Electroporación irreversible: ampliando las fronteras de la ablación / Irreversible electroporation: Beyond the limits of tumor ablation

La electroporación irreversible o IRE (irreversible electroporation) es una técnica de ablación tumoral no térmica basada en la aplicación de pulsos eléctricos de alto voltaje entre pares de agujas insertadas alrededor de un tumor. La corriente generada favorece la creación de nanoporos en la membrana plasmática, desencadenando la apoptosis. Por ello, la IRE puede utilizarse de manera segura en localizaciones cercanas a estructuras vasculares delicadas, contraindicadas para el resto de técnicas termoablativas. Actualmente la IRE se emplea con éxito para la ablación de tumores en páncreas, riñón e hígado y, de manera muy extendida, como opción terapéutica focal para el cáncer de próstata. La necesidad de un manejo anestésico específico y la colocación precisa y en paralelo de múltiples agujas implican un alto nivel de complejidad, siendo necesaria una gran experiencia del equipo intervencionista. No obstante, se trata de una técnica muy prometedora con una gran capacidad inmunológica sistémica que puede provocar un efecto a distancia del tumor tratado (efecto abscopal).(AU)

Irreversible electroporation (IRE) is a non-thermal tumor ablation technique. High-voltage electrical pulses are applied between pairs of electrodes inserted around and/or inside a tumor. The generated electric current induces the creation of nanopores in the cell membrane, triggering apoptosis. As a result, IRE can be safely used in areas near delicate vascular structures where other thermal ablation methods are contraindicated. Currently, IRE has demonstrated to be a successful ablation technique for pancreatic, renal, and liver tumors and is widely used as a focal therapeutic option for prostate cancer. The need for specific anesthetic management and accurate parallel placement of multiple electrodes entails a high level of complexity and great expertise from the interventional team is required. Nevertheless, IRE is a very promising technique with a remarkable systemic immunological capability and may impact on distant metastases (abscopal effect).(AU)

Irreversible electroporation: Beyond the limits of tumor ablation.

Irreversible Electroporation (IRE) is a non-thermal tumor ablation technique. High-voltage electrical pulses are applied between pairs of electrodes inserted around and/or inside a tumor. The generated electric current induces the creation of nanopores in the cell membrane, triggering apoptosis. As a result, IRE can be safely used in areas near delicate vascular structures where other thermal ablation methods are contraindicated. Currently, IRE has demonstrated to be a successful ablation technique for pancreatic, renal, and liver tumors and is widely used as a focal therapeutic option for prostate cancer. The need for specific anesthetic management and accurate parallel placement of multiple electrodes entails a high level of complexity and great expertise from the interventional team is required. Nevertheless, IRE is a very promising technique with a remarkable systemic immunological capability and may impact on distant metastases (abscopal effect).

Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

[Clinical and radiological effectiveness of natalizumab extended dosage interval in patients with relapsing multiple sclerosis]. / Efectividad clínica y radiológica del intervalo extendido de dosis con natalizumab en pacientes con esclerosis múltiple recurrente.

INTRODUCTION: Natalizumab (NTZ) is a very effective treatment approved for highly active multiple sclerosis. The main risk of treatment with NTZ is the possibility of developing progressive multifocal leukoencephalopathy, which is related to JC virus positivity and the number of NTZ infusions. This risk decreases with the extended dosage interval (EDI), which involves 9 or fewer infusions/year. However, it is a matter of controversy as to whether EDI remains effective in reducing recurrences and the presence of new lesions in magnetic resonance imaging (MRI). PATIENTS AND METHODS: A prospective observational study was conducted from 1 April 2019 to 30 June 2021, following up patients on NTZ treatment who switched to EDI. Patients should have at least one MRI six months after the start of EDI. The presence of attacks or MRI activity (new lesions in T2) during the EDI was recorded. RESULTS: Twenty-three patients with a mean age of 43.5 ± 9.4 years were included. The median number of NTZ infusions was 68 (minimum, 25; maximum, 127). The median interval between the start of the EDI and the last MRI was 14 months (minimum, 6; maximum, 25), and 23 months from the last medical follow-up visit (minimum, 7; maximum, 28). Two patients (8.7%) presented with attacks and two others (8.7%) showed MRI activity. CONCLUSIONS: EDI with NTZ maintains high clinical and activity effectiveness in MRI.

