Acceptability of venue-based HIV testing and prevention interventions for men who have sex with transgender women and transgender women in Lima, Perú: a formative, qualitative study.

BACKGROUND: Despite being at elevated risk for HIV, men who have sex with transgender women (MSTW) are an overlooked population in the global HIV response. Venue-based HIV interventions have previously had success reaching other HIV priority populations, including transgender women (TW). Similar approaches could be applied for MSTW. OBJECTIVE: To evaluate the prospective acceptability of venue-based HIV testing and prevention interventions for MSTW and TW in Lima, Peru. METHODS: In this exploratory qualitative study, we conducted in-depth interviews (IDI) and focus group discussions (FGD) with three types of participants: MSTW (7 IDIs, 1 FGD), TW (1 FGD), and owners of social venues frequented by MSTW/TW in Lima (2 IDIs). We elicited participants' attitudes and perceptions related to the following four hypothetical interventions delivered at social venues in Lima: rapid HIV testing; HIV self-test distribution; condom/lubricant distribution; and enrolment in a mobile app supporting HIV prevention. We performed a mixed deductive-inductive thematic analysis using the framework method, then applied the Theoretical Framework of Acceptability to classify the overall acceptability of each intervention. RESULTS: Condom/lubricant distribution and app-based HIV prevention information were highly acceptable among all participant types. The two HIV testing interventions had relatively lower acceptability; however, participants suggested this could be overcome if such interventions focused on ensuring discretion, providing access to healthcare professionals, and offering appropriate incentives. CONCLUSIONS: Overall, MSTW and TW shared similar favourable attitudes towards venue-based HIV interventions. Venue-based outreach warrants further exploration as a strategy for engaging MSTW and TW in HIV prevention activities.

Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.

BACKGROUND: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment. METHODS: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM. Proteome and metabolome composition were determined by mass spectrometry-based techniques. We performed neutrophil-GBM cell coculture experiments to evaluate the behavior of rGBM-enriched proteins in the tumor microenvironment. ELISA-based quantitation of candidate proteins was performed to test the association of their plasma concentrations in iGBM with the onset of recurrence. RESULTS: Proteomic profiles reflect increased immune cell infiltration and extracellular matrix reorganization in rGBM. ASAH1, SYMN, and GPNMB were highly enriched proteins in rGBM. Lipidomics indicates the downregulation of ceramides in rGBM. Cell analyses suggest a role for ASAH1 in neutrophils and its localization in extracellular traps. Plasma concentrations of ASAH1 and SYNM show an association with time to recurrence. CONCLUSIONS: We describe the potential importance of ASAH1 in tumor progression and development of rGBM via metabolic rearrangement and showcase the feedback from the tumor microenvironment to plasma proteome profiles. We report the potential of ASAH1 and SYNM as plasma markers of rGBM progression. The published datasets can be considered as a resource for further functional and biomarker studies involving additional -omics technologies.

Neuroprotective astroglial response to neural damage and its relevance to affective disorders.

Astrocytes not only support neuronal function with essential roles in synaptic neurotransmission, action potential propagation, metabolic support, or neuroplastic and developmental adaptations. They also respond to damage or dysfunction in surrounding neurons and oligodendrocytes by releasing neurotrophic factors and other molecules that increase the survival of the supported cells or contribute to mechanisms of structural and molecular restoration. The neuroprotective responsiveness of astrocytes is based on their ability to sense signals of degeneration, metabolic jeopardy and structural damage, and on their aptitude to locally deliver specific molecules to remedy threats to the molecular and structural features of their cellular partners. To the extent that neuronal and other glial cell disturbances are known to occur in affective disorders, astrocyte responsiveness to those disturbances may help to better understand the roles astrocytes play in affective disorders. The astrocytic sensing apparatus supporting those responses involves receptors for neurotransmitters, purines, cell adhesion molecules and growth factors. Astrocytes also share with the immune system the capacity of responding to cytokines released upon neuronal damage. In addition, in responses to specific signals astrocytes release unique factors such as clusterin or humanin that have been shown to exert potent neuroprotective effects. Astrocytes integrate the signals above to further deliver structural lipids, removing toxic metabolites, stabilizing the osmotic environment, normalizing neurotransmitters, providing anti-oxidant protection, facilitating synaptogenesis and acting as barriers to contain varied deleterious signals, some of which have been described in brain regions relevant to affective disorders and related animal models. Since various of the injurious signals that activate astrocytes have been implicated in different aspects of the etiopathology of affective disorders, particularly in relation to the diagnosis of depression, potentiating the corresponding astrocyte neuroprotective responses may provide additional opportunities to improve or complement available pharmacological and behavioral therapies for affective disorders.

