The clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations

Since the 2015 to 2016 outbreak in America, Zika virus (ZIKV) infected almost 900,000 patients. This international public health emergency was mainly associated with a significant increase in the number of newborns with congenital microcephaly and abnormal neurologic development, known as congenital Zika syndrome (CZS). Furthermore, Guillain–Barré syndrome (GBS), a neuroimmune disorder of adults, has also been associated with ZIKV infection. Currently, the number of ZIKV-infected patients has decreased, and most of the cases recently reported present as a mild and self-limiting febrile illness. However, based on its natural history of a typical example of reemerging pathogen and the lack of specific therapeutic options against ZIKV infection, new outbreaks can occur worldwide, demanding the attention of researchers and government authorities. Here, we discuss the clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations. Several studies have confirmed the tropism of ZIKV for neural progenitor stem cells by demonstrating the presence of ZIKV in the central nervous system (CNS) during fetal development, eliciting a deleterious inflammatory response that compromises neurogenesis and brain formation. Of note, while the neuropathology of CZS can be due to a direct viral neuropathic effect, adults may develop neuroimmune manifestations such as GBS due to poorly understood mechanisms. Antiganglioside autoantibodies have been detected in multiple patients with ZIKV infection–associated GBS, suggesting a molecular mimicry. However, further additional immunopathological mechanisms remain to be uncovered, paving the way for new therapeutic strategies.     

AIDS and associated syndromes: clinical manifestations

Numerous clinical and immunological manifestations are commonly observed in AIDS patients. Among these, Kaposi's sarcoma and major opportunistic infections appear today as clinical "markers" of the disease. Other signs and symptoms such as fever, diarrhea, lymphadenopathy and immunological abnormalities are currently recognized as "associated" disorders. One of the main problems faced by clinicians is to evaluate the significance of these "associated" abnormalities, especially when they occur in at risk populations. Much work is still needed to clarify whether they actually imply an individual predisposition to contract the disease, a minor form or some early stage of AIDS.     

Invasive aspergillosis: clinical manifestations and treatment

During the last decade the incidence of invasive aspergillosis has substantially grown due to the increasing use of powerful immunosupressive drugs in more patients. Unfortunately, the associated mortality with this infection is still very high and has not decreased in recent years. Pulmonary aspergillosis is by far the most frequent clinical picture of this infection, followed by sinus, tracheo-bronchial and central nervous system disease. The degree of immunosupression is the main factor influencing the evolution and dissemination of aspergillosis. Conventional amphotericin B has been the first-line therapy of invasive aspergillosis for the last 30 years, and most authors have long considered amphotericin B related toxicity as one of the main causes for the poor results obtained in the outcome of patients who developed this infection. Fortunately, in the last few years new safer and more effective drugs have been developed for the treatment of this entity. However, if we are really trying to substantially decrease invasive aspergillosis associated-mortality we should use these drugs earlier in the development of the infection, using new more sensitive diagnostic tests and/or a riskbase strategy which could identify patients at the highest risk to develop this infection.     

GTPases involved in vesicular trafficking: structures and mechanisms

Several types of GTPases play important roles in intracellular vesicular transport. These include the Rab and Arf families of the Ras superfamily, which are key regulators of several steps in the overall process. The basic structural and mechanistic properties of these proteins and their interactions with partner proteins and membranes are reviewed and compared in this article.     

Severe acute respiratory syndrome: clinical and laboratory manifestations

Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease with significant morbidity and mortality. An epidemic in 2003 affected 8,098 patients in 29 countries with 774 deaths. The aetiological agent is a new coronavirus spread by droplet transmission. Clinical and general laboratory manifestations included fever, chills, rigor, myalgia, malaise, diarrhoea, cough, dyspnoea, pneumonia, lymphopenia, neutrophilia, thrombocytopenia, and elevated serum lactate dehydrogenase (LD), alanine aminotransferase (ALT) and creatine kinase (CK) activities. Treatment has been empirical; initial potent antibiotic cover, followed by simultaneous ribavirin and corticosteroids, with or without pulse high-dose methylprednisolone, have been used. The postulated disease progression comprises (1) active viral infection, (2) hyperactive immune response, and (3) recovery or pulmonary destruction and death. We investigated serum LD isoenzymes and blood lymphocyte subsets of SARS patients, and found LD1 activity as the best biochemical prognostic indicator for death, while CD3+, CD4+, CD8+ and natural killer cell counts were promising predictors for intensive care unit (ICU) admission. Plasma cytokine and chemokine profiles showed markedly elevated Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1beta, IL-6 and IL-12, neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10) for at least two weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumor necrosis factor (TNF)-alpha and anti-inflammatory cytokine IL-10. Corticosteroid reduced IL-8, MCP-1 and IP-10 concentrations from 5-8 days after treatment. Measurement of biochemical markers of bone metabolism demonstrated significant but transient increase in bone resorption from Day 28-44 after onset of fever, when pulse steroid was most frequently given. With tapering down of steroid therapy, there was a decrease in bone resorption marker together with an increase in bone formation markers round Day 50, suggesting that some of the bone loss might be reversed. Our research studies on the chemical pathology and clinical immunology of SARS should have implications for the pathophysiology and therapy of this potentially lethal infection.     

Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms

Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.     

