Hantavirus

Hantaviruses are tri-segmented lipid-enveloped RNA viruses belonging to the Bunyaviridae family. Human infection corresponds to a zoonosis associated with two different clinical syndromes: hemorrhagic fever with renal syndrome that occurs in Asia and Europe and hantavirus cardiopulmonary syndrome (HCPS) that occurs in the North America, Central America and South America. The major pathogenic mechanisms in HCPS include (1) direct microvascular endothelial injury leading to increased capillary permeability and the development of noncardiogenic pulmonary edema and acute respiratory distress syndrome, and (2) exaggerated host immune response leading to secondary organ damage. The incubation period for this disease is quite long (6–39 days, median: 18 days); however, rapid progression to respiratory failure and shock can occur highlighting the importance of high index of clinical suspicion. Management revolves around high-quality supportive care. Various management and preventative strategies are currently being explored and warrant further examination to improve the overall outlook following infection with hantavirus.

Regulation and Intervention of Intracranial Pressure

Intracranial pressure is the total amount of pressure exerted by the brain, blood and cerebrocinal fluid in the rigid cranial space. Compliance is an indicator of the brain's tolerance for increased ICP, when compliance is exceeded, there will be a dramatic increase in the pressure/volume curve so that ICP will increase rapidly. In the injured brain, cerebral blood flow (CBF) is regulated to supply sufficient oxygen and substrates to the brain. Certain physiological factors such as hypercarbia, acidosis and hypoxemia cause vasodilation which causes an increase in CBF, seizure activity and fever will increase the level of brain metabolism and CBF. Cerebral edema is the most common cause of non-traumatic brain injury such as central nervous system infections, metabolic and systemic encephalopathy. Vasogenic brain edema occurs due to injury to the blood-brain barrier and increased capillary permeability in the area around the injury, or to inflammation, especially in CNS infections. Medical management of elevated intracranial pressure includes sedation, cerebrospinal fluid drainage, and osmotherapy with either mannitol or hypertonic salts.

Pulmonary Edema I: Cardiogenic Pulmonary Edema

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 29 references Keywords: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

Plasma Leak From the Circulation Contributes to Poor Outcomes for Preterm Infants: A Working Hypothesis

Preterm infants are at high risk of death and disability resulting from brain injury. Impaired cardiovascular function leading to poor cerebral oxygenation is a significant contributor to these adverse outcomes, but current therapeutic approaches have failed to improve outcome. We have re-examined existing evidence regarding hypovolemia and have concluded that in the preterm infant loss of plasma from the circulation results in hypovolemia; and that this is a significant driver of cardiovascular instability and thus poor cerebral oxygenation. High capillary permeability, altered hydrostatic and oncotic pressure gradients, and reduced lymphatic return all combine to increase net loss of plasma from the circulation at the capillary. Evidence is presented that early hypovolemia occurs in preterm infants, and that capillary permeability and pressure gradients all change in a way that promotes rapid plasma loss at the capillary. Impaired lymph flow, inflammation and some current treatment strategies may further exacerbate this plasma loss. A framework for testing this hypothesis is presented. Understanding these mechanisms opens the way to novel treatment strategies to support cardiovascular function and cerebral oxygenation, to replace current therapies, which have been shown not to change outcomes.

Effects of controlled ovarian stimulation on vascular barrier and endothelial glycocalyx: a pilot study

Purpose Controlled ovarian stimulation significantly amplifies the number of maturing and ovulated follicles as well as ovarian steroid production. The ovarian hyperstimulation syndrome (OHSS) increases capillary permeability and fluid extravasation. Vascular integrity intensely is regulated by an endothelial glycocalyx (EGX) and we have shown that ovulatory cycles are associated with shedding of EGX components. This study investigates if controlled ovarian stimulation impacts on the integrity of the endothelial glycocalyx as this might explain key pathomechanisms of the OHSS. Methods Serum levels of endothelial glycocalyx components of infertility patients (n=18) undergoing controlled ovarian stimulation were compared to a control group of healthy women with regular ovulatory cycles (n=17). Results Patients during luteal phases of controlled ovarian stimulation cycles as compared to normal ovulatory cycles showed significantly increased Syndecan-1 serum concentrations (12.6 ng/ml 6.1125th–19.1375th to 13.9 ng/ml 9.625th–28.975th; p=0.026), indicating shedding and degradation of the EGX. Conclusion A shedding of EGX components during ovarian stimulation has not yet been described. Our study suggests that ovarian stimulation may affect the integrity of the endothelial surface layer and increasing vascular permeability. This could explain key features of the OHSS and provide new ways of prevention of this serious condition of assisted reproduction.