New Organotin (IV) Compounds Derived from Dehydroacetic Acid and Thiosemicarbazides: Synthesis, Rational Design, Cytotoxic Evaluation, and Molecular Docking Simulation.

Organotin complexes were prepared through a one-pot reaction with three components by reacting thiosemicarbazide or 4-methyl-3-thiosemicarbazide or 4-phenylthiosemicarbazide, dehydroacetic acid (DHA) and dibutyl, diphenyl, dicyclohexyl, and bis[(trimethylsilyl)methyl]tin(IV) oxides; all complexes were characterized by infrared (IR), ultraviolet-visible (UV-vis), mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy. The 119Sn NMR revealed chemical shifts corresponding to a pentacoordinated environment in solution. The X-ray crystallography of the two complexes evidenced the formation of monomeric complexes with a pentacoordinated geometry around tin via three donor atoms from the ligand, the sulfur of the thiol, the nitrogen of the imine group, and the oxygen of the pyran ring. The geometries of the five-coordinated complexes 3a (Bu2SnL3), 3c (Ph2SnL3), and 3d (Cy2SnL3) acid were intermediate between square pyramidal and trigonal bipyramidal, and complex 1a (Bu2SnL1) adopted a bipyramidal trigonal geometry (BPT). The sulforhodamine B assay assessed the cytotoxicity of organotin(IV) complexes against the MDA-MB-231 and MCF-7 (human mammary adenocarcinoma) cell lines and one normal COS-7 (African green monkey kidney fibroblast). The IC50 values evidenced a significant antiproliferative effect on cancer cells; the complexes were more potent than the positive cisplatin control and the corresponding ligands, dehydroacetic acid thiosemicarbazone (L1), dehydroacetic acid-N(4)-methylthiosemicarbazone (L2), and dehydroacetic acid-N(4)-phenylthiosemicarbazone (L3). The IC50 values also indicated that the organotin(IV) complexes were more cytotoxic against the triple-negative breast cell line MDA-MB-231 than MCF-7, inducing significant morphological alterations. The interactions of organotin(IV) 1c (Ph2SnL1), 1d (Cy2SnL1), and 1e (((CH3)3SiCH2)2SnL1) were evaluated with ss-DNA by fluorescence; intensity changes of the fluorescence were indicative of the displacement of ethidium bromide (EB), confirming the interaction of the organotin(IV) complexes with ss-DNA; the results showed a DNA binding affinity. The thermodynamic parameters obtained through isothermal titration calorimetry showed that the interaction of 1c (Ph2SnL1), with ss-ADN, was exothermic. Molecular docking studies also demonstrated that the organotin(IV) complexes were intercalated in DNA by conventional hydrogen bonds, carbon-hydrogen bonds, and π-alkyl interactions. These complexes furthermore showed a greater affinity towards DNA than cisplatin.

Exploring the Antioxidant Potential of Tragia volubilis L.: Mitigating Chemotherapeutic Effects of Doxorubicin on Tumor Cells.

