Glucans: A Therapeutic Alternative for Sepsis Treatment.

Sepsis treatment is a challenging condition due to its complexity, which involves host inflammatory responses to a severe and potentially fatal infection, associated with organ dysfunction. The aim of this study was to analyze the scientific literature on the immunomodulatory effects of glucans in a murine model of systemic infection induced by cecal ligation and puncture. This study comprises an integrative literature review based on systematic steps, with searches carried out in the PubMed, ScienceDirect, Scopus, Web of Science, and Embase databases. In most studies, the main type of glucan investigated was ß-glucan, at 50 mg/kg, and a reduction of inflammatory responses was identified, minimizing the occurrence of tissue damage leading to increased animal survival. Based on the data obtained and discussed in this review, glucans represent a promising biotechnological alternative to modulate the immune response and could potentially be used in the clinical management of septic individuals.

Investigation of vagal sensory neurons in mice using optical vagal stimulation and tracheal neuroanatomy.

In rats and guinea pigs, sensory innervation of the airways is derived largely from the vagus nerve, with the extrapulmonary airways innervated by Wnt1+ jugular neurons and the intrapulmonary airways and lungs by Phox2b+ nodose neurons; however, our knowledge of airway innervation in mice is limited. We used genetically targeted expression of enhanced yellow fluorescent protein-channelrhodopsin-2 (EYFP-ChR2) in Wnt1+ or Phox2b+ tissues to characterize jugular and nodose-mediated physiological responses and airway innervation in mice. With optical stimulation, Phox2b+ vagal fibers modulated cardiorespiratory function in a frequency-dependent manner while right Wnt1+ vagal fibers induced a small increase in respiratory rate. Mouse tracheae contained sparse Phox2b-EYFP fibers but dense networks of Wnt1-EYFP fibers. Retrograde tracing from the airways showed limited tracheal innervation by the jugular sensory neurons, distinct from other species. These differences in physiology and vagal sensory distribution have important implications when using mice for studying airway neurobiology.

Chemotherapy-induced ovarian damage and protective strategies.

More than 9.2 million women worldwide suffer from cancer, and about 5% of them are at reproductive age. Chemotherapy-induced impairment of fertility affects the quality of life of these women. Several chemotherapeutic agents have been proven to cause apoptosis and autophagy by inducing DNA damage and cellular stress. Injuries to the ovarian stroma and micro-vessel network are also considered as pivotal factors resulting in ovarian dysfunction induced by chemotherapeutic agents. Primordial follicle pool over-activation may also be the mechanism inducing damage to the ovarian reserve. Although many studies have explored the mechanisms involved in chemotherapy-induced reproductive toxicity, the exact molecular mechanisms have not been elucidated. It is essential to understand the mechanisms involved in ovarian damage, in order to develop potential protective treatments to preserve fertility. In this article, we reviewed the current knowledge on the mechanism of chemotherapy-induced ovarian damage and possible protective strategies that prevent the ovary from such damages.

Mitochondrial stress response gene Clpp deficiency impairs oocyte competence and deteriorate cyclophosphamide-induced ovarian damage in young mice.

Chemotherapy is extensively used to treat cancers and is often associated with ovarian damage and leads to premature ovarian insufficiency and infertility, while the role of mitochondria during ovarian damage with chemotherapy remains unknown. This study used a mouse model with oocyte-specific deletion of mitochondrial stress response gene Caseinolytic peptidase P (Clpp) to investigate mitochondrial homeostasis in oocytes from mice receiving a chemotherapeutic drug cyclophosphamide (CTX). We found that oocyte-specific deletion of Clpp reduced fecundity of the mice at advanced age. The deletion led to meiotic defects with elevated abnormal spindle rate and aneuploidy rate with impaired mitochondrial function in the MII oocytes from 8-week-old mice. Upon CTX treatment at 8-week-old, the oocyte competence and folliculogenesis from the oocyte-specific Clpp knockout mice was further deteriorated with dramatic impairment of mitochondrial distribution and function including elevated ROS level, decreased mitochondrial membrane potential, respiratory chain activity and ATP production. Taken together, the results indicate that that ClpP was required for oocyte competence during maturation and early folliculogenesis, and its deficiency deteriorate cyclophosphamide-induced ovarian damage.

Associations Between Systemic and Cerebral Inflammation in an Ovine Model of Cardiopulmonary Bypass.

