Reliability of a point of care testing blood gas analyzer for measurement of lactate levels in cerebrospinal fluid.

Analysis of cerebrospinal fluid (CSF), including lactate, is key for diagnosis of acute meningitis. Since blood gas analyzers (BGA) enable rapid and safe blood-lactate measurements, we evaluated the reliability of RAPIDPoint 500 BGA to provide a fast and accurate measure of CSF lactate. In this study, CSF lactate levels were measured by a reference assay and on RAPIDPoint 500 BGA. Comparability was evaluated through difference analysis, using Bland Altman test, and linear regression analysis, using the Passing Bablok test. Agreement rate according to CSF lactate (≥3.5 and <3.5 mmol/L) was calculated using kappa (κ) statistic. Population study included 98 CSF samples. Concerning difference analysis, according to Bland-Altman test, bias was 0.13 mmol/L (CI 95%: -0.26 to 0.52 mmol/L. In regression analysis, according to Passing-Bablok equation a systematic difference between both assays was found. In concordance analysis, the interrate realibility was very high (κ: 0.964). According to our resuls, although a systematic difference was detected when lactate levels were measured on RAPIDPoint 500 BGA, the results from Bland-Altman test and the high agreement rate support that this POCT analyzer could be useful for a early and safe detection of patients with high probability of increased CSF lactate level.

Recurrent Glioblastoma: A Review of the Treatment Options.

Glioblastoma is a disease with a poor prognosis. Multiple efforts have been made to improve the long-term outcome, but the 5-year survival rate is still 5-10%. Recurrence of the disease is the usual way of progression. In this situation, there is no standard treatment. Different treatment options can be considered. Among them would be reoperation or reirradiation. There are different studies that have assessed the impact on survival and the selection of patients who may benefit most from these strategies. Chemotherapy treatments have also been considered in several studies, mainly with alkylating agents, with data mostly from phase II studies. On the other hand, multiple studies have been carried out with target-directed treatments. Bevacizumab, a monoclonal antibody with anti-angiogenic activity, has demonstrated activity in several studies, and the FDA has approved it for this indication. Several other TKI drugs have been evaluated in this setting, but no clear benefit has been demonstrated. Immunotherapy treatments have been shown to be effective in other types of tumors, and several studies have evaluated their efficacy in this disease, both immune checkpoint inhibitors, oncolytic viruses, and vaccines. This paper reviews data from different studies that have evaluated the efficacy of different forms of relapsed glioblastoma.

Interobserver Variability in Contouring Hepatocellular Carcinoma at a Tertiary Center.

BACKGROUND/AIM: The optimal imaging test for delineation of the gross tumor volume (GTV) in hepatocellular carcinoma has not been defined. The hypothesis is that magnetic resonance imaging (MRI) allows for better visualization of the extent of tumor and will optimize the accuracy of tumor delineation for liver stereotactic radiotherapy compared with computed tomography (CT) only. We evaluated the interobserver agreement in GTV of hepatocellular carcinoma in a multicenter panel and compared MRI and CT in GTV delineation. MATERIALS AND METHODS: After the institutional review boards approved the study, we analyzed anonymous CT and MRI obtained from five patients with hepatocellular carcinoma. Eight radiation oncologists at our center used CT and MRI to delineate five GTVs of liver tumors. In both CT and MRI, the GTV volumes were compared. RESULTS: The median GTV volume on MRI was 2.4 cm3 (range=0.59-15.6 cm3) compared to 3.5 cm3 (range=0.52-24.9 cm3) on CT (p=0.36). The GTV volume as defined on MRI was larger or at least as large as the GTV volume on CT in two cases. Variance and standard deviation between observers in CT and MRI were minor (6 vs. 7.87 cm3, and 2.5 vs. 2.8 cm3 respectively). CONCLUSION: In cases with well-defined tumors, CT is easier and reproducible. In cases with no defined tumor in CT, other tools are needed and MRI can be complementary. The interobserver variability in target delineation of hepatocellular carcinoma in this study is noteworthy.

SARS-CoV-2 Virus in Cancer Patients: A New Unknown in an Unsolved Equation.

INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.

Interobserver variability in gross tumor volume contouring in non-spine bone metastases.

