classic AIs in this Spanish population of asymptomatic patients.

Manejo odontológico del paciente con frenillo lingual corto: a propósito de un caso / Dental management of the patient with short lingual frenulum: a case report

Introducción: El frenillo lingual corto puede provocar dificultades en la lactancia durante los primeros meses de vida en el neonato. A partir del desarrollo del lenguaje puede ser la causa de una fonética inadecuada. El tratamiento quirúrgico del frenillo debe ir acompañado por un adecuado tratamiento multidisciplinar para favorecer la corrección de las dificultades en la pronunciación. El objetivo del presente artículo es presentar un caso clínico representativo del diagnóstico, tratamiento quirúrgico y rehabilitación miofuncional del frenillo lingual corto, así como analizar la evidencia científica disponible. Caso clínico: Se presenta un paciente varón de 6 años diagnosticado de anquiloglosia severa que acude por dificultad en la pronunciación del fonema “RR”. Se realiza el tratamiento quirúrgico del frenillo mediante electrobisturí y su seguimiento por un logopeda. Conclusiones: El diagnóstico de la patología y la planificación quirúrgica y miofuncional deben tener en cuenta la clasificación del frenillo, la edad del paciente y la anatomía de la región. El tratamiento de la patología asociada al frenillo lingual corto requiere de un equipo multidisciplinar para evitar la recidiva. (AU)

Introduction: The short lingual frenulum can cause breastfeeding difficulties during the first months of life in the neonate. From language development they can be the cause of inadequate phonetics. Surgical treatment of the frenulum must be accompanied by adequate multidisciplinary treatment to improve the correction of pronunciation difficulties. The objective of this article is to present a representative clinical case of the diagnosis, surgical treatment and myofunctional rehabilitation of the short lingual frenulum, as well as to update the available scientific evidence. Case Report: A 6-year-old male patient is presented, diagnosed with severe ankyloglossia who came due to difficulty in pronouncing the phoneme “RR”. Surgical treatment of the frenulum was performed using electrocautery and its follow-up by a speech therapist. Conclusions: The diagnosis of the pathology and the surgical and myofunctional planning must take into account the classification of the frenulum, the age of the patient and the anatomy of the region. The treatment of the pathology associated with short lingual frenulum requires a multidisciplinary team to avoid recurrence. (AU)

Manejo odontológico del paciente con frenillo lingual corto: a propósito de un caso / Dental management of the patient with short lingual frenulum: a case report

Introducción: El frenillo lingual corto puede provocar dificultades en la lactancia durante los primeros meses de vida en el neonato. A partir del desarrollo del lenguaje puede ser la causa de una fonética inadecuada. El tratamiento quirúrgico del frenillo debe ir acompañado por un adecuado tratamiento multidisciplinar para favorecer la corrección de las dificultades en la pronunciación. El objetivo del presente artículo es presentar un caso clínico representativo del diagnóstico, tratamiento quirúrgico y rehabilitación miofuncional del frenillo lingual corto, así como analizar la evidencia científica disponible. Caso clínico: Se presenta un paciente varón de 6 años diagnosticado de anquiloglosia severa que acude por dificultad en la pronunciación del fonema “RR”. Se realiza el tratamiento quirúrgico del frenillo mediante electrobisturí y su seguimiento por un logopeda. Conclusiones: El diagnóstico de la patología y la planificación quirúrgica y miofuncional deben tener en cuenta la clasificación del frenillo, la edad del paciente y la anatomía de la región. El tratamiento de la patología asociada al frenillo lingual corto requiere de un equipo multidisciplinar para evitar la recidiva. (AU)

Introduction: The short lingual frenulum can cause breastfeeding difficulties during the first months of life in the neonate. From language development they can be the cause of inadequate phonetics. Surgical treatment of the frenulum must be accompanied by adequate multidisciplinary treatment to improve the correction of pronunciation difficulties. The objective of this article is to present a representative clinical case of the diagnosis, surgical treatment and myofunctional rehabilitation of the short lingual frenulum, as well as to update the available scientific evidence. Case Report: A 6-year-old male patient is presented, diagnosed with severe ankyloglossia who came due to difficulty in pronouncing the phoneme “RR”. Surgical treatment of the frenulum was performed using electrocautery and its follow-up by a speech therapist. Conclusions: The diagnosis of the pathology and the surgical and myofunctional planning must take into account the classification of the frenulum, the age of the patient and the anatomy of the region. The treatment of the pathology associated with short lingual frenulum requires a multidisciplinary team to avoid recurrence. (AU)

Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury.

