Efficacy and Safety of Celiac Plexus Neurolysis in the Treatment of Chronic Pain Secondary to Oncological Pathology of the Upper Hemiabdomen: A Systematic Review and Meta-Analysis.

Objectives: The management of chronic pain among patients with abdominal cancer is complex; against that, the neurolysis of the celiac plexus (CPN) is the best technique at the moment to determine the efficacy and safety in the treatment of chronic pain secondary to oncological pathology of the upper abdomen. Material and Methods: This was a systematic review of controlled clinical trials between 2000 and 2021, in the sources MEDLINE/PubMed, Cochrane, Scopus, Web of Science, and Google Scholar. Three independent evaluators analysed the results of the bibliographical research. The quality of the studies was assessed with the Jadad scale and the mean difference (95% confidence interval) and heterogeneity of the studies (I2) were calculated with Review Manager 5.3. Results: Seven hundred and forty-four publications were identified, including 13 studies in the qualitative synthesis and three studies in the quantitative synthesis. No difference was found in the decrease in pain intensity between 1 and 12 weeks after the intervention, comparing the experimental group with the control (P > 0.05). The adverse effects related to neurolysis were not serious and transitory, mentioning the most frequent adverse effects and reporting a percentage between 21% and 67% (with 17% for echoendoscopic neurolysis and 49% for percutaneous neurolysis). Conclusion: Celiac plexus neurolysis for the treatment of severe chronic pain secondary to oncological pathology in the upper hemiabdomen produces similar pain relief as conventional pharmacological analgesic treatment. It is a safe analgesic technique since the complications are mild and transitory.

Annexin A5 stabilizes matrix vesicle-biomimetic lipid membranes: unravelling a new role of annexins in calcification.

Matrix vesicles are a special class of extracellular vesicles thought to actively contribute to both physiologic and pathologic mineralization. Proteomic studies have shown that matrix vesicles possess high amounts of annexin A5, suggesting that the protein might have multiple roles at the sites of calcification. Currently, Annexin A5 is thought to promote the nucleation of apatitic minerals close to the inner leaflet of the matrix vesicles' membrane enriched in phosphatidylserine and Ca2+. Herein, we aimed at unravelling a possible additional role of annexin A5 by investigating the ability of annexin A5 to adsorb on matrix-vesicle biomimetic liposomes and Langmuir monolayers made of dipalmitoylphosphatidylserine (DPPS) and dipalmitoylphosphatidylcholine (DPPC) in the absence and in the presence of Ca2+. Differential scanning calorimetry and dynamic light scattering measurements showed that Ca2+ at concentrations in the 0.5-2.0 mM range induced the aggregation of liposomes probably due to the formation of DPPS-enriched domains. However, annexin A5 avoided the aggregation of liposomes at Ca2+ concentrations lower than 1.0 mM. Surface pressure versus surface area isotherms showed that the adsorption of annexin A5 on the monolayers made of a mixture of DPPC and DPPS led to a reduction in the area of excess compared to the theoretical values, which confirmed that the protein favored attractive interactions among the membrane lipids. The stabilization of the lipid membranes by annexin A5 was also validated by recording the changes with time of the surface pressure. Finally, fluorescence microscopy images of lipid monolayers revealed the formation of spherical lipid-condensed domains that became unshaped and larger in the presence of annexin A5. Our data support the model that annexin A5 in matrix vesicles is recruited at the membrane sites enriched in phosphatidylserine and Ca2+ not only to contribute to the intraluminal mineral formation but also to stabilize the vesicles' membrane and prevent its premature rupture.

NPP1 and TNAP hydrolyze ATP synergistically during biomineralization.