Background and Aim: The optimal imaging test for gross tumor volume (GTV) delineation in non-spine bone metastases has not been defined. The use of stereotactic body radiotherapy (SBRT) requires accurate target delineation. Magnetic resonance imaging (MRI) and/or 18fludesoxyglucose positron emission tomography (18FDG-PET) allow for better visualization of the extent of bone metastases and optimizes the accuracy of tumor delineation for stereotactic radiotherapy compared to computed tomography (CT) alone. We evaluated the interobserver agreement in GTV of non-spine bone metastases in a single center and compared MRI and/or 18FDG-PET and CT in GTV delineation. Methods: Anonymous CT and MRI and/or 18FDG-PET obtained from 10 non-spine bone metastases were analyzed by six radiation oncologists at our center. Images acquired by CT and MRI and/or 18FDG-PET were used to delineate 10 GTVs of non-spine bone metastases in the pelvis, extremities, and skull. The cases showed different characteristics: blastic and lytic metastases, and different primary cancers (lung, breast, prostate, rectum, urothelial, and biliary). In both CT and MRI and/or 18FDG-PET, the GTV volumes were compared. The index of agreement was evaluated according to Landis and Koch protocol. Results: The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT (P=0.25). The median GTV volume on MRI was 3.15 cc (0.027-70.64 cc) compared to 2.8 cc on CT (0.075-77.95 cc). Interobserver variance and standard deviation were lower in CT than MRI (576.3 vs. 722.2 and 24.0 vs. 26.9, respectively). The level of agreement was fair (kappa=0.36) between CT and MRI. The median GTV volume on 18FDG-PET in five patients was 5.8 cc (0.46-64.17 cc), compared to 4.1 cc on CT (0.99-54.2 cc) (P=0.236). Interobserver variance and standard deviation in CT, MRI, and 18FDG-PET were 576.3 versus 722.2 versus 730.5 and 24 versus 26.9 versus 27.0, respectively. The level of agreement was slight (kappa=0.08) between CT and 18FDG-PET. Conclusions: Interobserver variance in non-spine bone metastases was equal when MRI and PET were compared to CT. CT was associated with the lowest variance and standard deviation. Compared to CT GTVs, the GTVs rendered from MRI images had fair agreement, while the GTVs rendered from 18FDG-PET had only slight agreement. Relevance for Patients: The delimitation of the treatment volume in non-spine bone metastases with SBRT is important for the results determining its efficacy. It is therefore essential to know the variability and to manage it to achieve the highest quality of treatment.

Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.

Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in in vivo experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual's capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.

Biomarkers for Immunotherapy in Poorly Differentiated Sinonasal Tumors.

The sinonasal cavities harbor a wide variety of rare cancer types. Histopathological classification can be challenging, especially for poorly differentiated tumors. Despite advances in surgery and radio-chemotherapy, the 5-year survival rate is still very low. Thus, there is an unmet clinical need for new therapeutic options. We retrospectively evaluated poorly differentiated tumors of 9 different histological subtypes from 69 patients who had received conventional treatments for the presence of CD8+ tumor-infiltrating lymphocytes (TILs), as well as the expression of PD-L1 and microsatellite instability (MSI) markers MLH1, MSH2, MSH6 and PMS2, as biomarkers for immunotherapy. CD8+ TILs were present in 23/69 (33%) cases, PD-L1 expression was observed in 23/69 (33%), and markers for MSI positivity in 5/69 (7%) cases. CD8+ TILs correlated with PD-L1 positivity, while both were mutually exclusive with MSI markers. None of the biomarkers were associated with clinical features as age, gender or tumor stage. Cases with CD8+ TILs and PD-L1 positivity showed a tendency toward worse disease-specific survival. Immune checkpoint inhibitors are emerging as new options for treatment of many tumor types. Our results indicate that also a substantial subset of patients with poorly differentiated sinonasal tumors may be a candidate to be treated with this promising new therapy.

Role of steroids in conservative treatment of parapharyngeal and retropharyngeal abscess in children.

PURPOSE: To characterize the clinical features and outcomes of pediatric patients with retropharyngeal (RPA) or parapharyngeal abscesses (PPA) managed only with medical treatment and showing the importance of early symptoms and imaging studies in the diagnosis of deep neck space infections (DNIs) in children. METHODS: A retrospective analysis of all patients diagnosed with RPA and PPA between 2007 and 2017 was performed in Hospital Universitario Central de Asturias. RESULTS: 30 children were identified, with 11 RPA and 19 PPA. 23 children (76.7%) were under 5 years old, and all were treated with intravenous amoxicillin/clavulanic acid and corticosteroids. Torticollis and fever were present in all patients. The mean length of hospital stay was 7.5 days. There were no complications associated. CONCLUSION: DNIs can be treated in a conservative way, reserving the surgical drainage for cases with a complication associated (airway compromise, lack of response to antibiotic therapy, immunocompromised patients). Treatment with intravenous antibiotics and corticosteroids is a safe option, reducing the duration of symptoms and the length of hospital stay.

