CNS Macrophages and Infant Infections.

The central nervous system (CNS) harbors its own immune system composed of microglia in the parenchyma and CNS-associated macrophages (CAMs) in the perivascular space, leptomeninges, dura mater, and choroid plexus. Recent advances in understanding the CNS resident immune cells gave new insights into development, maturation and function of its immune guard. Microglia and CAMs undergo essential steps of differentiation and maturation triggered by environmental factors as well as intrinsic transcriptional programs throughout embryonic and postnatal development. These shaping steps allow the macrophages to adapt to their specific physiological function as first line of defense of the CNS and its interfaces. During infancy, the CNS might be targeted by a plethora of different pathogens which can cause severe tissue damage with potentially long reaching defects. Therefore, an efficient immune response of infant CNS macrophages is required even at these early stages to clear the infections but may also lead to detrimental consequences for the developing CNS. Here, we highlight the recent knowledge of the infant CNS immune system during embryonic and postnatal infections and the consequences for the developing CNS.

Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses.

Hydrogen sulfide (H2S) is a biologically relevant signaling molecule in mammals. Along with the volatile substances nitric oxide (NO) and carbon monoxide (CO), H2S is defined as a gasotransmitter. It plays a physiological role in a variety of functions, including synaptic transmission, vascular tone, angiogenesis, inflammation, and cellular signaling. The generation of H2S is catalyzed by cystathionine ß-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). The expression of CBS and CSE is tissue specific, with CBS being expressed predominantly in the brain, and CSE in peripheral tissues, including lungs. CSE expression and activity are developmentally regulated, and recent studies suggest that CSE plays an important role in lung alveolarization during fetal development. In the respiratory tract, endogenous H2S has been shown to participate in the regulation of important functions such as airway tone, pulmonary circulation, cell proliferation or apoptosis, fibrosis, oxidative stress, and inflammation. In the past few years, changes in the generation of H2S have been linked to the pathogenesis of a variety of acute and chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary disease. Recently, our laboratory made the critical discovery that cellular H2S exerts broad-spectrum antiviral activity both in vitro and in vivo, in addition to independent antiinflammatory activity. These findings have important implications for the development of novel therapeutic strategies for viral respiratory infections, as well as other inflammatory lung diseases, especially in light of recent significant efforts to generate controlled-release H2S donors for clinical therapeutic applications.

Study of host-microbe interactions in zebrafish.

All animals are ecosystems, home to diverse microbial populations. Animal-associated microbes play important roles in the normal development and physiology of their hosts, but can also be agents of infectious disease. Traditionally, mice have been used to study pathogenic and beneficial associations between microbes and vertebrate animals. The zebrafish is emerging as a valuable new model system for host-microbe interaction studies, affording researchers with the opportunity to survey large populations of hosts and to visualize microbe-host associations at a cellular level in living animals. This chapter provides detailed protocols for the analysis of zebrafish-associated microbial communities, the derivation and husbandry of germ-free zebrafish, and the modeling of infectious disease in different stages of zebrafish development via different routes of inoculation. These protocols offer a starting point for researchers to address a multitude of questions about animals' coexistence with microorganisms.

[Ultrasound in the evaluation of intrauterine infection during pregnancy].

Ultrasound has an important role in the detection and follow- up of intrauterine infection. Viral infections are a major cause of fetal morbidity and mortality. Transplacental transmission of the virus, even in sub-clinical maternal infection, may result in a severe congenital syndrome. Prenatal detection of viral infection is based on fetal sonographic findings and PCR to identify the specific infectious agent. Most affected fetuses appear sonographically normal, but serial scanning may reveal evolving findings. Common sonographic abnormalities, although non-specific, may be indicative of fetal viral infections. These include growth restriction, ascites, hydrops, ventriculomegaly, intracranial calcifications, hydrocephaly, microcephaly, cardiac anomalies, hepatosplenomegaly, echogenic bowel, placentomegaly and abnormal amniotic fluid volume. Some of the pathognomonic sonographic findings enable diagnosis of a specific congenital syndrome (e.g., ventriculomegaly and intracranial and hepatic calcifications in cytomegalovirus or in toxoplasma; eye and cardiac anomalies in congenital Rubella syndrome; limb contractures and cerebral anomalies in Varicella Zoster virus). When abnormalities are detected on ultrasound, a thorough fetal evaluation is recommended because of multiorgan involvement.

Umbilical pressure measurement in the evaluation of nonimmune hydrops fetalis.

OBJECTIVE: Nonimmune hydrops fetalis continues to have a perinatal mortality rate > 50%. Although many abnormalities are associated with nonimmune hydrops fetalis, the direct mechanism by which the hydrops occurs is often obscure, even after delivery. There are at least three possible mechanisms for hydrops: heart failure (whether primary or a secondary effect of obstructed venous return), lymphatic malformation, and liver or peritoneal disease. The development of safe access to the fetal circulation by cordocentesis allows for the measurement of the umbilical venous pressure, which is closely related to the fetal central venous pressure. The premise that nonimmune hydrops fetalis of cardiac origin could be distinguished from that of noncardiac origin was examined by measuring the umbilical venous pressure. STUDY DESIGN: Umbilical venous pressure was measured during indicated diagnostic cordocentesis in three groups of fetuses: 20 with nonimmune hydrops fetalis, four with a cardiac malformation but without nonimmune hydrops fetalis, and eight with immune hydrops (fetal hemolytic disease). In 16 of 20 fetuses with nonimmune hydrops fetalis the serum total protein and albumin concentrations were also measured. RESULTS: Presumed inadequate cardiac output, as indicated by an elevated umbilical venous pressure, was the mechanism of nonimmune hydrops fetalis in 13 of 20 (65%). The pathologic condition included arrhythmia, cardiothoracic abnormalities, severe polycythemia and hyperviscosity, viral infection, and severe anemia. Successful antenatal treatment normalized the umbilical venous pressure. Nonimmune hydrops fetalis secondary to noncardiac mechanisms did not progress in severity and was not amenable to antenatal therapy. Hypoproteinemia and hypoalbuminemia were found in only six of 16 cases and were similarly distributed between cardiac and noncardiac mechanisms. CONCLUSIONS: This is the first report where the measurement of umbilical venous pressure was applied to the evaluation of nonimmune hydrops fetalis. Cardiac dysfunction was the most common mechanism causing hydrops. The finding of a normal umbilical venous pressure greatly reduces the likelihood that the heart is the cause of the hydrops, even when there is a coexistent heart malformation. This immediate information allows the practitioner either to focus on therapeutic interventions that might lower the umbilical venous pressure or to look for noncardiac causes for the hydrops.

Laboratory diagnosis of fetal infections.

In utero infections of the fetus can lead to significant morbidity and mortality in the newborn child. The signs and symptoms of clinical disease, however, do not always suggest a given pathogen. The laboratory must be able to provide an early and accurate diagnosis of the causative agent so that prompt and appropriate antimicrobial therapy and medical care can be initiated. The scope of this article includes the methods employed by the laboratory to assist in the diagnosis of bacterial, fungal, parasitic, and viral infections of the fetus. Where appropriate, detection methods were addressed for the diagnosis of the major pathogens responsible for infection during the birth process.

Viruses as teratogens.

There is nothing unique about rubella viruses or cytomegaloviruses. They are classic teratogens and, in this respect, not only follow but exemplify most of the principles of human teratology.