TITLE: Efectividad clínica y radiológica del intervalo extendido de dosis con natalizumab en pacientes con esclerosis múltiple recurrente.Introducción. El natalizumab (NTZ) es un tratamiento de alta eficacia aprobado para la esclerosis múltiple de alta actividad. El principal riesgo del tratamiento con NTZ es la posibilidad de desarrollar una leucoencefalopatía multifocal progresiva, que está en relación con la positividad al virus JC y el número de infusiones del NTZ. Este riesgo disminuye con el intervalo extendido de dosis (IED), lo que supone 9 infusiones/año o menos. Sin embargo, es materia de controversia si el IED mantiene la efectividad sobre la reducción de las recurrencias y la presencia de nuevas lesiones en la resonancia magnética (RM). Pacientes y métodos. Se ha realizado un estudio observacional prospectivo desde el 1 de abril de 2019 hasta el 30 de junio de 2021, siguiendo a los pacientes en tratamiento con NTZ que se pasaron al IED. Los pacientes deberían tener al menos una RM a los seis meses del inicio del IED. Se registró la presencia de brotes o de actividad en la RM (nuevas lesiones en T2) durante el IED. Resultados. Se incluyó a 23 pacientes con una media de edad de 43,5 ± 9,4 años. La mediana de infusiones de NTZ fue de 68 (mínimo, 25; máximo, 127). La mediana del intervalo entre el inicio del IED y la última RM fue de 14 meses (mínimo, 6; máximo, 25), y de 23 meses respecto a la última visita de seguimiento médico (mínimo, 7; máximo, 28). Dos pacientes (8,7%) presentaron brotes y otros dos pacientes (8,7%) presentaron actividad en la RM. Conclusiones. El IED de NTZ mantiene una alta efectividad clínica y de actividad en la RM.

Efectividad clínica y radiológica del intervalo extendido de dosis con natalizumab en pacientes con esclerosis múltiple recurrente / Clinical and radiological effectiveness of natalizumab extended dosage interval in patients with relapsing multiple sclerosis

Introducción: El natalizumab (NTZ) es un tratamiento de alta eficacia aprobado para la esclerosis múltiple de alta actividad. El principal riesgo del tratamiento con NTZ es la posibilidad de desarrollar una leucoencefalopatía multifocal progresiva, que está en relación con la positividad al virus JC y el número de infusiones del NTZ. Este riesgo disminuye con el intervalo extendido de dosis (IED), lo que supone 9 infusiones/año o menos. Sin embargo, es materia de controversia si el IED mantiene la efectividad sobre la reducción de las recurrencias y la presencia de nuevas lesiones en la resonancia magnética (RM). Pacientes y métodos: Se ha realizado un estudio observacional prospectivo desde el 1 de abril de 2019 hasta el 30 de junio de 2021, siguiendo a los pacientes en tratamiento con NTZ que se pasaron al IED. Los pacientes deberían tener al menos una RM a los seis meses del inicio del IED. Se registró la presencia de brotes o de actividad en la RM (nuevas lesiones en T2) durante el IED. Resultados: Se incluyó a 23 pacientes con una media de edad de 43,5 ± 9,4 años. La mediana de infusiones de NTZ fue de 68 (mínimo, 25; máximo, 127). La mediana del intervalo entre el inicio del IED y la última RM fue de 14 meses (mínimo, 6; máximo, 25), y de 23 meses respecto a la última visita de seguimiento médico (mínimo, 7; máximo, 28). Dos pacientes (8,7%) presentaron brotes y otros dos pacientes (8,7%) presentaron actividad en la RM. Conclusiones: El IED de NTZ mantiene una alta efectividad clínica y de actividad en la RM.(AU)

Introduction: Natalizumab (NTZ) is a very effective treatment approved for highly active multiple sclerosis. The main risk of treatment with NTZ is the possibility of developing progressive multifocal leukoencephalopathy, which is related to JC virus positivity and the number of NTZ infusions. This risk decreases with the extended dosage interval (EDI), which involves 9 or fewer infusions/year. However, it is a matter of controversy as to whether EDI remains effective in reducing recurrences and the presence of new lesions in magnetic resonance imaging (MRI). Patients and methods: A prospective observational study was conducted from 1 April 2019 to 30 June 2021, following up patients on NTZ treatment who switched to EDI. Patients should have at least one MRI six months after the start of EDI. The presence of attacks or MRI activity (new lesions in T2) during the EDI was recorded. Results: Twenty-three patients with a mean age of 43.5 ± 9.4 years were included. The median number of NTZ infusions was 68 (minimum, 25; maximum, 127). The median interval between the start of the EDI and the last MRI was 14 months (minimum, 6; maximum, 25), and 23 months from the last medical follow-up visit (minimum, 7; maximum, 28). Two patients (8.7%) presented with attacks and two others (8.7%) showed MRI activity. Conclusions: EDI with NTZ maintains high clinical and activity effectiveness in MRI.(AU)

Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis.

