Elevated Peripheral Brain-Derived Neurotrophic Factor Level Associated With Decreasing Insulin Secretion May Forecast Memory Dysfunction in Patients With Long-Term Type 2 Diabetes

BackgroundWith the progressive course of diabetes and the decline in islet function, the cognitive dysfunction of patients aggravated.ObjectiveWe aimed to investigate the roles of brain-derived neurotrophic factor (BDNF) and the Val66Met polymorphism in mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 169 Chinese patients with T2DM were involved and divided into long-term (diabetes duration >10 years) and short-term (diabetes duration ≤10 years) diabetes, and in each group, the patients were separated as MCI and the control. Demographic characteristics, clinical variables, and cognitive performances were assessed. The plasma BDNF level was measured via enzyme-linked immunosorbent assay. The Val66Met polymorphisms were analyzed.ResultsLong-term T2DM have lower 2 h postprandial C-peptide (p < 0.05). The BDNF level was slightly higher in patients with MCI than in the controls in each duration group without statistical significance. The relationship of BDNF to Montreal Cognitive Assessment was not proven either. However, in the long-term diabetes group, BDNF concentration remained as an independent factor of logical memory test (β = −0.27; p < 0.05), and they were negatively correlated (r = −0.267; p = 0.022); BDNF was also negatively correlated with fasting C-peptide (r = −0.260; p = 0.022), 2 h postprandial C-peptide (r = −0.251; p = 0.028), and homeostasis model assessment of insulin resistance (r = −0.312; p = 0.006). In genotypic groups, BDNF Val/Val performed better in logical memory test than Met/Met and Val/Met.ConclusionElevated peripheral BDNF level associated with declined islet function, when combined with its Val66Met polymorphism, may forecast memory dysfunction in patients with long-term T2DM.

Gene Therapy for Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.

Serotonergic Neurons in the Chick Brainstem Express Various Serotonin Receptor Subfamily Genes

Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulatory neurotransmitter. In mammals, 5-HT plays an important role in the regulation of many mental states and the processing of emotions in the central nervous system. Serotonergic neurons in the central nervous system, including the dorsal raphe (DR) and median raphe (MR) nuclei, are spatially clustered in the brainstem and provide ascending innervation to the entire forebrain and midbrain. Both between and within the DR and MR, these serotonergic neurons have different cellular characteristics, developmental origin, connectivity, physiology, and related behavioral functions. Recently, an understanding of the heterogeneity of the DR and MR serotonergic neurons has been developed at the molecular level. In birds, emotion-related behavior is suggested to be modulated by the 5-HT system. However, correspondence between the raphe nuclei of birds and mammals, as well as the cellular heterogeneity in the serotonergic neurons of birds are poorly understood. To further understand the heterogeneity of serotonergic neurons in birds, we performed a molecular dissection of the chick brainstem using in situ hybridization. In this study, we prepared RNA probes for chick orthologs of the following serotonin receptor genes: 5-HTR1A, 5-HTR1B, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2A, 5-HTR2B, 5-HTR2C, 5-HTR3A, 5-HTR4, 5-HTR5A, and 5-HTR7. We showed that the expression pattern of 5-HT receptors in the serotonin neurons of chick DR and MR may vary, suggesting heterogeneity among and within the serotonin neurons of the DR and MR in the chick brainstem. Our findings regarding the molecular properties of serotonergic neurons in the bird raphe system will facilitate a good understanding of the correspondence between bird and mammalian raphes.

Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

Cancer tissue consists of heterogenous cell types, and cancer stem cells (CSCs) are a subpopulation of the tissue which possess therapy resistance, tumor reconstruction capability, and are responsible for metastasis. Intrahepatic cholangiocarcinoma (iCCA) is one of the most common type of liver cancer that is highly aggressive with poor prognosis. Since no target therapy is efficient in improving patient outcomes, new therapeutic approaches need to be developed. CSC is thought to be a promising therapeutic target because of its resistance to therapy. Accumulating evidences suggests that there are many factors (surface marker, stemness-related genes, etc.) and mechanisms (epithelial-mesenchymal transition, mitochondria activity, etc.) which are linked to CSC-like phenotypes. Nevertheless, limited studies are reported about the application of therapy using these mechanisms, suggesting that more precise understandings are still needed. In this review, we overview the molecular mechanisms which modulate CSC-like phenotypes, and discuss the future perspective for targeting CSC in iCCA.