BACKGROUND: Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown. METHODS: Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation. FINDINGS: Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis. INTERPRETATION: TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury. FUNDING: Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.

Lateral pterygoid muscle ultrasound-guided injection: A technical note.

BACKGROUND: Temporomandibular disorders (TMDs) are a frequent cause of orofacial pain, causing functional disability and a negative impact on quality of life. Botulinum toxin (BTX-A) injection in lateral pterygoid muscle (LPM) is one of the treatment modalities proposed, but the blind puncture guided by EMG carries a risk of vascular puncture or diffusion of the toxin to nearby muscles. We describe an ultrasound-guided approach and evaluate the spread of the injection in a fresh human cadaver. METHODS: A fresh human cadaver was injected. An out-of-plane approach was performed using a convex probe, injecting 1.0 ml of 0.25% methylene blue dye into the LPM. After, a dissection was performed to isolate the lateral pterygoid muscle and assess the spread of the dye. RESULTS: Ultrasound-guided injection allowed to visualize in real-time the spread of the dye within the LPM. The deep and superficial muscles nearby to LPM were not stained by the dye, but upper and lower head of LPM was heavily stained. CONCLUSION: Ultrasound-guided approach for the injection of BTX-A into the LPM could be considered a successful and safe treatment for myofascial pain related to TMD. Therefore, further clinical studies are needed to study the reproducibility of ultrasound guided LPM injection and to evaluate the clinical results.

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.

Cross-species single-cell comparison of systemic and cardiac inflammatory responses after cardiac injury.

The immune system coordinates the response to cardiac injury and is known to control regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Here we profiled the inflammatory response to heart injury using single cell transcriptomics to compare and contrast two experimental models with disparate outcomes. We used adult mice, which like humans lack the ability to fully recover and zebrafish which spontaneously regenerate after heart injury. The extracardiac reaction to cardiomyocyte necrosis was also interrogated to assess the specific peripheral tissue and immune cell reaction to chronic stress. Cardiac macrophages are known to play a critical role in determining tissue homeostasis by healing versus scarring. We identified distinct transcriptional clusters of monocytes/macrophages in each species and found analogous pairs in zebrafish and mice. However, the reaction to myocardial injury was largely disparate between mice and zebrafish. The dichotomous response to heart damage between the mammalian and zebrafish monocytes/macrophages may underlie the impaired regenerative process in mice, representing a future therapeutic target.

Familial CD45RA- T cells to treat severe refractory infections in immunocompromised patients.

Background: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and Aspergillus infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA- cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective. Methods: We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA- T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and Aspergillus-specific memory T-cells. We also present the method for selecting the best donors for CD45RA- cells in each case and the procedure to isolate and store these cells. Results: The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA- memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes. Conclusion: The use of familial CD45RA- T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.

Comparison of vertical and extended vertical rectus abdominis myocutaneous flaps. An anatomical study.

The extended vertical rectus abdominis myocutaneous (eVRAM) flap has been proposed for reconstruction of large pelviperineal defects where traditional VRAM flap could be insufficient. To compare the dimensions of VRAM and eVRAM flaps an anatomical study was performed. Ten VRAM and ten eVRAM flaps were dissected in ten fresh adult cadavers. Length, width and volume of all the flaps were measured. Length and volume were significantly larger in eVRAM flap compared to VRAM flap (36.55 cm vs. 30.15, p=.005; and 315.5 vs. 244 mL, p=.012, respectively). No differences were observed in flap width. The eVRAM flap could be a better option than traditional VRAM for reconstruction of big pelviperineal defects when bulkier tissue, larger skin paddle and/or longer arch of rotation are needed for reconstruction.