In vivo application of an implantable tri-anchored methylene blue-based electrochemical pH sensor.

The development of robust implantable sensors is important in the successful advancement of personalised medicine as they have the potential to provide in situ real-time data regarding the status of health and disease and the effectiveness of treatment. Tissue pH is a key physiological parameter and herein, we report the design, fabrication, functionalisation, encapsulation and protection of a miniaturised, self-contained, electrochemical pH sensor system and characterisation of sensor performance. Notably for the first time in this environment the pH sensor was based on a methylene blue redox reporter which showed remarkable robustness, accuracy and sensitivity. This was achieved by encapsulation of a self-assembled monolayer containing methylene blue entrapped within a Nafion layer. Another powerful feature was the incorporation, within the same implanted device, of a fabricated on-chip Ag/AgCl reference electrode - vital in any electrochemical sensor, but often ignored. When utilised in vivo, the sensor allowed accurate tracking of externally induced pH changes within a naturally occurring ovine lung cancer model, and correlated well with single point laboratory measurements made on extracted arterial blood, whilst enabling in vivo time-dependent measurements. The sensors functioned robustly whilst implanted, and maintained in vitro function once extracted and together, these results demonstrate proof-of-concept of the ability to sense real-time intratumoral tissue pH changes in vivo.

[UPOINT phenotypic classification of a sample of female patients with bladder pain syndrome: Results of a national multicentric observational study.] / Clasificación fenotípica UPOINT de una muestra de mujeres con síndrome de dolor vesical: resultados de un estudio observacional multicéntrico nacional.

OBJECTIVES: To study the possibility of classifying patients with BPS by UPOINT phenotypes and their correlation with the results of different BPS diagnostic tools. MATERIAL AND METHODS: Epidemiological, observational, longitudinal and multicentric study performed according to clinical practice. A total of 319 women with BPS were included, 79 with new diagnosis and 240 in follow-up. Sociodemographic and clinical data were collected together with results of cystoscopy, biopsy and physical examination. Patients completed a 3-day Bladder Diary (3dBD) and Patient Reported Outcomes (PROs). All the patients were classified according to the 6 UPOINT domains and their distribution was described according to the clinical history, diagnostic tests, urinary symptoms and PROs' scores. RESULTS: 92.8% of the patients had affectation in more than one phenotype, however, there were no remarkable differences in the clinical and sociodemographic variables according to the number of affected domains. The percentage of patients with 3C classification was higher in the urinary (8.2%), organ-specific (9.0%) and neurological (10.9%) phenotypes. Around 90% had high voiding frequency, regardless of the phenotype. The improvement reported by the PROs was superior in the neurological and tenderness phenotypes. The worst scores were associated with a greater number of affected domains. CONCLUSIONS: The present study is the first one carried out in Spain on a phenotypic classification of women with BPS, with data from routine clinical practice. The results point out that patients with several domains affected present more affectation on the BPS, worse HRQo Land higher anxiety.

OBJETIVOS: Estudiar la posibilidad de clasificar a las pacientes con SDV por los fenotipos UPOINT y su correlación con los resultados de otras herramientas diagnósticas para SDV. MATERIAL Y MÉTODOS: Estudio epidemiológico, observacional, longitudinal y multicéntrico realizado según la práctica clínica habitual. Se incluyeron 319 mujeres con SDV, 79 de nuevo diagnóstico y 240 en seguimiento. Se recogieron datos sociodemográficos y clínicos y resultados de la cistoscopia, biopsia y exploración física. Las pacientes cumplimentaron un diario miccional de 3 días y los Patient Reported Outcomes (PROs). Todas las pacientes fueron clasificadas según los 6 dominios UPOINT y se describió su distribución según la historia clínica, pruebas diagnósticas, síntomas urinarios y las puntuaciones de los PROs. RESULTADOS: El 92,8% de las pacientes tenían afectación en más de un fenotipo, sin embargo, no hubo diferencias destacables en las variables clínicas y sociodemográficas según el número de dominios afectados. El porcentaje de pacientes con clasificación 3C fue mayor en los fenotipos urológico (8,2%), órgano-específico (9,0%) y neurológico (10,9%). Alrededor del 90% presentaron frecuencia miccional elevada, independientemente del fenotipo. La mejoría reportada por los PROs fue superior en los fenotipos neurológico y tenderness. Las peores puntuaciones se asociaron a un mayor número de dominios afectados. CONCLUSIONES: El presente estudio es el primero realizado en España sobre una clasificación fenotípica de mujeres con SDV, basándose en datos de práctica clínica habitual. Los resultados obtenidos señalan una tendencia a que pacientes con afectación de varios dominios fenotípicos presentan mayor afectación por el SDV, peor CVRS y mayor ansiedad.

Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial.

INTRODUCTION: Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. MATERIAL AND METHODS: This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). RESULTS: Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%). CONCLUSIONS: These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.

Identification of genetic targets in acute myeloid leukaemia for designing targeted therapy.

Few effective therapies exist for acute myeloid leukaemia (AML), in part due to the molecular heterogeneity of this disease. We sought to identify genes crucial to deregulated AML signal transduction pathways which, if inhibited, could effectively eradicate leukaemia stem cells. Due to difficulties in screening primary cells, most previous studies have performed next-generation sequencing (NGS) library knockdown screens in cell lines. Using carefully considered methods including evaluation at multiple timepoints to ensure equitable gene knockdown, we employed a large NGS short hairpin RNA (shRNA) knockdown screen of nearly 5 000 genes in primary AML cells from six patients to identify genes that are crucial for leukaemic survival. Across various levels of stringency, genome-wide bioinformatic analysis identified a gene in the NOX family, NOX1, to have the most consistent knockdown effectiveness in primary cells (P = 5∙39 × 10-5 , Bonferroni-adjusted), impacting leukaemia cell survival as the top-ranked gene for two of the six AML patients and also showing high effectiveness in three of the other four patients. Further investigation of this pathway highlighted NOX2 as the member of the NOX family with clear knockdown efficacy. We conclude that genes in the NOX family are enticing candidates for therapeutic development in AML.

Astrocytic release of ATP through type 2 inositol 1,4,5-trisphosphate receptor calcium signaling and social dominance behavior in mice.

Brain mitochondrial function is critical for numerous neuronal processes. We recently identified a link between brain energy and social dominance, where higher levels of mitochondrial function resulted in increased social competitive ability. The underlying mechanism of this link, however, remains unclear. Here, we investigated the contribution of astrocytic release of adenosine triphosphate (ATP) through the type 2 inositol 1,4,5-triphosphate receptor to social dominance behavior. Mice lacking the type 2 inositol 1,4,5-triphosphate receptor were characterized for their social dominance behavior, as well as their performance on a nonsocial task, the Morris Water Maze. In parallel, we also examined mitochondrial function in the medial prefrontal cortex, nucleus accumbens, and hippocampus to investigate how deficiencies in astrocytic ATP could modulate overall mitochondrial function. While knockout mice showed similar competitive ability compared with their wild-type littermates, dominant knockout mice exhibited a significant delay in exerting their dominance during the initial encounter. Otherwise, there were no differences in anxiety and exploratory traits, spatial learning and memory, or brain mitochondrial function in either light or dark circadian phases. Our findings point to a marginal role of astrocytic ATP through IP3 R2 in social competition, suggesting that, under basal conditions, the neuronal compartment is predominant for social dominance exertion.

Bladder diary characteristics and progress in patients with painful bladder syndrome. / Características del diario miccional y su evolución en pacientes con síndrome de dolor vesical.

OBJECTIVES: The utility and importance of the 3-day Bladder Diary (3dBD) for the diagnosis and management of patients with Bladder Pain Syndrome (BPS) was analyzed. MATERIAL AND METHODS: Epidemiological, observational, longitudinal and multicentric study, carried out under usual conditions of clinical practice. 37 Functional Urology and Urodynamics units included 329 women with BPS according to the criteria of the International Society for the Study of Bladder Pain Syndrome (ESSIC). Of all patients included, 319 were evaluable (79 with new diagnosis and 240 in follow-up). Sociodemographic and clinical variables were collected together with variables related to cystoscopy, biopsy and physical examination and BPS diagnostic tests. Patients completed the "Bladder Pain/Interstitial Cystitis - Symptom Score"(BPIC-SS), "Patient Global Impression of Severity" (PGI-S) and "EuroQoL-5D-5L" (EQ-5D-5L) questionnaires besides of the 3dBD. Results of the 3dBD were described according to urinary symptoms and the symptoms reported through questionnaires, in addition their association was studied. RESULTS: In anamnesis, 74.9% of patients reported increased Urinary Frequency (UF), 59.6% urgency and72.7% nocturia compared to 88.7%, 55.9% and 73.6% as reflected in the 3dBD. The highest correlation indexes (CI) were obtained between BPIC-SS and UF/24h (0.45) and between UF/24 h and PGI-S (-0.36) and EQ-5D-5L (-0.33). Mean voiding volume was higher in patients with better BPIC-SS score (163.72 (SD 68.02ml) y 154.1 (SD 70.63 ml)), at 6 and 12 months. CONCLUSIONS: 3dBD has proven to be a useful and complementary tool to the anamnesis in the evaluation of the repercussion of pain in the micturition pattern and for the differential diagnosis of the symptoms of BPS patients. It also allows to obtain complete and objective information about the symptoms. Although it is necessary to incorporate other tools that complete the clinical characterization of these patients.