Several plants of the genus Tragia L. have shown antibacterial, fungicidal, and antiproliferative activity, among other types of activities; however, most species of the genus have not been investigated. Tragia volubilis L. is native to tropical America and Africa, and although it has been reported as medicinal in the literature, it has not been thoroughly investigated. In this study, the phytochemical screening, isolation, and identification of compounds and the determination of the antioxidant activity of the aqueous extract of Tragia volubilis L. and its partitions were carried out. Ethyl acetate and n-butanol partitions of the extract present high antioxidant activity according to the Antioxidant Activity Index. Due to their activity, these partitions were tested on RKO cells as a representative model, both individually and in combination with Doxorubicin. It was found that the partitions significantly reduced the effect of Doxorubicin, as well as the expression of proteins involved in DNA damage and cell death. While the reduction of the chemotherapeutic effect of Doxorubicin on tumor cells may not be a desired outcome in therapeutic settings, the findings of the study are valuable in revealing the antioxidant potential of Tragia volubilis L. and its partitions. This highlights the importance of carefully regulating the application of antioxidants, especially in the context of cancer chemotherapy.

Multicentre, prospective, randomized control non-inferiority trial of bladder catheter management in colon surgery.

AIM: Perioperative bladder catheterization is a controversial issue. Most current recommendations are based on data from open surgery extrapolated to enhanced recovery after surgery or fast-track programmes ranging between 24 and 48 h. The aim of this study is to provide a rationale for reducing catheterization time while at the same time avoiding acute urine retention (AUR), in patients undergoing scheduled laparoscopic colon surgery. METHOD: This is a multicentre, prospective, controlled, randomized non-inferiority study of bladder catheter management in patients undergoing scheduled laparoscopic colon surgery, randomized into two groups: experimental (with catheter removal immediately after surgery) and control (with catheter removal 24 h post-surgery). The main outcome will be the development of AUR, and secondary outcomes the development of urinary infection within the first 30 days and hospital stay. Demographic, surgical and pathological variables will also be evaluated, especially the development of adverse effects assessed according to the Clavien scale and the Comprehensive Complication Index. Following the literature, we assume an incidence of AUR of 11% and a margin of non-inferiority (delta) of 8% and estimate that a sample size of 208 patients per group will be required (with an estimated 10% of losses per group). CONCLUSIONS: In this study we try to demonstrate that the bladder catheter can be removed immediately after scheduled laparoscopic colon surgery, without increasing acute urine retention. This measure would offers the benefits of earlier mobilization and reduces catheter-related morbidity.

Reduced length of nodes of Ranvier and altered proteoglycan immunoreactivity in prefrontal white matter in major depressive disorder and chronically stressed rats.

Major depressive disorder (MDD) and chronic unpredictable stress (CUS) in animals feature comparable cellular and molecular disturbances that involve neurons and glial cells in gray and white matter (WM) in prefrontal brain areas. These same areas demonstrate disturbed connectivity with other brain regions in MDD and stress-related disorders. Functional connectivity ultimately depends on signal propagation along WM myelinated axons, and thus on the integrity of nodes of Ranvier (NRs) and their environment. Various glia-derived proteoglycans interact with NR axonal proteins to sustain NR function. It is unclear whether NR length and the content of associated proteoglycans is altered in prefrontal cortex (PFC) WM of human subjects with MDD and in experimentally stressed animals. The length of WM NRs in histological sections from the PFC of 10 controls and 10 MDD subjects, and from the PFC of control and CUS rats was measured. In addition, in WM of the same brain region, five proteoglycans, tenascin-R and NR protein neurofascin were immunostained or their levels measured with western blots. Analysis of covariance and t-tests were used for group comparisons. There was dramatic reduction of NR length in PFC WM in both MDD and CUS rats. Proteoglycan BRAL1 immunostaining was reduced at NRs and in overall WM of MDD subjects, as was versican in overall WM. Phosphacan immunostaining and levels were increased in both in MDD and CUS. Neurofascin immunostaining at NRs and in overall WM was significantly increased in MDD. Reduced length of NRs and increased phosphacan and neurocan in MDD and stressed animals suggest that morphological and proteoglycan changes at NRs in depression may be related to stress exposure and contribute to connectivity alterations. However, differences between MDD and CUS for some NR related markers may point to other mechanisms affecting the structure and function of NRs in MDD.

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.