OBJECTIVE: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. METHODS: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. RESULTS: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6-10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. CONCLUSION: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.

Re-focusing on Agnathia-Otocephaly complex.

OBJECTIVES: Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing. MATERIALS AND METHODS: In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998-2019) in order (i) to study etiology (genetic causes, iatrogenic causes…) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies. RESULTS: In our 10 patients' cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1. CONCLUSIONS: From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown. CLINICAL RELEVANCE: We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.

Infiltrating endometriosis: diagnostic keys in abdominal ultrasonography. / Endometriosis infiltrante: claves diagnósticas en la ecografía abdominal.

OBJECTIVE: Endometriosis is the presence of endometrial tissue outside the uterus. Endometriosis of the bowel and urinary tract are types of extragenital endometriosis that manifest with nonspecific symptoms, but their detection involves specific therapeutic strategies. Although the characteristics of the disease on transvaginal ultrasonography and on magnetic resonance imaging have been described in many publications, few references describe its characteristics on abdominal ultrasonography. This paper illustrates the findings for infiltrating endometriosis involving the bowel and urinary tract on abdominal ultrasonography and shows the usefulness of this technique for identifying signs of the disease that have been described with other techniques. Knowledge of infiltrating endometriosis and its ultrasonographic features will enable radiologists to suggest its diagnosis and to include it in the differential diagnosis of pelvic pain in women of child-bearing age. CONCLUSION: Abdominal ultrasonography is a useful tool in the diagnosis of extragenital endometriosis. Familiarity with the ultrasonographic appearance of this entity facilitates the diagnostic orientation and management of patients with pelvic pain.

Usefulness of intestinal ultrasound in inflammatory bowel disease. / Utilidad de la ecografía intestinal en la enfermedad inflamatoria intestinal.

Imaging techniques play a fundamental role in the initial diagnosis and follow-up of inflammatory bowel disease. Intestinal ultrasound has high sensitivity and specificity in patients with suspected Crohn's disease and in the detection of inflammatory activity. This technique enables the early diagnosis of intra-abdominal complications such as stenosis, fistulas, and abscesses. It has also proven useful in monitoring the response to treatment and in detecting postsurgical recurrence. Technical improvements in ultrasound scanners, technological advances such as ultrasound contrast agents and elastography, and above all increased experience have increased the role of ultrasound in the evaluation of the gastrointestinal tract. The features that make ultrasound especially attractive include its wide availability, its noninvasiveness and lack of ionizing radiation, its low cost, and its good reproducibility, which is important because it is easy to repeat the study and the study is well tolerated during follow-up. This review summarizes the role of intestinal ultrasound in the detection and follow-up of inflammatory bowel disease.

Bowel ultrasound: examination techniques and normal and pathologic patterns. / Ecografía intestinal: técnicas de examen, patrones normales y patológicos.

Ultrasound is being increasingly used to study the digestive tract because it has certain advantages over other techniques such as endoscopy, CT enterography, and MR enterography. Ultrasound can be used to evaluate the bowel wall and the elements that surround it without the need for contrast agents; its ability to evaluate the elasticity and peristalsis of these structures is increasing interest in its use. This article describes the techniques and modalities of bowel ultrasound, as well as the normal features of the bowel wall and contiguous structures. It uses a practical approach to review the main pathological findings and their interpretation, and the different patterns of presentation, which will help orient the diagnosis.

[Infection by SARS-CoV-2 in pregnancy and possibility of transmission to neonates: A systematic revision]. / Infección por SARS-CoV-2 en el embarazo y posibilidad de transmisión al neonato: una revisión sistemática.

Studies published on COVID-19, pregnancy and neonate disease until 30 April 2020 are revised. We found 33 articles including 553 pregnant women and 456 deliveries. The more frequent symptoms in the pregnant women were fever, cough and dyspnoea. About two thirds deliveries were carried out via Caesarean rate; 5.9% women were admitted in the ICU and 4% required mechanic ventilation. No maternal death was reported. Prematurity occurred in 22.3% deliveries and 38.3% neonates required admission in the ICU. Only one neonatal death was reported (0.4%) and 13 neonates (3.4%) suffered COVID-19. The available information does not allow to state whether transmission to neonates occurred transplacentarily.

Differential biomarker profiles between unprovoked venous thromboembolism and cancer.