Matrix vesicles (MVs) are a special class of extracellular vesicles released by mineralizing cells during bone and tooth mineralization that initiate the precipitation of apatitic minerals by regulating the extracellular ratio between inorganic phosphate (Pi), a calcification promoter, and pyrophosphate (PPi), a calcification inhibitor. The Pi/PPi ratio is thought to be controlled by two ecto-phosphatases present on the outer leaflet of the MVs' membrane: ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) that produces PPi as well as Pi from ATP and tissue-nonspecific alkaline phosphatase (TNAP) that hydrolyzes both ATP and PPi to generate Pi. However, if and how these enzymes act in concert in MVs are still unclear. Herein, we investigated the role of NPP1 and TNAP in ATP hydrolysis during MV-mediated biomineralization using proteoliposomes as a biomimetic model for MVs. Proteoliposomes composed by 1,2-dipalmitoylphosphatidylcholine (DPPC) and harboring NPP1 alone, TNAP alone, or both together at different molar ratios (1:1, 10:1, and 1:10) were fabricated. After 48 h of incubation with ATP, TNAP-containing proteoliposomes consumed more ATP than NPP1-containing vesicles (270 and 210 nmol, respectively). Both types of vesicles comparatively formed ADP (205 and 201 nmol, respectively), while NPP1-containing vesicles hydrolyzed AMP less efficiently than TNAP-containing proteoliposomes (10 and 25 nmol, respectively). In vitro mineralization assays showed that in the presence of ATP, TNAP-harboring proteoliposomes mineralized through a sigmoidal single-step process, while NPP1-harboring vesicles displayed a two-step mineralization process. ATR-FTIR analyses showed that the minerals produced by TNAP-harboring proteoliposomes were structurally more similar to hydroxyapatite than those produced by NPP1-harboring vesicles. Our results with proteoliposomes indicate that the pyrophosphohydrolase function of NPP1 and the phosphohydrolase activity of TNAP act synergistically to produce a Pi/PPi ratio conducive to mineralization and the synergism is maximal when the two enzymes are present at equimolar concentrations. The significance of these findings for hypophosphatasia is discussed.

Critical Current Density in d-Wave Hubbard Superconductors.

In this work, the Generalized Hubbard Model on a square lattice is applied to evaluate the electrical current density of high critical temperature d-wave superconductors with a set of Hamiltonian parameters allowing them to reach critical temperatures close to 100 K. The appropriate set of Hamiltonian parameters permits us to apply our model to real materials, finding a good quantitative fit with important macroscopic superconducting properties such as the critical superconducting temperature (Tc) and the critical current density (Jc). We propose that much as in a dispersive medium, in which the velocity of electrons can be estimated by the gradient of the dispersion relation ∇ε(k), the electron velocity is proportional to ∇E(k) in the superconducting state (where E(k)=(ε(k)-µ)2+Δ2(k) is the dispersion relation of the quasiparticles, and k is the electron wave vector). This considers the change of ε(k) with respect to the chemical potential (µ) and the formation of pairs that gives rise to an excitation energy gap Δ(k) in the electron density of states across the Fermi level. When ε(k)=µ at the Fermi surface (FS), only the term for the energy gap remains, whose magnitude reflects the strength of the pairing interaction. Under these conditions, we have found that the d-wave symmetry of the pairing interaction leads to a maximum critical current density in the vicinity of the antinodal k-space direction (π,0) of approximately 1.407236×108 A/cm2, with a much greater current density along the nodal direction (π2,π2) of 2.214702×109 A/cm2. These results allow for the establishment of a maximum limit for the critical current density that could be attained by a d-wave superconductor.

Shedding Light on the Role of Na,K-ATPase as a Phosphatase during Matrix-Vesicle-Mediated Mineralization.