BACKGROUND: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. METHODS: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. FINDINGS: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. INTERPRETATION: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. FUNDING: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Osteogénesis Imperfecta: Entre la ficción y la realidad / Imperfect Osteogenesis: Between Fiction and Reality

Los largometrajes han sido utilizados como una herramienta de aprendizaje llamativa en el campo de la salud, esto debido a que ciertas enfermedades que suelen ser raras dentro de la población se prestan para desarrollar una historia en base a las mismas. La Osteogénesis imperfecta conocida también como la enfermedad de los huesos de cristal, es un trastorno genético bastante diverso, si bien el 90 % de los casos se presentan con mutaciones de herencia de tipo autosómicas dominantes, un 10 % restante corresponde a mutaciones autosómicas recesivas o de causa desconocida. En el presente trabajo hemos generado una recopilación de aspectos relevantes sobre esta enfermedad correlacionando con la trama de dos trabajos cinematográficos, Frágiles y El protegido; esto con el fin de analizarlo como una posible herramienta para el aprendizaje de esta enfermedad y de otras patologías de carácter genético. (AU)

Feature films have been used as a striking learning tool in the field of health, this because certain diseases that are usually rare within the population lend themselves to developing a story based on them. Imperfect Osteogenesis also known as crystal bone disease, is a fairly diverse genetic disorder, although 90 % of cases present with autosomal dominant inherited mutations, the remaining 10 % corresponds to autosomal recessive mutations or of unknown cause. In the present work we have generated a compilation of relevant aspects about this disease correlating with the plot of two cinematographic works, Fragile and The Protected; this in order to analyze it as a possible tool for learning about this disease and other pathologies of a genetic nature. (AU)

On the representativeness and stability of a set of EFMs.

MOTIVATION: Elementary flux modes are a well-known tool for analyzing metabolic networks. The whole set of elementary flux modes (EFMs) cannot be computed in most genome-scale networks due to their large cardinality. Therefore, different methods have been proposed to compute a smaller subset of EFMs that can be used for studying the structure of the network. These latter methods pose the problem of studying the representativeness of the calculated subset. In this article, we present a methodology to tackle this problem. RESULTS: We have introduced the concept of stability for a particular network parameter and its relation to the representativeness of the EFM extraction method studied. We have also defined several metrics to study and compare the EFM biases. We have applied these techniques to compare the relative behavior of previously proposed methods in two case studies. Furthermore, we have presented a new method for the EFM computation (PiEFM), which is more stable (less biased) than previous ones, has suitable representativeness measures, and exhibits better variability in the extracted EFMs. AVAILABILITY AND IMPLEMENTATION: Software and additional material are freely available at https://github.com/biogacop/PiEFM.

Astrocytes as Context for the Involvement of Myelin and Nodes of Ranvier in the Pathophysiology of Depression and Stress-Related Disorders.

Astrocytes, despite some shared features as glial cells supporting neuronal function in gray and white matter, participate and adapt their morphology and neurochemistry in a plethora of distinct regulatory tasks in specific neural environments. In the white matter, a large proportion of the processes branching from the astrocytes' cell bodies establish contacts with oligodendrocytes and the myelin they form, while the tips of many astrocyte branches closely associate with nodes of Ranvier. Stability of myelin has been shown to greatly depend on astrocyte-to-oligodendrocyte communication, while the integrity of action potentials that regenerate at nodes of Ranvier has been shown to depend on extracellular matrix components heavily contributed by astrocytes. Several lines of evidence are starting to show that in human subjects with affective disorders and in animal models of chronic stress there are significant changes in myelin components, white matter astrocytes and nodes of Ranvier that have direct relevance to connectivity alterations in those disorders. Some of these changes involve the expression of connexins supporting astrocyte-to-oligodendrocyte gap junctions, extracellular matrix components produced by astrocytes around nodes of Ranvier, specific types of astrocyte glutamate transporters, and neurotrophic factors secreted by astrocytes that are involved in the development and plasticity of myelin. Future studies should further examine the mechanisms responsible for those changes in white matter astrocytes, their putative contribution to pathological connectivity in affective disorders, and the possibility of leveraging that knowledge to design new therapies for psychiatric disorders.