Automated Quantitative Analysis of ex vivo Blood-Brain Barrier Permeability Using Intellesis Machine-Learning

BackgroundAn increase in blood brain barrier permeability commonly precedes neuro-inflammation and cognitive impairment in models of dementia. Common methods to estimate capillary permeability have potential confounders, or require laborious and subjective semi-manual analysis.New methodHere we used snap frozen mouse and rat brain sections that were double-immunofluorescent labeled for immunoglobulin G (IgG; plasma protein) and laminin-α4 (capillary basement membrane). A Machine Learning Image Analysis program (Zeiss ZEN Intellisis) was trained to recognize and segment laminin-α4 to equivocally identify blood vessels in large sets of images. An IgG subclass based on a threshold intensity was segmented and quantitated only in extravascular regions. The residual parenchymal IgG fluorescence is indicative of blood-to-brain extravasation of IgG and was accurately quantitated.ResultsAutomated machine-learning and threshold based segmentation of only parenchymal IgG extravasation accentuates otherwise indistinct capillary permeability, particularly frequent in minor BBB leakage. Comparison with Existing Methods: Large datasets can be processed and analyzed quickly and robustly to provide an overview of vascular permeability throughout the brain. All human bias or ambiguity involved in classifying and measuring leakage is removed.ConclusionHere we describe a fast and precise method of visualizing and quantitating BBB permeability in mouse and rat brain tissue, while avoiding the confounding influence of unphysiological conditions such as perfusion and eliminating any human related bias from analysis.

Non-immunologic hydrops fetalis and coronavirus disease (COVID-19) – A case report

Non-immune hydrops fetalis is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities. The prevalence of non-immune hydrops fetalis is unknown. Currently, about 90% of cases of hydrops fetalis are non-immune hydrops fetalis. Non-immune hydrops fetalis causes are multi-factorial. The pathophysiological mechanism of non-immunologic hydrops fetalis is related to abnormal fluid transportation between plasma and tissues. This is due to the increase in hydrostatic capillary pressure and capillary permeability and a reduction of the plasma osmotic pressure or lymphatic flow. A variety of viral infection agents have been associated with non-immune hydrops fetalis like parvovirus B19, herpes simplex virus, cytomegalovirus, Toxoplasma gondii, Treponema pallidum, but even other viruses that attack the maternal and fetus during pregnancy cannot be excluded as possible causes of non-immune hydrops fetalis. We present one case of non-immune hydrops fetalis who was diagnosed intra-uterine, three weeks after recovery from Coronavirus disease (COVID-19). After much investigation, we could not find any known factor that may be the cause of non-immunologic hydrops fetalis. Therefore, we predisposed a possible causal connection between nonimmunologic hydrops fetalis and Coronavirus disease (COVID-19).

Brown Spiders’ Phospholipases-D with Potential Therapeutic Applications: Functional Assessment of Mutant Isoforms

Phospholipases-D (PLDs) found in Loxosceles spiders’ venoms are responsible for the dermonecrosis triggered by envenomation. PLDs can also induce other local and systemic effects, such as massive inflammatory response, edema, and hemolysis. Recombinant PLDs reproduce all of the deleterious effects induced by Loxosceles whole venoms. Herein, wild type and mutant PLDs of two species involved in accidents—L. gaucho and L. laeta—were recombinantly expressed and characterized. The mutations are related to amino acid residues relevant for catalysis (H12-H47), magnesium ion coordination (E32-D34) and binding to phospholipid substrates (Y228 and Y228-Y229-W230). Circular dichroism and structural data demonstrated that the mutant isoforms did not undergo significant structural changes. Immunoassays showed that mutant PLDs exhibit conserved epitopes and kept their antigenic properties despite the mutations. Both in vitro (sphingomyelinase activity and hemolysis) and in vivo (capillary permeability, dermonecrotic activity, and histopathological analysis) assays showed that the PLDs with mutations H12-H47, E32-D34, and Y228-Y229-W230 displayed only residual activities. Results indicate that these mutant toxins are suitable for use as antigens to obtain neutralizing antisera with enhanced properties since they will be based on the most deleterious toxins in the venom and without causing severe harmful effects to the animals in which these sera are produced.

Kinetics of Immunoglobulins in Septic Shock Patients Treated With an IgM- and IgA-Enriched Intravenous Preparation: An Observational Study

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg).Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed.Results: In the interval D0–D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS.Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.