Matrix vesicles (MVs) contain the whole machinery necessary to initiate apatite formation in their lumen. We suspected that, in addition to tissue-nonspecific alkaline phosphatase (TNAP), Na,K,-ATPase (NKA) could be involved in supplying phopshate (Pi) in the early stages of MV-mediated mineralization. MVs were extracted from the growth plate cartilage of chicken embryos. Their average mean diameters were determined by Dynamic Light Scattering (DLS) (212 ± 19 nm) and by Atomic Force Microcopy (AFM) (180 ± 85 nm). The MVs had a specific activity for TNAP of 9.2 ± 4.6 U·mg-1 confirming that the MVs were mineralization competent. The ability to hydrolyze ATP was assayed by a colorimetric method and by 31P NMR with and without Levamisole and SBI-425 (two TNAP inhibitors), ouabain (an NKA inhibitor), and ARL-67156 (an NTPDase1, NTPDase3 and Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) competitive inhibitor). The mineralization profile served to monitor the formation of precipitated calcium phosphate complexes, while IR spectroscopy allowed the identification of apatite. Proteoliposomes containing NKA with either dipalmitoylphosphatidylcholine (DPPC) or a mixture of 1:1 of DPPC and dipalmitoylphosphatidylethanolamine (DPPE) served to verify if the proteoliposomes were able to initiate mineral formation. Around 69-72% of the total ATP hydrolysis by MVs was inhibited by 5 mM Levamisole, which indicated that TNAP was the main enzyme hydrolyzing ATP. The addition of 0.1 mM of ARL-67156 inhibited 8-13.7% of the total ATP hydrolysis in MVs, suggesting that NTPDase1, NTPDase3, and/or NPP1 could also participate in ATP hydrolysis. Ouabain (3 mM) inhibited 3-8% of the total ATP hydrolysis by MVs, suggesting that NKA contributed only a small percentage of the total ATP hydrolysis. MVs induced mineralization via ATP hydrolysis that was significantly inhibited by Levamisole and also by cleaving TNAP from MVs, confirming that TNAP is the main enzyme hydrolyzing this substrate, while the addition of either ARL-6715 or ouabain had a lesser effect on mineralization. DPPC:DPPE (1:1)-NKA liposome in the presence of a nucleator (PS-CPLX) was more efficient in mineralizing compared with a DPPC-NKA liposome due to a better orientation of the NKA active site. Both types of proteoliposomes were able to induce apatite formation, as evidenced by the presence of the 1040 cm-1 band. Taken together, the findings indicated that the hydrolysis of ATP was dominated by TNAP and other phosphatases present in MVs, while only 3-8% of the total hydrolysis of ATP could be attributed to NKA. It was hypothesized that the loss of Na/K asymmetry in MVs could be caused by a complete depletion of ATP inside MVs, impairing the maintenance of symmetry by NKA. Our study carried out on NKA-liposomes confirmed that NKA could contribute to mineral formation inside MVs, which might complement the known action of PHOSPHO1 in the MV lumen.

The Chemokine MIG is Associated with an Increased Risk of COVID-19 Mortality in Mexican Patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emergent viral disease in which the host inflammatory response modulates the clinical outcome. Severe outcomes are associated with an exacerbation of inflammation in which chemokines play an important role as the attractants of immune cells to the tissues. OBJECTIVE: To evaluate the relationship of the chemokines IL-8, RANTES, MIG, MCP-1, and IP-10 with COVID-19 severity and outcomes in Mexican patients. METHODS: We analyzed the serum levels of IL-8, RANTES, MIG, MCP-1 and IP-10 in 148 COVID-19 hospitalized patients classified as mild (n=20), severe (n=61), and critical (n=67), as well as in healthy individuals (n=10), by flow cytometry bead array assay. RESULTS: Chemokine levels were higher in patients than in the healthy individuals, but only MIG, MCP-1, and IP-10 increased according to the disease severity, showing the highest levels in the critical group. MIG, MCP-1, and IP-10 levels were also higher in COVID-19 patients with comorbidities such as renal disease, type 2 diabetes, and hypertension. Moreover, elevated MIG levels seem to be related to organic failure/shock, and an increased risk of death. CONCLUSIONS: Our results suggest that the increased levels of MCP-1, IP-10, and especially MIG might be useful in predicting severe COVID-19 outcomes and could be promising therapeutic targets.

Mineralization Profile of Annexin A6-Harbouring Proteoliposomes: Shedding Light on the Role of Annexin A6 on Matrix Vesicle-Mediated Mineralization.