BACKGROUND: Intraoperative inflammation may contribute to postoperative neurocognitive disorders after cardiac surgery requiring cardiopulmonary bypass (CPB). However, the relative contributions of general anesthesia (GA), surgical site injury, and CPB are unclear. METHODS: In adult female sheep, we investigated (1) the temporal profile of proinflammatory and anti-inflammatory cytokines and (2) the extent of microglia activation across major cerebral cortical regions during GA and surgical trauma with and without CPB (N = 5/group). Sheep were studied while conscious, during GA and surgical trauma, with and without CPB. RESULTS: Plasma tumor necrosis factor-alpha (mean [95% confidence intervals], 3.7 [2.5-4.9] vs 1.6 [0.8-2.3] ng/mL; P = .0004) and interleukin-6 levels (4.4 [3.0-5.8] vs 1.6 [0.8-2.3] ng/mL; P = .029) were significantly higher at 1.5 hours, with a further increase in interleukin-6 at 3 hours (7.0 [3.7-10.3] vs 1.8 [1.1-2.6] ng/mL; P < .0001) in animals undergoing CPB compared with those that did not. Although cerebral oxygen saturation was preserved throughout CPB, there was pronounced neuroinflammation as characterized by greater microglia circularity within the frontal cortex of sheep that underwent CPB compared with those that did not (0.34 [0.32-0.37] vs 0.30 [0.29-0.32]; P = .029). Moreover, microglia had fewer branches within the parietal (7.7 [6.5-8.9] vs 10.9 [9.4-12.5]; P = .001) and temporal (7.8 [7.2-8.3] vs 9.9 [8.2-11.7]; P = .020) cortices in sheep that underwent CPB compared with those that did not. CONCLUSIONS: CPB enhanced the release of proinflammatory cytokines beyond that initiated by GA and surgical trauma. This systemic inflammation was associated with microglial activation across 3 major cerebral cortical regions, with a phagocytic microglia phenotype within the frontal cortex, and an inflammatory microglia phenotype within the parietal and temporal cortices. These data provide direct histopathological evidence of CPB-induced neuroinflammation in a large animal model and provide further mechanistic data on how CPB-induced cerebral inflammation might drive postoperative neurocognitive disorders in humans.

Meteorological parameters and cases of COVID-19 in Brazilian cities: an observational study.

Meteorological parameters modulate transmission of the SARS-Cov-2 virus, the causative agent related to coronavirus disease-2019 (COVID-19) development. However, findings across the globe have been inconsistent attributed to several confounding factors. The aim of the present study was to investigate the relationship between reported meteorological parameters from July 1 to October 31, 2020, and the number of confirmed COVID-19 cases in 4 Brazilian cities: São Paulo, the largest city with the highest number of cases in Brazil, and the cities with greater number of cases in the state of Parana during the study period (Curitiba, Londrina and Maringa). The assessment of meteorological factors with confirmed COVID-19 cases included atmospheric pressure, temperature, relative humidity, wind speed, solar irradiation, sunlight, dew point temperature, and total precipitation. The 7- and 15-day moving averages of confirmed COVID-19 cases were obtained for each city. Pearson's correlation coefficients showed significant correlations between COVID-19 cases and all meteorological parameters, except for total precipitation, with the strongest correlation with maximum wind speed (0.717, <0.001) in São Paulo. Regression tree analysis demonstrated that the largest number of confirmed COVID-19 cases was associated with wind speed (between ≥0.3381 and <1.173 m/s), atmospheric pressure (<930.5mb), and solar radiation (<17.98e+3). Lower number of cases was observed for wind speed <0.3381 m/s and temperature <23.86°C. Our results encourage the use of meteorological information as a critical component in future risk assessment models.

The Influence of Tool Wear on the Mechanical Performance of AA6061-T6 Refill Friction Stir Spot Welds.