Pentacoordinated Organotin(IV) Complexes as an Alternative in the Design of Highly Efficient Optoelectronic and Photovoltaic Devices: Synthesis and Photophysical Characterization.

The synthesis of four pentacoordinated organotin(IV) complexes prepared in a one-pot reaction from 2-hydroxy-1-naphthaldehyde, 2-amino-3-hydroxypyridine and organotin oxides is reported. The complexes were characterized by UV-Vis, IR, MS, 1H, 13C and 119Sn NMR techniques. The compound based on 2,2-diphenyl-6-aza-1,3-dioxa-2-stannanaphtho[1,2-h]pyrido[3,2-d]cyclononene revealed the formation of a monomeric complex with a distorted five-coordinated molecular geometry intermediate between the trigonal bipyramidal and square pyramidal. In order to find possible applications in photovoltaic devices, hybrid films of organotin(IV) complexes embedded in poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with graphene were deposited. The topographic and mechanical properties were examined. The film with the complex integrated into the cyclohexyl substituent has high plastic deformation, with a maximum stress of 1.69 × 107 Pa and a Knoop hardness of 0.061. The lowest values of 1.85 eV for the onset gap and 3.53 eV for the energy gap were obtained for the heterostructure having the complex with the phenyl substituent. Bulk heterojunction devices were fabricated; these devices showed ohmic behavior at low voltages and a space-charge-limited current (SCLC) conduction mechanism at higher voltages. A value of 0.02 A was found for the maximum carried current. The SCLC mechanism suggests hole mobility values of between 2.62 × 10-2 and 3.63 cm2/V.s and concentrations of thermally excited holes between 2.96 × 1018 and 4.38 × 1018 m-3.

Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.

Peripheral T-cell lymphomas (PTCLs), especially angioimmunoblastic and follicular TCLs, have a dismal prognosis because of the lack of efficient therapies, and patients' symptoms are often dominated by an inflammatory phenotype, including fever, night sweats, weight loss, and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on T-cell follicular helper-type PTCL (TFH-PTCL) disease progression and symptoms. We showed that ITK-SYK-driven murine PTCLs and primary human TFH-PTCL xenografts both induced inflammation in mice, including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving interferon gamma (CD4+ malignant T cells) and interleukin 6 (IL-6; activated granulocytes), ultimately inducing broad JAK activation (JAK1/2/3 and TYK2) in both cell types. Inflammatory granulocyte depletion via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox), or IL-6 deletion within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration, and enhanced mouse survival. Furthermore, unselective JAK inhibitors (ruxolitinib) inhibited both TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions, and an intact JAK/STAT signaling pathway for TFH-PTCL development and also support broad JAK inhibition as an effective treatment strategy in early disease stages.

Role of stress-related glucocorticoid changes in astrocyte-oligodendrocyte interactions that regulate myelin production and maintenance.

Repeated activation of stress responses and elevated corticosteroids result in alterations of neuronal physiology and metabolism, and lead to disturbances of normal connectivity between neurons in various brain regions. In addition, stress responses are also associated with anomalies in the function of glial cells, particularly astrocytes and oligodendrocytes, which in turn may further contribute to the mechanisms of neuronal dysfunction. The actions of corticosteroids on astrocytes are very likely mediated by the presence of intracellular and cell membrane-bound CORT receptors. Although apparently less abundant than in astrocytes, activation of CORT receptors in oligodendrocytes also leads to structural changes that are reflected in myelin maintenance and plasticity. The close interactions between astrocytes and oligodendrocytes through extracellular matrix molecules, soluble factors and astrocyte-oligodendrocyte gap junctions very likely mediate part of the disturbances in myelin structure, leading to plastic myelin adaptations or pathological myelin disruptions that may significantly influence brain connectivity. Likewise, the intimate association of the tips of some astrocytes processes with a majority of nodes of Ranvier in the white matter suggest that stress and overexposure to corticosteroids may lead to remodeling of node of Ranvier and their specific extracellular milieu.

A combined study on structures and vibrational spectra of the antiviral rimantadine using SQMFF and DFT calculations.