BACKGROUND: The relationship between cancer and venous thromboembolic disease (VTD) are complex because the activated coagulation factors are not only involved in thrombosis but also in malignant processes, such as angiogenesis and metastasis. OBJECTIVE: To compare phenotypes of extracellular vesicles (EVs), and levels of D-dimer, soluble P-selectin (sP-selectin) and antigenic tissue factor (TF) between unprovoked VTD patients, who did not develop cancer during one-year follow-up, and those with advanced stage of cancer but not associated with VTD. METHODS: A prospective study in which we included 138 unprovoked VTD patients and 67 advanced cancer patients, who did not develop thrombosis. Levels of EVs of different cellular origin (platelet, endothelium and leukocyte), EVs positive for tissue factor (TF) and P-selectin glycoprotein ligand 1 were quantified by flow cytometry. D-dimer, soluble P-selectin (sP-selectin) and antigenic TF were determined by ELISA. RESULTS: TF-positive EVs, D-dimer, and sP-selectin were markedly elevated in unprovoked VTD patients compared to cancer patients without association with thrombosis. CONCLUSIONS: Levels of TF-positive EVs, D-dimer and sP-selectin are able to discriminate between unprovoked VTD patients not related to cancer and cancer patients not associated with VTD. These results could lead to the application of EVs as biomarkers of both diseases. Key messages: Circulating EVs, specifically TF-positive EVs, in combination with plasmatic markers of hypercoagulable states, such as D-dimer, sP-selectin and antigen TF, are able to discriminate between cancer patients without thrombosis and patients with unprovoked VTD. Research fields could be opened. Future studies will assess if these biomarkers together serve as predicting thrombotic events in cancer populations.

Historical exposure to non-persistent environmental pollutants and risk of type 2 diabetes in a Spanish sub-cohort from the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND: Environmental factors are believed to account for a substantial burden of type 2 diabetes mellitus (T2DM). Non-persistent environmental pollutants (npEPs) are a group of widely-used chemicals identified as endocrine/metabolic disrupting chemicals and obesogens. The aim of this study was to analyse the potential associations of serum levels of three groups of npEPs with the risk of incident T2DM. METHODS: This is a longitudinal study within a sub-sample of Granada EPIC-Spain cohort (n = 670). We quantified serum concentrations of 7 npEPs: four parabens (Methylparaben (MP) ethylparaben (EP), propylparaben (PP) and butilparaben (BP); two benzophenones: Benzophenone 1 (BP1), Benzophenone 3 (BP3); and Bisphenol A (BPA). Exposure was assessed by means of chemical analyses of serum samples collected at recruitment, and information on potential confounders was gathered by using validated questionnaires at baseline. Follow-up was performed by review of patients' clinical records. Cox Proportional Hazards Models were used for the statistical analyses. RESULTS: Median follow-up time was 23 years. There were 182 (27%) incident T2DM diagnoses in our sub-cohort. MP was the most frequently detected npEP, 88.42% samples above the limit of detection, and BP showed the lowest percentage of detection (19.21%). Those individuals within the fourth PP quartile (0.53-9.24 ng/ml) showed a statistically significant increased risk of T2DM (HR = 1.668 p = 0.012), while BP1 concentrations showed an inverse non-significant trend with the risk. CONCLUSIONS: We evidenced a potential contribution of npEP exposure on T2DM, but no clear trend was observed. However, limitations in relation to exposure estimation might influence our findings and further research is warranted to confirm our results.

Magnetic vortex nucleation and annihilation in bi-stable ultra-small ferromagnetic particles.

Vortex-mediated magnetization reversal in individual ultra-small (∼100 nm) ferromagnetic particles at low temperatures is studied by nanoSQUID magnetometry. At zero applied bias field, the flux-closure magnetic state (vortex) and the quasi uniform configuration are bi-stable. This stems from the extremely small size of the nanoparticles that lies very close to the limit of single-domain formation. The analysis of the temperature-dependent (from 0.3 to 70 K) hysteresis of the magnetization allows us to infer the nature of the ground state magnetization configuration. The latter corresponds to a vortex state as also confirmed by electron holography experiments. Based on the simultaneous analysis of the vortex nucleation and annihilation data, we estimate the magnitude of the energy barriers separating the quasi single-domain and the vortex state and their field dependence. For this purpose, we use a modified power-law scaling of the energy barriers as a function of the applied bias field. These studies are essential to test the thermal and temporal stability of flux-closure states stabilized in ultra-small ferromagnets.

An initial experience with intraoperative O-Arm for deep brain stimulation surgery: can it replace post-operative MRI?