The Refill Friction Stir Spot Welding (RFSSW) process-an alternative solid-state joining technology-has gained momentum in the last decade for the welding of aluminum and magnesium alloys. Previous studies have addressed the influence of the RFSSW process on the microstructural and mechanical properties of the AA6061-T6 alloy. However, there is a lack of knowledge on how the tool wear influences the welding mechanical behavior for this alloy. The present work intended to evaluate and understand the influence of RFSSW tool wear on the mechanical performance of AA6061-T6 welds. Firstly, the welding parameters were optimized through the Designing of Experiments (DoE), to maximize the obtained ultimate lap shear force (ULSF) response. Following the statistical analysis, an optimized condition was found that reached a ULSF of 8.45 ± 0.08 kN. Secondly, the optimized set of welding parameters were applied to evaluate the wear undergone by the tool. The loss of worn-out material was systematically investigated by digital microscopy and the assessment of tool weight loss. Tool-wear-related microstructural and local mechanical property changes were assessed and compared with the yielded ULSF, and showed a correlation. Further investigations demonstrated the influence of tool wear on the height of the hook, which was located at the interface between the welded plates and, consequently, its effects on the observed fracture mechanisms and ULSF. These results support the understanding of tool wear mechanisms and helped to evaluate the tool lifespan for the selected commercial RFSSW tool which is used for aluminum alloys.

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal.

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

Multivariate diallel analysis by factor analysis for establish mega-traits.

In plant breeding, the dialelic models univariate have aided the selection of parents for hybridization. Multivariate analyses allow combining and associating the multiple pieces of information of the genetic relationships between traits. Therefore, multivariate analyses might refine the discrimination and selection of the parents with greater potential to meet the goals of a plant breeding program. Here, we propose a method of multivariate analysis used for stablishing mega-traits (MTs) in diallel trials. The proposed model is applied in the evaluation of a multi-environment complete diallel trial with 90 F1's of simple maize hybrids. From a set of 14 traits, we demonstrated how establishing and interpreting MTs with agronomic implication. The diallel analyzes based on mega-traits present an important evolution in statistical procedures since the selection is based on several traits. We believe that the proposed method fills an important gap of plant breeding. In our example, three MTs were established. The first, formed by plant stature-related traits, the second by tassel size-related traits, and the third by grain yield-related traits. Individual and joint diallel analysis using the established MTs allowed identifying the best hybrid combinations for achieving F1's with lower plant stature, tassel size, and higher grain yield.

Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats.

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 µg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

Chemoattraction and Recruitment of Activated Immune Cells, Central Autonomic Control, and Blood Pressure Regulation.

Inflammatory mediators play a critical role in the regulation of sympathetic outflow to cardiovascular organs in hypertension. Emerging evidence highlights the involvement of immune cells in the regulation of blood pressure. However, it is still unclear how these immune cells are activated and recruited to key autonomic brain regions to regulate sympathetic outflow to cardiovascular organs. Chemokines such as C-C motif chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß), are upregulated both peripherally and centrally in hypertension. More specifically, they are upregulated in key autonomic brain regions that control sympathetic activity and blood pressure such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. Furthermore, this upregulation of inflammatory mediators is associated with the infiltration of immune cells to these brain areas. Thus, expression of pro-inflammatory chemokines and cytokines is a potential mechanism promoting invasion of immune cells into key autonomic brain regions. In pathophysiological conditions, this can result in abnormal activation of brain circuits that control sympathetic nerve activity to cardiovascular organs and ultimately in increases in blood pressure. In this review, we discuss emerging evidence that helps explain how immune cells are chemoattracted to autonomic nuclei and contribute to changes in sympathetic outflow and blood pressure.

Stretchable Low Impedance Electrodes for Bioelectronic Recording from Small Peripheral Nerves.

Monitoring of bioelectric signals in peripheral sympathetic nerves of small animal models is crucial to gain understanding of how the autonomic nervous system controls specific body functions related to disease states. Advances in minimally-invasive electrodes for such recordings in chronic conditions rely on electrode materials that show low-impedance ionic/electronic interfaces and elastic mechanical properties compliant with the soft and fragile nerve strands. Here we report a highly stretchable low-impedance electrode realized by microcracked gold films as metallic conductors covered with stretchable conducting polymer composite to facilitate ion-to-electron exchange. The conducting polymer composite based on poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) obtains its adhesive, low-impedance properties by controlling thickness, plasticizer content and deposition conditions. Atomic Force Microscopy measurements under strain show that the optimized conducting polymer coating is compliant with the micro-crack mechanics of the underlying Au-layer, necessary to absorb the tensile deformation when the electrodes are stretched. We demonstrate functionality of the stretchable electrodes by performing high quality recordings of renal sympathetic nerve activity under chronic conditions in rats.