In this research, a combined study on structures and vibrational spectra of antiviral rimantadine have been performed using hybrid B3LYP/6-311++G∗∗ calculations and the scaled quantum force field (SQMFF) procedure. Harmonic force fields and scaled force constants of Free Base (FB), Cationic (CA) and Hydrochloride (HCl) species derived from the antiviral rimantadine have been calculated in gas phase and in aqueous solution using normal internal coordinates and scaling factors. Good correlations were acquired comparing the theoretical IR, Raman, 1H- 13C-NMR and UV spectra of three species with the analogous experimental ones, suggesting probably, the presence of all them in both phases. The main force constants of three species have evidenced lower values than the corresponding to antiviral amantadine. The ionic character of N1-H33⋯Cl36 bond of HCl species in aqueous solution evidence positive Mulliken charge on N1 atom indicating that this species is as CA one. Rimantadine presents higher solvation energies in water than other antiviral species, such as chloroquin, niclosamide, cidofovir and brincidofovir. The FB and HCl species of rimantadine are slightly less reactive than the corresponding to amantadine while the opposite is observed for the CA species. The predicted ECD spectra for the FB and CA species show positive Cotton effect different from the negative observed for the HCl one. These different behaviours of three species of rimantadine could probably explain the differences observed in the intensities of bands predicted in the electronic spectra of these species.

Astroglia in the Vulnerability to and Maintenance of Stress-Mediated Neuropathology and Depression.

Significant stress exposure and psychiatric depression are associated with morphological, biochemical, and physiological disturbances of astrocytes in specific brain regions relevant to the pathophysiology of those disorders, suggesting that astrocytes are involved in the mechanisms underlying the vulnerability to or maintenance of stress-related neuropathology and depression. To understand those mechanisms a variety of studies have probed the effect of various modalities of stress exposure on the metabolism, gene expression and plasticity of astrocytes. These studies have uncovered the participation of various cellular pathways, such as those for intracellular calcium regulation, neuroimmune responses, extracellular ionic regulation, gap junctions-based cellular communication, and regulation of neurotransmitter and gliotransmitter release and uptake. More recently epigenetic modifications resulting from exposure to chronic forms of stress or to early life adversity have been suggested to affect not only neuronal mechanisms but also gene expression and physiology of astrocytes and other glial cells. However, much remains to be learned to understand the specific role of those and other modifications in the astroglial contribution to the vulnerability to and maintenance of stress-related disorders and depression, and for leveraging that knowledge to achieve more effective psychiatric therapies.

An Update of the Sanguinarine and Benzophenanthridine Alkaloids' Biosynthesis and Their Applications.

Benzophenanthridines belong to the benzylisoquinolic alkaloids, representing one of the main groups of this class. These alkaloids include over 120 different compounds, mostly in plants from the Fumariaceae, Papaveraceae, and Rutaceae families, which confer chemical protection against pathogens and herbivores. Industrial uses of BZD include the production of environmentally friendly agrochemicals and livestock food supplements. However, although mainly considered toxic compounds, plants bearing them have been used in traditional medicine and their medical applications as antimicrobials, antiprotozoals, and cytotoxic agents have been envisioned. The biosynthetic pathways for some BZD have been established in different species, allowing for the isolation of the genes and enzymes involved. This knowledge has resulted in a better understanding of the process controlling their synthesis and an opening of the gates towards their exploitation by applying modern biotechnological approaches, such as synthetic biology. This review presents the new advances on BDZ biosynthesis and physiological roles. Industrial applications, mainly with pharmacological approaches, are also revised.

Transplantation of hematopoietic progenitors in myelofibrosis.