OBJETIVOS: Se analizó la utilidad e importancia del Diario Miccional de 3 días (DM3d) en el diagnóstico y manejo de las pacientes con Síndrome de Dolor Vesical (SDV).MATERIAL Y MÉTODOS: Estudio epidemiológico, observacional, longitudinal y multicéntrico, realizado en condiciones de práctica clínica habitual. 37 unidades de Urología Funcional y Urodinámica incluyeron 329 mujeres con SDV bajo criterio de la International Society for the Study of Bladder Pain Syndrome (ESSIC). 319 pacientes fueron evaluables (79 de nuevo diagnóstico y 240 en seguimiento). Se recogieron variables sociodemográficas y clínicas, variables relacionadas con la cistoscopia, biopsia y exploración física, y pruebas diagnósticas para el SDV. Las pacientes completaron los cuestionarios "Bladder Pain/Interstitial Cystitis ­Symptom Score" (BPIC-SS), "Patient Global Impression of Severity" (PGI-S), "EuroQoL-5D-5L" (EQ-5D-5L) y el DM3d. Se describieron los resultados del DM3d según los síntomas miccionales y los síntomas comunicados por las pacientes a través de cuestionarios y se estudiós u asociación. RESULTADOS: En la anamnesis, el 74,9% de pacientes reportaron frecuencia miccional (FM) aumentada, 59,6% urgencia miccional y 72,7% nocturia frente al 88,7%, 55,9%, 73,6% que reflejó el DM3d. Los mayores índices de correlación (ICC) se obtuvieron entre las puntuaciones BPIC-SS y FM/24h (0,45) y entre FM/24h y PGI-S (-0,36) y EQ-5D-5L (-0,33). El Volumen Miccional medio fue superior en las pacientes con mejor puntuación en BPIC-SS, a los 6 y 12 meses (163,72 (DE 68,02 ml) y 154,1 (DE 70,63 ml)). CONCLUSIONES: El DM3d ha demostrado ser una herramienta útil y complementaria a la anamnesis en la evaluación de la repercusión del dolor en el patrón miccional y en el diagnóstico diferencial de los síntomas de estas pacientes. Además, permite obtener información completa y objetiva de los síntomas. Si bien es necesario incorporar otras herramientas que terminen de completar la caracterización clínica de estas pacientes.

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies.

The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.

Miniaturisation of a peptide-based electrochemical protease activity sensor using platinum microelectrodes.

Proteases are ideal target biomarkers as they have been implicated in many disease states, including steps associated with cancer progression. Electrochemical peptide-based biosensors have attracted much interest in recent years. However, the significantly large size of the electrodes typically used in most of these platforms has led to performance limitations. These could be addressed by the enhancements offered by microelectrodes, such as rapid response times, improved mass transport, higher signal-to-noise and sensitivity, as well as more localised and less invasive measurements. We present the production and characterisation of a miniaturised electrochemical biosensor for the detection of trypsin, based on 25 µm diameter Pt microelectrodes (rather than the ubiquitous Au electrodes), benchmarked by establishing the equivalent Pt macroelectrode response in terms of quantitative response to the protease, the kinetics of cleavage and the effects of non-specific protein binding and temperature. Interestingly, although there was little difference between Au and Pt macroelectrode response, significant differences were observed between the responses of the Pt macroelectrode and microelectrode systems indicative of increased reproducibility in the microelectrode SAM structure and sensor performance between the electrodes, increased storage stability and a decrease in the cleavage rate at functionalised microelectrodes, which is mitigated by measurement at normal body temperature. Together, these results demonstrate the robustness and sensitivity of the miniaturised sensing platform and its ability to operate within the clinically-relevant concentration ranges of proteases in normal and disease states. These are critical features for its translation into implantable devices.