Crossbreeding effects on growth and efficiency in beef cow-calf systems: evaluation of Angus, Caracu, Hereford and Nelore breed direct, maternal and heterosis effects.

The objective of this study was to determine breed additive and heterosis effects on growth curves, total milk yield (TMY), calf weaning weight (WW), predicted energy intake (EI), and cow efficiency (CE) of purebred and crossbred beef cows raised in Southern Brazil. The data were from 175 purebred and crossbred cows representing eight genetic groups: Angus (A), Hereford (H), Nelore (N), A × H (AH), H × A (HA), A × N (AN), N × A (NA), and Caracu (C) × A (CA). Growth of the cows was modeled using the nonlinear Brody function and machine milking was used to assess TMY. WW was linearly adjusted to 210 d. EI was predicted with an equation in which the independent variables were estimates of parameters of the Brody function and TMY. The ratio of WW to EI estimated CE. Taurine-indicine heterosis effects were significant for all traits, and greater than those for taurine breed crosses. In general, crossbred cows were heavier at maturity, matured earlier, produced more milk, weaned heavier calves, and were predicted to consume more energy. Thus, they were more efficient than purebred cows, despite their greater predicted feed intake. Among the purebreds, A cows matured most rapidly, weighed the least at maturity, produced the most milk, weaned the heaviest calves, were predicted to consume the least energy; and were therefore most efficient among the breeds that were evaluated. These results are useful as inputs to bioeconomic models that can be used to predict productive and economic outcomes from crossbreeding and to facilitate recommendations for beef producers of southern Brazil and other similar subtropical climatic regions.

Causes of bruising in carcasses of beef cattle during farm, transport, and slaughterhouse handling in Brazil.

This study aimed to assess preslaughter factors responsible for the occurrence of bruises to front, rib, loin, hip, and round sites of cattle carcasses. Data from the slaughter of 148 loads of cattle were assessed, totaling 4,611 carcasses. Evaluated bruising factor variables were animal gender, journey distance (km), vehicle type (m²), journey time (hours), load density (kg/m2 ), handling and facilities conditions (optimal, acceptable, and unacceptable), and unloading waiting time (min). Gender had the strongest influence on carcass bruising, being the first variable to enter in the majority of models related to the carcass sites. Female carcasses displayed higher bruising in all sites. Densities above 401 kg/m² caused more bruising. With the exception of the loin, unacceptable, and acceptable conditions assigned to farm facilities and handling resulted in higher average bruising. Articulated vehicles with a greater load capacity were more likely to cause bruising. The effects of variables causing bruises act differently in the various carcass sites. In this sense, the results of this study suggested possible management practices for specific problems during the preslaughter period to minimize losses by bruising to different carcass sites.

In renovascular hypertension, TNF-α type-1 receptors in the area postrema mediate increases in cardiac and renal sympathetic nerve activity and blood pressure.

AIMS: Neuroinflammation is a common feature in renovascular, obesity-related, and angiotensin II mediated hypertension. There is evidence that increased release of the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) contributes to the development of the hypertension, but the underlying neural mechanisms are unclear. Here, we investigated whether TNF-α stimulates neurons in the area postrema (AP), a circumventricular organ, to elicit sympathetic excitation, and increases in blood pressure (BP). METHODS AND RESULTS: In rats with renovascular hypertension, AP neurons that expressed TNF-α type-1 receptor (TNFR1) remained constantly activated (expressed c-Fos) and injection of TNFR1 neutralizing antibody into the AP returned BP (systolic: ∼151 mmHg) to normotensive levels (systolic: ∼108 mmHg). Nanoinjection of TNF-α (100 pg/50 nL) into the AP of anaesthetized normotensive rats increased BP (∼16 mmHg) and sympathetic nerve activity, predominantly to the heart (∼53%), but also to the kidneys (∼35%). These responses were abolished by prior injection of a TNFR1 neutralizing antibody (1 ng/50 nL) within the same site. TNFR1 were expressed in the somata of neurons activated by TNF-α that were retrogradely labelled from the rostral ventrolateral medulla (RVLM). CONCLUSION: These findings indicate that in renovascular hypertension, blocking TNFR1 receptors in the AP significantly reduces BP, while activation of TNFR1 expressing neurons in the AP by TNF-α increases BP in normotensive rats. This is mediated, in part, by projections to the RVLM and an increase in both cardiac and renal sympathetic nerve activity. These findings support the notion that proinflammatory cytokines and neuroinflammation are important pathological mechanisms in the development and maintenance of hypertension.

