Laparoscopic-assisted Resection of a Retroperitoneal Lumbar Nerve Root Neurofibroma: A Case Report / Ressecção assistida por laparoscopia de neurofibroma retroperitoneal da raiz nervosa lombar: Relato de caso

Abstract We present a case of a 59-year-old patient with chronic low back pain, caused by a retroperitoneal intraneural tumour. Laparoscopic excision was performed and histology revealed a spinal nerve root neurofibroma. Post-operatively, the patient developed partial motor and sensitive deficits due to tumoral nerve entrapment, with progressive recovery with rehabilitation. This report reviews the literature on this sparsely reported condition, highlighting the utility of laparoscopy in its management.

Resumo Apresentamos o caso de uma paciente de 59 anos com lombalgia crônica causada por tumor intraneural retroperitoneal. A excisão laparoscópica foi realizada e a histologia revelou um neurofibroma da raiz do nervo espinhal. No período pós-operatório, a paciente desenvolveu déficits motores e sensitivos parciais devido ao encarceramento do nervo tumoral, com recuperação progressiva à reabilitação. Este relato revisa a literatura sobre essa doença pouco descrita, destacando a utilidade da laparoscopia em seu tratamento.

A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa.

Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.

Zika virus: Critical crosstalk between pathogenesis, cytopathic effects, and macroautophagy.

Zika virus (ZIKV) is a re-emerging positive-sense RNA arbovirus. Its genome encodes a polyprotein that is cleaved by proteases into three structural proteins (Envelope, pre-Membrane, and Capsid) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). These proteins have essential functions in viral replication cycle, cytopathic effects, and host cellular response. When infected by ZIKV, host cells promote macroautophagy, which is believed to favor virus entry. Although several authors have attempted to understand this link between macroautophagy and viral infection, little is known. Herein, we performed a narrative review of the molecular connection between macroautophagy and ZIKV infection while focusing on the roles of the structural and nonstructural proteins. We concluded that ZIKV proteins are major virulence factors that modulate host-cell machinery to its advantage by disrupting and/or blocking specific cellular systems and organelles' function, such as endoplasmic reticulum stress and mitochondrial dysfunction.

Serotonergic Modulation of the Excitation/Inhibition Balance in the Visual Cortex.

Serotonergic neurons constitute one of the main systems of neuromodulators, whose diffuse projections regulate the functions of the cerebral cortex. Serotonin (5-HT) is known to play a crucial role in the differential modulation of cortical activity related to behavioral contexts. Some features of the 5-HT signaling organization suggest its possible participation as a modulator of activity-dependent synaptic changes during the critical period of the primary visual cortex (V1). Cells of the serotonergic system are among the first neurons to differentiate and operate. During postnatal development, ramifications from raphe nuclei become massively distributed in the visual cortical area, remarkably increasing the availability of 5-HT for the regulation of excitatory and inhibitory synaptic activity. A substantial amount of evidence has demonstrated that synaptic plasticity at pyramidal neurons of the superficial layers of V1 critically depends on a fine regulation of the balance between excitation and inhibition (E/I). 5-HT could therefore play an important role in controlling this balance, providing the appropriate excitability conditions that favor synaptic modifications. In order to explore this possibility, the present work used in vitro intracellular electrophysiological recording techniques to study the effects of 5-HT on the E/I balance of V1 layer 2/3 neurons, during the critical period. Serotonergic action on the E/I balance has been analyzed on spontaneous activity, evoked synaptic responses, and long-term depression (LTD). Our results pointed out that the predominant action of 5-HT implies a reduction in the E/I balance. 5-HT promoted LTD at excitatory synapses while blocking it at inhibitory synaptic sites, thus shifting the Hebbian alterations of synaptic strength towards lower levels of E/I balance.

5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development.

Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT2A or 5-HT1A and 5-HT7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT1A, 5-HT2A, and 5-HT7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.

Transcriptome Meta-Analysis Confirms the Hidradenitis Suppurativa Pathogenic Triad: Upregulated Inflammation, Altered Epithelial Organization, and Dysregulated Metabolic Signaling.

Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers.

An overview of Zika virus genotypes and their infectivity.

Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.

An overview of Zika virus genotypes and their infectivity

ABSTRACT Zika virus (ZIKV) is an enveloped, single-stranded RNA arbovirus belonging to the genus Flavivirus. It was first isolated from a sentinel monkey in Uganda in 1947. More recently, ZIKV has undergone rapid geographic expansion and has been responsible for outbreaks in Southeast Asia, the Pacific Islands, and America. In this review, we have highlighted the influence of viral genetic variants on ZIKV pathogenesis. Two major ZIKV genotypes (African and Asian) have been identified. The Asian genotype is subdivided into Southwest Asia, Pacific Island, and American strains, and is responsible for most outbreaks. Non-synonymous mutations in ZIKV proteins C, prM, E, NS1, NS2A, NS2B, NS3, and NS4B were found to have a higher prevalence and association with virulent strains of the Asian genotype. Consequently, the Asian genotype appears to have acquired higher cellular permissiveness, tissue persistence, and viral tropism in human neural cells. Therefore, mutations in specific coding regions of the Asian genotype may enhance ZIKV infectivity. Considering that mutations in the genomes of emerging viruses may lead to new virulent variants in humans, there is a potential for the re-emergence of new ZIKV cases in the future.

Luminescent Ru(II) Phenanthroline Complexes as a Probe for Real-Time Imaging of Aß Self-Aggregation and Therapeutic Applications in Alzheimer's Disease.

The complexes cis-[Ru(phen)2(Apy)2]2+, Apy = 4-aminopyridine and 3,4-aminopyridine, are stable in aqueous solution with strong visible absorption. They present emission in the visible region with long lifetime that accumulates in the cytoplasm of Neuro2A cell line without appreciable cytotoxicity. The complexes also serve as mixed-type reversible inhibitors of human AChE and BuChE with high active site contact. cis-[Ru(phen)2(3,4Apy)2]2+ competes efficiently with DMPO by the OH• radical. Luminescence using fluorescence lifetime imaging (FLIM) enables real-time imaging of the conformational changes of the self-aggregation of Aß with incubation of complexes (0-24 h) in phosphate buffer at micromolar concentrations. By this technique, we identified protofibrills in the self-assembly of Aß1-40 and globular structures in the short fragment Aß15-21 in aqueous solution.