Airway Closure and Expiratory Flow Limitation in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is mostly characterized by the loss of aerated lung volume associated with an increase in lung tissue and intense and complex lung inflammation. ARDS has long been associated with the histological pattern of diffuse alveolar damage (DAD). However, DAD is not the unique pathological figure in ARDS and it can also be observed in settings other than ARDS. In the coronavirus disease 2019 (COVID-19) related ARDS, the impairment of lung microvasculature has been pointed out. The airways, and of notice the small peripheral airways, may contribute to the loss of aeration observed in ARDS. High-resolution lung imaging techniques found that in specific experimental conditions small airway closure was a reality. Furthermore, low-volume ventilator-induced lung injury, also called as atelectrauma, should involve the airways. Atelectrauma is one of the basic tenet subtending the use of positive end-expiratory pressure (PEEP) set at the ventilator in ARDS. Recent data revisited the role of airways in humans with ARDS and provided findings consistent with the expiratory flow limitation and airway closure in a substantial number of patients with ARDS. We discussed the pattern of airway opening pressure disclosed in the inspiratory volume-pressure curves in COVID-19 and in non-COVID-19 related ARDS. In addition, we discussed the functional interplay between airway opening pressure and expiratory flow limitation displayed in the flow-volume curves. We discussed the individualization of the PEEP setting based on these findings.

Somatosensory-Evoked Potentials as a Marker of Functional Neuroplasticity in Athletes: A Systematic Review

BackgroundSomatosensory-evoked potentials (SEP) represent a non-invasive tool to assess neural responses elicited by somatosensory stimuli acquired via electrophysiological recordings. To date, there is no comprehensive evaluation of SEPs for the diagnostic investigation of exercise-induced functional neuroplasticity. This systematic review aims at highlighting the potential of SEP measurements as a diagnostic tool to investigate exercise-induced functional neuroplasticity of the sensorimotor system by reviewing studies comparing SEP parameters between athletes and healthy controls who are not involved in organized sports as well as between athlete cohorts of different sport disciplines.MethodsA systematic literature search was conducted across three electronic databases (PubMed, Web of Science, and SPORTDiscus) by two independent researchers. Three hundred and ninety-seven records were identified, of which 10 cross-sectional studies were considered eligible.ResultsDifferences in SEP amplitudes and latencies between athletes and healthy controls or between athletes of different cohorts as well as associations between SEP parameters and demographic/behavioral variables (years of training, hours of training per week & reaction time) were observed in seven out of 10 included studies. In particular, several studies highlight differences in short- and long-latency SEP parameters, as well as high-frequency oscillations (HFO) when comparing athletes and healthy controls. Neuroplastic differences in athletes appear to be modality-specific as well as dependent on training regimens and sport-specific requirements. This is exemplified by differences in SEP parameters of various athlete populations after stimulation of their primarily trained limb.ConclusionTaken together, the existing literature suggests that athletes show specific functional neuroplasticity in the somatosensory system. Therefore, this systematic review highlights the potential of SEP measurements as an easy-to-use and inexpensive diagnostic tool to investigate functional neuroplasticity in the sensorimotor system of athletes. However, there are limitations regarding the small sample sizes and inconsistent methodology of SEP measurements in the studies reviewed. Therefore, future intervention studies are needed to verify and extend the conclusions drawn here.

Near-Infrared Spectroscopy as a Tool for Marine Mammal Research and Care

Developments in wearable human medical and sports health trackers has offered new solutions to challenges encountered by eco-physiologists attempting to measure physiological attributes in freely moving animals. Near-infrared spectroscopy (NIRS) is one such solution that has potential as a powerful physio-logging tool to assess physiology in freely moving animals. NIRS is a non-invasive optics-based technology, that uses non-ionizing radiation to illuminate biological tissue and measures changes in oxygenated and deoxygenated hemoglobin concentrations inside tissues such as skin, muscle, and the brain. The overall footprint of the device is small enough to be deployed in wearable physio-logging devices. We show that changes in hemoglobin concentration can be recorded from bottlenose dolphins and gray seals with signal quality comparable to that achieved in human recordings. We further discuss functionality, benefits, and limitations of NIRS as a standard tool for animal care and wildlife tracking for the marine mammal research community.