Prevalence and morphometric analysis of the retromolar canal in a Spanish population sample: a helical CT scan study

Background: The retromolar canal (RMC) is an anatomical variation of the mandibular canal (MC) whose identification and study should be considered given its implication in the surgical procedures of the retromolar area. The prevalence of the RMC widely varies according to previous studies and may be influenced by the followed study method. This work aimed to evaluate the prevalence of the RMC in a Spanish population sample. Material and Methods: For this purpose, 225 CT scan images (with a higher resolution than the cone beam CT used in other previous studies) from the Hospital Clínico Universitario de Valencia were analyzed. The Osirix MD® radiological image analysis system was applied to analyse the dimensions, location in the retromolar area and morphologic characteristics of the RMC by classifying them according to their typology. Furthermore, the relations between the RMC and gender, age and laterality were studied. Results: RMC prevalence was 23.1%. No significant relation between the presence of the canal and gender, age or laterality was found. Type Ia was the commonest type with a prevalence of 40.8%. Conclusions: Based on the results of this study, the RMC should be considered a frequent anatomical variation whose complete study is very important in daily clinical practice.(AU)

Bilateral vertebral arteries arising distal to the left subclavian artery: embryological and anatomical description.

Abnormalities in the origin of vertebral arteries are relatively uncommon, but extremely rare when this abnormality happens on both sides. We present an anatomic variation in which both vertebral arteries came from the proximal descending thoracic aorta beyond the left subclavian artery with no other supra-aortic vessels accompanying the abnormality. The right vertebral artery took a retro-oesophageal course (lusoria artery), while the right and the left vertebral arteries enter the transverse foramina at the 7th cervical vertebra. From an embryological point of view, and overall controversial, this anomaly can be explained by the bilateral persistence of the 8th intersegmental artery as the origin of vertebral artery, instead of the dorsal segment of the 7th intersegmental artery being the origin, which is normally the case. The adequate identification of vertebral artery anomalies in complementary explorations is very important to avoid misdiagnosed vertebral occlusions or unexpected vertebral artery injuries during supra-aortic trunks, thyroid, and oesophagus open surgeries, among others, or even over the course of endovascular procedures.

Extracellular vesicles of human diabetic retinopathy retinal tissue and urine of diabetic retinopathy patients are enriched for the junction plakoglo bin protein.

Introduction: Diabetic Retinopathy (DR) is a potentially blinding retinal disorder that develops through the pathogenesis of diabetes. The lack of disease predictors implies a poor prognosis with frequent irreversible retinal damage and vision loss. Extracellular Vesicles (EVs) present a novel opportunity for pre-symptomatic disease diagnosis and prognosis, both severely limited in DR. All biological fluids contain EVs, which are currently being studied as disease biomarkers. EV proteins derived from urine have emerged as potential noninvasive biomarkers. Methods: In this study, we isolated EVs from DR retinal tissue explants and from DR patients' urine, and characterized the vesicles, finding differences in particle number and size. Next, we performed proteomic analysis on human explanted DR retinal tissue conditioned media, DR retinal EVs and DR urinary EVs and compared to normal human retinal tissue, retinal EVs, and urinary EVs, respectively. Results: Our system biology analysis of DR tissue and EV expression profiles revealed biological pathways related to cell-to-cell junctions, vesicle biology, and degranulation processes. Junction Plakoglobin (JUP), detected in DR tissue-derived EVs and DR urinary EVs, but not in controls, was revealed to be a central node in many identified pathogenic pathways. Proteomic results were validated by western blot. Urinary EVs obtained from healthy donors and diabetic patient without DR did not contain JUP. Conclusion: The absence of JUP in healthy urinary EVs provide the basis for development of a novel Diabetic Retinopathy biomarker, potentially facilitating diagnosis.