Glycinergic neurotransmission in the rostral ventrolateral medulla controls the time course of baroreflex-mediated sympathoinhibition.

KEY POINTS: To maintain appropriate blood flow to various tissues of the body under a variety of physiological states, autonomic nervous system reflexes regulate regional sympathetic nerve activity and arterial blood pressure. Our data obtained in anaesthetized rats revealed that glycine released in the rostral ventrolateral medulla (RVLM) plays a critical role in maintaining arterial baroreflex sympathoinhibition. Manipulation of brainstem nuclei with known inputs to the RVLM (nucleus tractus solitarius and caudal VLM) unmasked tonic glycinergic inhibition in the RVLM. Whole-cell, patch clamp recordings demonstrate that both GABA and glycine inhibit RVLM neurons. Potentiation of neurotransmitter release from the active synaptic inputs in the RVLM produced saturation of GABAergic inhibition and emergence of glycinergic inhibition. Our data suggest that GABA controls threshold excitability, wherreas glycine increases the strength of inhibition under conditions of increased synaptic activity within the RVLM. ABSTRACT: The arterial baroreflex is a rapid negative-feedback system that compensates changes in blood pressure by adjusting the output of presympathetic neurons in the rostral ventrolateral medulla (RVLM). GABAergic projections from the caudal VLM (CVLM) provide a primary inhibitory input to presympathetic RVLM neurons. Although glycine-dependent regulation of RVLM neurons has been proposed, its role in determining RVLM excitability is ill-defined. The present study aimed to determine the physiological role of glycinergic neurotransmission in baroreflex function, identify the mechanisms for glycine release, and evaluate co-inhibition of RVLM neurons by GABA and glycine. Microinjection of the glycine receptor antagonist strychnine (4 mm, 100 nL) into the RVLM decreased the duration of baroreflex-mediated inhibition of renal sympathetic nerve activity (control = 12 ± 1 min; RVLM-strychnine = 5.1 ± 1 min), suggesting that RVLM glycine plays a critical role in regulating the time course of sympathoinhibition. Blockade of output from the nucleus tractus solitarius and/or disinhibition of the CVLM unmasked tonic glycinergic inhibition of the RVLM. To evaluate cellular mechanisms, RVLM neurons were retrogradely labelled (prior injection of pseudorabies virus PRV-152) and whole-cell, patch clamp recordings were obtained in brainstem slices. Under steady-state conditions GABAergic inhibition of RVLM neurons predominated and glycine contributed less than 25% of the overall inhibition. By contrast, stimulation of synaptic inputs in the RVLM decreased GABAergic inhibition to 53%; and increased glycinergic inhibition to 47%. Thus, under conditions of increased synaptic activity in the RVLM, glycinergic inhibition is recruited to strengthen sympathoinhibition.

Direct and maternal breed additive and heterosis effects on growth traits of beef cattle raised in southern Brazil.

The objective of this study was to compare growth from birth to slaughter of different breed groups that were raised in Rio Grande do Sul, Brazil and estimate the consequent breed additive and heterosis effects. Caracu (C), Hereford (H), and Nelore (N) sires were mated with Angus (A) dams, and A sires were mated with H and N dams to produce a first generation of crossbred progeny that was contemporary with purebred A, H, and N calves. Heifers from this first generation (G1) were mated with Brangus (BN) and Braford (BO) sires to produce a second generation (G2) of progeny. Data were analyzed to estimate breed group means, individual and maternal breed additive effects, and heterosis effects on birth weight, weaning weight, preweaning average daily gain, yearling weight, postweaning average daily gain, fattening phase initial weight (around 19 mo), final weight (around 24 mo), average daily gain in the fattening phase, and age at slaughter. In general, crossbred calves outperformed purebred calves. Angus-N and CA crossbred cows weaned heavier calves. Individual taurine-indicine heterosis (Z) significantly increased weaning weight. The AN, NA, and CA steers were heaviest at yearling, whereas NA, CA, AN, and HA had the greatest final weights. However, AH steers were 1 mo older at slaughter than NA contemporaries. Taurine breed effects on postweaning traits and final weight were greater than for N. Maternal breed effects on birth weight and average daily gain in the fattening phase were greater for A and H than for N. In conclusion, heterosis effects were sufficiently large for use of N to be recommended as a component of such systems, despite their relatively low-breed additive effects compared with taurine breeds. Moreover, germplasm from the tropically adapted Bos taurus C may be particularly useful when increased milk production is desired. With the breed and heterosis effects derived in the present study, it is possible to predict the performance and infer which breed and breed crosses will perform better in crossbreeding systems designed for the subtropical conditions of southern Brazil and similar regions.