Neural mechanisms involved in pituitary control

The final common pathway of hypothalamo-hypophyseal regulation is composed of neurosecretory neurons elaborating over 20 different neurotransmitters or neuropeptides. Cell bodies of these neurons are located in four major hypothalamic structures (supraoptic and paraventricular nuclei, the preoptic hypothalamic area, and the arcuate-ventromedial region). Their axons build up the tuberoinfundibular bundle, which innervates the median eminence and the posterior pituitary. In those structures, neurosecretory nerve terminals release their secretion product into a microcirculation across neurovascular junctions. Each of the five adenohypophyseal cell types, as well as secretory cells of the intermediate lobe, express specific receptors for several neurotransmitters, many of which are colocalised in the same neuron. In addition, most pituitary neuropeptide receptors are located on more than one cell type. Consequently, pituitary secretion is controlled by multiple neural signals.

Integration of these signals by the cell is achieved by reciprocal interactions between receptor coupling mechanisms. Those involve protein complexes which activate or inhibit adenylate cyclase, as well as mediation by phospholipases. Depending upon its particular mode of coupling, each transmitter-receptor complex can determine activation of phospholipase A or C, phosphoinositide-induced opening of Ca²⁺ channels, or formation of arachidonic acid, a precursor of prostaglandins and leukotrienes. The present chapter reviews the cellular distribution and the coupling pathways of major neural signals driving pituitary functions, and discusses the functional consequences of reciprocal interactions between adenylate cyclase and phospholipase modulation.     

Vestibular mechanisms involved in idiopathic scoliosis

Patients affected by idiopathic scoliosis (IS) show not only a spinal deformity, but also postural and oculomotor deficits suggesting that such syndrome can be related to a vestibular disfunction. It appears, however, that, in children, a slight unbalance in the activity of vestibular complex of both sides escapes the neuronal mechanisms responsible for vestibular compensation and leads to the spinal curvature which characterises IS. Such process could be reinforced by a disrupted integration of vestibular and visual signals at cortical level, leading to an altered perception of the vertical and to abnormal motor commands. In addition to the classical ascending and descending pathways arising from the vestibular nuclei, which utilize glutamate or GABA as neurotransmitters, labyrinthine afferents may also affect spinal, cerebellar and cerebrocortical structures, through the noradrenergic and serotoninergic systems, which originate from the locus coeruleus and the raphe nuclei, respectively. Due to the role of these neuromodulators in brain plasticity, a disruption in the activity of monoaminergic neurons could favour the development of postural and oculomotor deficits. An impaired release of monoamine at cerebrocortical level could also explain the cognitive deficits which may occur in IS patients.     

Lithium neuroprotection: molecular mechanisms and clinical implications

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3beta activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including beta-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.     

Molecular and cellular mechanisms involved in transepithelial transport

Conclusions Our current understanding of vesicular transport across polarized epithelial cells is largely derived from studies of various cell lines in vitro and rat liver in vivo. It may be assumed that the basic mechanisms and cellular machineries which control membrane protein sorting, coated pit-mediated internalization, membrane fusion and fission, play important roles in the phenomenon of selective transcytosis. At the present, however, no general rules have been established that explain the traffic of different membrane proteins and ligands across specific epithelial cell types. For example, the pattern of protein movement that seems to represent a default pathway in certain cell types appears to be signal-mediated in others.The dissection at the molecular level of the components involved in transepithelial traffic of membrane proteins will require complementary experimental approaches, including the isolation of specific transcytotic carrier vesicles, their biochemical characterization, the reconstitution of the various steps in cell-free systems, and analysis of the traffic patterns of transcytotic proteins in different cell types after transfection and in transgenic animals.     

Aspirin and cancer: biological mechanisms and clinical outcomes

Evidence on aspirin and cancer comes from two main sources: (1) the effect of aspirin upon biological mechanisms in cancer, and (2) clinical studies of patients with cancer, some of whom take aspirin. A series of systematic literature searches identified published reports relevant to these two sources. The effects of aspirin upon biological mechanisms involved in cancer initiation and growth appear to generate reasonable expectations of effects upon the progress and mortality of cancer. Clinical evidence on aspirin appears overall to be favourable to the use of aspirin, but evidence from randomized trials is limited, and inconsistent. The main body of evidence comes from meta-analyses of observational studies of patients with a wide range of cancers, about 25% of whom were taking aspirin. Heterogeneity is large but, overall, aspirin is associated with increases in survival and reductions in metastatic spread and vascular complications of different cancers. It is important that evaluations of aspirin used as an adjunct cancer treatment are based upon all the available relevant evidence, and there appears to be a marked harmony between the effects of aspirin upon biological mechanisms and upon the clinical progress of cancer.     

Germination of spores of Bacillales and Clostridiales species: mechanisms and proteins involved

Under conditions that are not conducive to growth, such as nutrient depletion, many members of the orders Bacillales and Clostridiales can sporulate, generating dormant and resistant spores that can survive in the absence of nutrients for years under harsh conditions. However, when nutrients are again present, these spores can return to active growth through the process of germination. Many of the components of the spore germination machinery are conserved between spore forming members of the Bacillales and Clostridiales orders. However, recent studies have revealed significant differences between the germination of spores of Clostridium perfringens and that of spores of a number of Bacillus species, both in the proteins and in the signal transduction pathways involved. In this review, the roles of components of the spore germination machinery of C. perfringens and several Bacillus species and the bioinformatic analysis of germination proteins in the Bacillales and Clostridiales orders are discussed and models for the germination of spores of these two orders are proposed.