Deep brain stimulation (DBS) is used to treat movement disorders, severe psychiatric disorders, and neuropathic pain, among other diseases. Advanced neuroimaging techniques allow direct or indirect localization of the target site, which is verified in many centers by the intraoperative recording of unitary neuronal activity. Intraoperative image acquisition technology (e.g., O-Arm) is increasingly used for accurate electrode positioning throughout the surgery. The aim of our study is to analyze the initial experience of our team in the utilization of O-Arm for planning DBS and monitoring its precision and accuracy throughout the procedure. The study included 13 patients with movement disorders. All underwent DBS with the intraoperative O-arm image acquisition system (iCT) and Medtronic StealthStation S7 cranial planning system, placing a total of 25 electrodes. For each patient, we calculated the difference between real and theoretic x, y, z coordinates, using the paired Student's t test to evaluate absolute and directional differences and the one-sample Student's t test to analyze differences in Euclidean distances. No statistically significant differences were found in absolute, directional, or Euclidean distances between intended and actual x, y, and z coordinates, based on iCT scan. Our experience confirms that utilization of the O-Arm system in DBS provides accurate and precise verification of electrode placements throughout the procedure. Recent studies found no significant differences between iCT and postoperative MRI, the current gold standard. Further prospective studies are warranted to test the elimination of postoperative MRI when this system is used.

Septo-optic dysplasia caused by a novel FLNA splice site mutation: a case report.

BACKGROUND: Septo-optic dysplasia (SOD), also known as de-Morsier syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain including absence of the septum pellucidum and corpus callosum dysgenesis. The variable presentation of SOD includes visual, neurologic, and/or hypothalamic-pituitary endocrine defects. The unclear aetiology of a large proportion of SOD cases underscores the importance of identifying novel SOD-associated genes. CASE PRESENTATION: To identify the disease-causing gene in a male infant with neonatal hypoglycaemia, dysmorphic features, and hypoplasia of the optic nerve and corpus callosum, we designed a targeted next-generation sequencing panel for brain morphogenesis defects. We identified a novel hemizygous deletion, c.6355 + 4_6355 + 5delAG, in intron 38 of the FLNA gene that the patient had inherited from his mother. cDNA studies showed that this variant results in the production of 3 aberrant FLNA transcripts, the most abundant of which results in retention of intron 38 of FLNA. CONCLUSIONS: We report for the first time a case of early-onset SOD associated with a mutation in the FLNA gene. This finding broadens the spectrum of genetic causes of this rare disorder and expands the phenotypic spectrum of the FLNA gene.

Transforming Growth Factor Beta 1 and Vascular Risk in Alcoholics.

INTRODUCTION: Transforming growth factor beta-1 (TGF-ß1) is a pleiotropic cytokine. Its relationship with atherosclerosis is debatable, protective or deleterious effects have been described. Alcoholics are at increased vascular risk. Although TGF-ß1 is increased in alcoholics, its role on vascular risk factors has not been analyzed. This is the objective of this study. PATIENTS AND METHODS: 79 heavy alcoholics and 34 controls were included. Calcium deposition in the aortic arch was assessed in the plain thorax X-ray film. Ankle-brachial index was recorded in 48 patients. All the patients underwent complete laboratory evaluation, including serum levels of TGF-ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, and interferon-γ (IFN-γ).We analyzed the relationships between TGF-ß1 and vascular risk factors by both univariate (parametric or non parametric tests), or multivariate analysis to discern on which variables TGF-ß1 levels depend. RESULTS: Serum TGF-ß1 levels were higher among patients (t = 2.73; P = 0.008), but no differences exist among cirrhotics (17246 ± 11,021 pg/mL) and non-cirrhotics (21,340 ± 12,442 pg/mL). TGF-ß1 showed significant correlations with total cholesterol (r = 0.28; P = 0.017) and HDL- cholesterol (r = 0.25; P = 0.042), and inverse correlations with body mass index (BMI; ρ = -0.37; P = 0.004), IL-4 (ρ = -0.31; P = 0.009), INF-γ (ρ = -0.28; P = 0.001), and IL-6 (ρ = -0.38; P = 0.001). By multivariate analysis, only BMI, IL-6 and HDL-cholesterol showed independent relationships with TGF-ß1. No relationships were observed with ankle-brachial index or calcium in the aortic arch, hypertension, diabetes, left ventricular hypertrophy or atrial fibrillation. CONCLUSION: TGF-ß1 levels are increased in alcoholics, but are unrelated to vessel wall calcification or arterial stiffness.