The role of the blood-brain barrier in hypertension.

NEW FINDINGS: What is the topic of this review? This review highlights the importance of the blood-brain barrier in the context of diseases involving autonomic dysfunction, such as hypertension and heart failure. What advances does it highlight? It highlights the potential role of pro-inflammatory cytokines, leucocytes and angiotensin II in disrupting the blood-brain barrier in cardiovascular diseases. Advances are highlighted in our understanding of neurovascular unit cells, astrocytes and microglia, with a specific emphasis on their pathogenic roles within the brain. The blood-brain barrier (BBB) is a crucial barrier that provides both metabolic and physical protection to an immune-privileged CNS. The BBB has been shown to be disrupted in hypertension. This review addresses the importance of the BBB in maintaining homeostasis in the context of diseases related to autonomic dysfunction, such as hypertension. We highlight the potentially important roles of the immune system and neurovascular unit in the maintenance of the BBB, whereby dysregulation may lead to autonomic dysfunction in diseases such as heart failure and hypertension. Circulating leucocytes and factors such as angiotensin II and pro-inflammatory cytokines are thought ultimately to downregulate endothelial tight junction proteins that are a crucial component of the BBB. The specific mechanisms underlying BBB disruption and their role in contributing to autonomic dysfunction are not yet fully understood but are a growing area of interest. A greater understanding of these systems and advances in our knowledge of the molecular mechanisms causing BBB disruption will allow for the development of future therapeutic interventions in the treatment of autonomic imbalance associated with diseases such as heart failure and hypertension.

Activation of Medulla-Projecting Perifornical Neurons Modulates the Adrenal Sympathetic Response to Hypoglycemia: Involvement of Orexin Type 2 (OX2-R) Receptors.

Iatrogenic hypoglycemia in response to insulin treatment is commonly experienced by patients with type 1 diabetes and can be life threatening. The body releases epinephrine in an attempt to counterregulate hypoglycemia, but the neural mechanisms underlying this phenomenon remain to be elucidated. Orexin neurons in the perifornical hypothalamus (PeH) project to the rostral ventrolateral medulla (RVLM) and are likely to be involved in epinephrine secretion during hypoglycemia. In anesthetized rats, we report that hypoglycemia increases the sympathetic preganglionic discharge to the adrenal gland by activating PeH orexin neurons that project to the RVLM (PeH-RVLM). Electrophysiological characterization shows that the majority of identified PeH-RVLM neurons, including a subpopulation of orexin neurons, are activated in response to hypoglycemia or glucoprivation. Furthermore, the excitatory input from the PeH is mediated by orexin type 2 receptors in the RVLM. These results suggest that activation of orexin PeH-RVLM neurons and orexin type 2 receptors in the RVLM facilitates epinephrine release by increasing sympathetic drive to adrenal chromaffin cells during hypoglycemia.

Neural pathways that control the glucose counterregulatory response.

Glucose is an essential metabolic substrate for all bodily tissues. The brain depends particularly on a constant supply of glucose to satisfy its energy demands. Fortunately, a complex physiological system has evolved to keep blood glucose at a constant level. The consequences of poor glucose homeostasis are well-known: hyperglycemia associated with uncontrolled diabetes can lead to cardiovascular disease, neuropathy and nephropathy, while hypoglycemia can lead to convulsions, loss of consciousness, coma, and even death. The glucose counterregulatory response involves detection of declining plasma glucose levels and secretion of several hormones including glucagon, adrenaline, cortisol, and growth hormone (GH) to orchestrate the recovery from hypoglycemia. Low blood glucose leads to a low brain glucose level that is detected by glucose-sensing neurons located in several brain regions such as the ventromedial hypothalamus, the perifornical region of the lateral hypothalamus, the arcuate nucleus (ARC), and in several hindbrain regions. This review will describe the importance of the glucose counterregulatory system and what is known of the neurocircuitry that underpins it.