The objective of this work is to generate recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles published between 1999 and 2015 (January) was used as a source of scientific evidence. The recommendations were produced through a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and the European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention, and management of post-transplant relapse. Patients with intermediate-2 or high-risk disease and age < 70 years should be considered candidates for allo-SCT. Patients with intermediate-risk 1 disease and age < 65 years should be considered candidates if they have refractory transfusion-dependent anemia, or a peripheral blood (PB) blast percentage > 2%, or adverse cytogenetics. Splenectomy before transplantation must be decided on a case-by-case basis. Patients with intermediate-2 or high-risk disease who lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor should be enrolled in a protocol that uses HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for transplants from HLA-matched unrelated donors and siblings. The optimal intensity of the conditioning regimen has yet to be defined. Strategies such as discontinuation of immunosuppressive drugs, infusion of donor lymphocytes, or both were considered adequate to prevent clinical relapse. In conclusion, we provide consensus-based recommendations aimed at optimizing allo-SCT in PMF. Unmet clinical needs were highlighted.

El objetivo de este trabajo es generar recomendaciones sobre el manejo del trasplante alogénico de células madre (alo-SCT) en la mielofibrosis primaria (MFP). Se utilizó una revisión sistemática integral de artículos publicados entre 1999 y 2015 (enero) como fuente de evidencia científica. Las recomendaciones se produjeron mediante un proceso Delphi en el que participó un panel de 23 expertos designados por la European LeukemiaNet y el European Blood and Marrow Transplantation Group. Las preguntas clave incluyeron la selección de pacientes, la selección de donantes, el manejo previo al trasplante, el régimen de acondicionamiento, el manejo posterior al trasplante, la prevención y el manejo de la recaída después del trasplante. Los pacientes con enfermedad de riesgo intermedio 2 o alto y edad < 70 años deben ser considerados candidatos para alo-SCT. Los pacientes con enfermedad de riesgo intermedio 1 y edad < 65 años deben ser considerados candidatos si presentan anemia refractaria dependiente de transfusiones, o un porcentaje de blastos en sangre periférica > 2%, o citogenética adversa. La esplenectomía previa al trasplante debe decidirse caso por caso. Los pacientes con enfermedad de riesgo intermedio 2 o alto que carecen de un hermano compatible con el antígeno leucocitario humano (HLA) o de un donante no emparentado deben inscribirse en un protocolo que utilice donantes no idénticos de HLA. PB se consideró la fuente más apropiada de células madre hematopoyéticas para trasplantes de hermanos y donantes no emparentados compatibles con HLA. La intensidad óptima del régimen de acondicionamiento aún debe definirse. Se consideraron adecuadas estrategias como la suspensión de los fármacos inmunosupresores, la infusión de linfocitos del donante o ambas para evitar la recaída clínica. En conclusión, proporcionamos recomendaciones basadas en consenso destinadas a optimizar el alo-SCT en MFP. Se destacaron las necesidades clínicas insatisfechas.

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

La trombocitemia esencial (TE) es una neoplasia mieloproliferativa crónica Filadelfia negativa que tiene su principal involucro en la línea megacariopoyética, generando trombocitosis sostenida en la sangre periférica y un incremento en el número de megacariocitos maduros en médula ósea. Además de una marcada trombocitosis, se caracteriza por un mayor riesgo trombótico o hemorrágico y la presencia de síntomas constitucionales. Los pacientes con TE tienen un riesgo bajo, pero conocido, de evolución de la enfermedad a mielofibrosis y/o leucemia aguda. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. Los tratamientos actualmente disponibles para los pacientes con TE están dirigidos principalmente a minimizar el riesgo de trombosis y/o hemorragia.

Pregnancy in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are associated with a significant risk of thrombosis and the hypercoagulable environment of pregnancy increases this risk. The most frequent gestational complications consist of spontaneous abortion, thrombosis, bleeding, and hypertensive disease of pregnancy. Treatment depends on thrombotic risk, gestational trimester, and myeloproliferative neoplasm.

Las neoplasias mieloproliferativas (NMP) están asociadas a un riesgo notable de trombosis y el entorno de hipercoagulabilidad propio del embarazo aumenta este riesgo. Las complicaciones gestacionales más frecuentes consisten en: aborto espontáneo, trombosis, sangrado y enfermedad hipertensiva del embarazo. El tratamiento depende del riesgo trombótico, trimestre gestacional y neoplasia mieloproliferativa.