Right Ventricular Function in Acute Respiratory Distress Syndrome: Impact on Outcome, Respiratory Strategy and Use of Veno-Venous Extracorporeal Membrane Oxygenation

Acute respiratory distress syndrome (ARDS) is characterized by protein-rich alveolar edema, reduced lung compliance and severe hypoxemia. Despite some evidence of improvements in mortality over recent decades, ARDS remains a major public health problem with 30% 28-day mortality in recent cohorts. Pulmonary vascular dysfunction is one of the pivot points of the pathophysiology of ARDS, resulting in a certain degree of pulmonary hypertension, higher levels of which are associated with morbidity and mortality. Pulmonary hypertension develops as a result of endothelial dysfunction, pulmonary vascular occlusion, increased vascular tone, extrinsic vessel occlusion, and vascular remodeling. This increase in right ventricular (RV) afterload causes uncoupling between the pulmonary circulation and RV function. Without any contractile reserve, the right ventricle has no adaptive reserve mechanism other than dilatation, which is responsible for left ventricular compression, leading to circulatory failure and worsening of oxygen delivery. This state, also called severe acute cor pulmonale (ACP), is responsible for excess mortality. Strategies designed to protect the pulmonary circulation and the right ventricle in ARDS should be the cornerstones of the care and support of patients with the severest disease, in order to improve prognosis, pending stronger evidence. Acute cor pulmonale is associated with higher driving pressure (≥18 cmH2O), hypercapnia (PaCO2 ≥ 48 mmHg), and hypoxemia (PaO2/FiO2 < 150 mmHg). RV protection should focus on these three preventable factors identified in the last decade. Prone positioning, the setting of positive end-expiratory pressure, and inhaled nitric oxide (INO) can also unload the right ventricle, restore better coupling between the right ventricle and the pulmonary circulation, and correct circulatory failure. When all these strategies are insufficient, extracorporeal membrane oxygenation (ECMO), which improves decarboxylation and oxygenation and enables ultra-protective ventilation by decreasing driving pressure, should be discussed in seeking better control of RV afterload. This review reports the pathophysiology of pulmonary hypertension in ARDS, describes right heart function, and proposes an RV protective approach, ranging from ventilatory settings and prone positioning to INO and selection of patients potentially eligible for veno-venous extracorporeal membrane oxygenation (VV ECMO).

The Contribution of Liver Sinusoidal Endothelial Cells to Clearance of Therapeutic Antibody

Many chronic inflammatory diseases are treated by administration of “biological” therapies in terms of fully human and humanized monoclonal antibodies or Fc fusion proteins. These tools have widespread efficacy and are favored because they generally exhibit high specificity for target with a low toxicity. However, the design of clinically applicable humanized antibodies is complicated by the need to circumvent normal antibody clearance mechanisms to maintain therapeutic dosing, whilst avoiding development of off target antibody dependent cellular toxicity. Classically, professional phagocytic immune cells are responsible for scavenging and clearance of antibody via interactions with the Fc portion. Immune cells such as macrophages, monocytes, and neutrophils express Fc receptor subsets, such as the FcγR that can then clear immune complexes. Another, the neonatal Fc receptor (FcRn) is key to clearance of IgG in vivo and serum half-life of antibody is explicitly linked to function of this receptor. The liver is a site of significant expression of FcRn and indeed several hepatic cell populations including Kupffer cells and liver sinusoidal endothelial cells (LSEC), play key roles in antibody clearance. This combined with the fact that the liver is a highly perfused organ with a relatively permissive microcirculation means that hepatic binding of antibody has a significant effect on pharmacokinetics of clearance. Liver disease can alter systemic distribution or pharmacokinetics of antibody-based therapies and impact on clinical effectiveness, however, few studies document the changes in key membrane receptors involved in antibody clearance across the spectrum of liver disease. Similarly, the individual contribution of LSEC scavenger receptors to antibody clearance in a healthy or chronically diseased organ is not well characterized. This is an important omission since pharmacokinetic studies of antibody distribution are often based on studies in healthy individuals and thus may not reflect the picture in an aging or chronically diseased population. Therefore, in this review we consider the expression and function of key antibody-binding receptors on LSEC, and the features of therapeutic antibodies which may accentuate clearance by the liver. We then discuss the implications of this for the design and utility of monoclonal antibody-based therapies.