Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned.     

Zebrafish disease models in hematology: Highlights on biological and translational impact

Zebrafish (Danio rerio) has proven to be a versatile and reliable in vivo experimental model to study human hematopoiesis and hematological malignancies. As vertebrates, zebrafish has significant anatomical and biological similarities to humans, including the hematopoietic system. The powerful genome editing and genome-wide forward genetic screening tools have generated models that recapitulate human malignant hematopoietic pathologies in zebrafish and unravel cellular mechanisms involved in these diseases. Moreover, the use of zebrafish models in large-scale chemical screens has allowed the identification of new molecular targets and the design of alternative therapies. In this review we summarize the recent achievements in hematological research that highlight the power of the zebrafish model for discovery of new therapeutic molecules. We believe that the model is ready to give an immediate translational impact into the clinic.     

Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature

Background

Extraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population.

Case presentation

We describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship.

Conclusion

In childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit.

     

Is foraging innovation lost following colonization of a less variable environment? A case study in surface‐ vs. cave‐dwelling Asellus aquaticus

Behavioral innovation is a key process for successful colonization of new habitat types. However, it is costly due to the necessary cognitive and neural demands and typically connected to ecological generalism. Therefore, loss of behavioral innovativeness is predicted following colonization of new, simple, and invariable environments. We tested this prediction by studying foraging innovativeness in the freshwater isopod Asellus aquaticus. We sampled its populations along the route of colonizing a thermokarstic water‐filled cave (simple, stable habitat with only bacterial mats as food) from surface habitats (variable environment, wide variety of food). The studied cave population separated from the surface populations at least 60,000 years ago. Animals were tested both with familiar and novel food types (cave food: bacterial mats; surface food: decaying leaves). Irrespective of food type, cave individuals were more likely to feed than surface individuals. Further, animals from all populations fed longer on leaves than on bacteria, even though leaves were novel for the cave animals. Our results support that cave A. aquaticus did not lose the ability to use the ancestral (surface) food type after adapting to a simple, stable, and highly specialized habitat.     

Regulation of tumor phenotypes by caveolin-1 and sphingolipid-controlled membrane signaling complexes

Aberrant (glyco)sphingolipid expression deeply affects several properties of tumor cells that are involved in tumor progression and metastasis formation: cell adhesion (to the extracellular matrix or to the endothelium of blood vessels), motility, recognition and invasion of host tissues. In particular, (glyco)sphingolipids might contribute to the modulation of integrin-dependent interactions of tumor cells (determining their adhesion, motility and invasiveness) with the extracellular matrix as well as with host cells present in the stromal compartment of the tumor. A model based on solid experimental evidence has been proposed: (glyco)sphingolipids at the cell surface interact with plasma membrane receptors (e.g., integrin receptors and growth factor receptors) and adapter molecules (including tetraspanins) forming signaling complexes that are able to influence the activity of signal transduction molecules oriented at the cytosolic surface of the plasma membrane (mainly the Src kinases pathway members). The function of these signaling complexes appears to be strictly dependent on their (glyco)sphingolipid composition, and likely on specific sphingolipid-protein interactions. From this point of view, particularly intriguing is the connection between (glyco)sphingolipids and caveolin-1, a membrane protein that plays multiple roles as a suppressor of tumor growth and metastasis in ovarian, breast and colon human carcinomas.     

Epidermal growth factor induces intracellular Ca2+ oscillations in microvascular endothelial cells

An increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) may play a role in the proliferative effect of several growth factors. In this study, the changes in [Ca(2+)](i) elicited by epidermal growth factor (EGF) in rat cardiac microvascular endothelial cells (CMEC) have been investigated by using fura-2 conventional and confocal microscopy. A large heterogeneity in the latency and in the pattern of the Ca(2+) response was found at each dose of EGF (2.5-100 ng/ml), whereas some cells displayed a non-oscillatory behavior and others exhibited a variable number of Ca(2+) oscillations. On average, the fraction of responsive cells, the total number of oscillations and the duration of the Ca(2+) signal were higher at around 10 ng/ml EGF, while there was no dose-dependence in the lag time and in the amplitude of the [Ca(2+)](i) increase. EGF-induced Ca(2+) spikes were abolished by the tyrosine kinase inhibitor genistein, but not by its inactive analogue daidzein, and by the phospholipase C blocker NCDC. Only 1-2 transients could be elicited in Ca(2+)-free solution, while re-addition of extracellular Ca(2+) recovered the spiking activity. The oscillatory signal was prevented by the SERCA inhibitor thapsigargin and abolished by the calcium entry blockers Ni(2+) and La(3+). Moreover, EGF-induced Ca(2+) transients were abolished by the InsP(3) receptor blocker caffeine, while ryanodine was without effect. Confocal imaging microscopy showed that the Ca(2+) response to EGF was localized both in the cytoplasm and in the nucleus. We suggest that EGF-induced [Ca(2+)](i) increase may play a role in the proliferative action of EGF on endothelial cells.     

Real-Time PCR Investigation of Potential Vectors, Reservoirs, and Shedding Patterns of Feline Hemotropic Mycoplasmas

Three hemotropic mycoplasmas have been identified in pet cats: Mycoplasma haemofelis, “Candidatus Mycoplasma haemominutum,” and “Candidatus Mycoplasma turicensis.” The way in which these agents are transmitted is largely unknown. Thus, this study aimed to investigate fleas, ticks, and rodents as well as saliva and feces from infected cats for the presence of hemotropic mycoplasmas, to gain insight into potential transmission routes for these agents. DNA was extracted from arthropods and from rodent blood or tissue samples from Switzerland and from salivary and fecal swabs from two experimentally infected and six naturally infected cats. All samples were analyzed with real-time PCR, and some positive samples were confirmed by sequencing. Feline hemotropic mycoplasmas were detected in cat fleas and in a few Ixodes sp. and Rhipicephalus sp. ticks collected from animals but not in ticks collected from vegetation or from rodent samples, although the latter were frequently Mycoplasma coccoides PCR positive. When shedding patterns of feline hemotropic mycoplasmas were investigated, “Ca. Mycoplasma turicensis” DNA was detected in saliva and feces at the early but not at the late phase of infection. M. haemofelis and “Ca. Mycoplasma haemominutum” DNA was not amplified from saliva and feces of naturally infected cats, despite high hemotropic mycoplasma blood loads. Our results suggest that besides an ostensibly indirect transmission by fleas, direct transmission through saliva and feces at the early phase of infection could play a role in the epizootiology of feline hemotropic mycoplasmas. Neither the investigated tick nor the rodent population seems to represent a major reservoir for feline hemotropic mycoplasmas in Switzerland.