The biochemical machinery involved in matrix vesicles-mediated bone mineralization involves a specific set of lipids, enzymes, and proteins. Annexins, among their many functions, have been described as responsible for the formation and stabilization of the matrix vesicles' nucleational core. However, the specific role of each member of the annexin family, especially in the presence of type-I collagen, remains to be clarified. To address this issue, in vitro mineralization was carried out using AnxA6 (in solution or associated to the proteoliposomes) in the presence or in the absence of type-I collagen, incubated with either amorphous calcium phosphate (ACP) or a phosphatidylserine-calcium phosphate complex (PS-CPLX) as nucleators. Proteoliposomes were composed of 1,2-dipalmitoylphosphatidylcholine (DPPC), 1,2-dipalmitoylphosphatidylcholine: 1,2-dipalmitoylphosphatidylserine (DPPC:DPPS), and DPPC:Cholesterol:DPPS to mimic the outer and the inner leaflet of the matrix vesicles membrane as well as to investigate the effect of the membrane fluidity. Kinetic parameters of mineralization were calculated from time-dependent turbidity curves of free Annexin A6 (AnxA6) and AnxA6-containing proteoliposomes dispersed in synthetic cartilage lymph. The chemical composition of the minerals formed was investigated by Fourier transform infrared spectroscopy (FTIR). Free AnxA6 and AnxA6-proteoliposomes in the presence of ACP were not able to propagate mineralization; however, poorly crystalline calcium phosphates were formed in the presence of PS-CPLX, supporting the role of annexin-calcium-phosphatidylserine complex in the formation and stabilization of the matrix vesicles' nucleational core. We found that AnxA6 lacks nucleation propagation capacity when incorporated into liposomes in the presence of PS-CPLX and type-I collagen. This suggests that AnxA6 may interact either with phospholipids, forming a nucleational core, or with type-I collagen, albeit less efficiently, to induce the nucleation process.

The Usefulness of Peripheral Blood Cell Counts to Distinguish COVID-19 from Dengue during Acute Infection.

COVID-19 and dengue disease are challenging to tell apart because they have similarities in clinical and laboratory features during the acute phase of infection, leading to misdiagnosis and delayed treatment. The present study evaluated peripheral blood cell count accuracy to distinguish COVID-19 non-critical patients from non-severe dengue cases between the second and eleventh day after symptom onset. A total of 288 patients infected with SARS-CoV-2 (n = 105) or dengue virus (n = 183) were included in this study. Neutrophil, platelet, and lymphocyte counts were used to calculate the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the neutrophil-lymphocyte*platelet ratio (NLPR). The logistic regression and ROC curves analysis revealed that neutrophil and platelet counts, NLR, LPR, and NLPR were higher in COVID-19 than dengue. The multivariate predictive model showed that the neutrophils, platelets, and NLPR were independently associated with COVID-19 with a good fit predictive value (p = 0.1041). The neutrophil (AUC = 0.95, 95% CI = 0.84-0.91), platelet (AUC = 0.89, 95% CI = 0.85-0.93) counts, and NLR (AUC = 0.88, 95% CI = 0.84-0.91) were able to discriminate COVID-19 from dengue with high sensitivity and specificity values (above 80%). Finally, based on predicted probabilities on combining neutrophils and platelets with NLR or NLPR, the adjusted AUC was 0.97 (95% CI = 0.94-0.98) to differentiate COVID-19 from dengue during the acute phase of infection with outstanding accuracy. These findings might suggest that the neutrophil, platelet counts, and NLR or NLPR provide a quick and cost-effective way to distinguish between dengue and COVID-19 in the context of co-epidemics in low-income tropical regions.

Three-dimensional cell-laden collagen scaffolds: From biochemistry to bone bioengineering.

The bones can be viewed as both an organ and a material. As an organ, the bones give structure to the body, facilitate skeletal movement, and provide protection to internal organs. As a material, the bones consist of a hybrid organic/inorganic three-dimensional (3D) matrix, composed mainly of collagen, noncollagenous proteins, and a calcium phosphate mineral phase, which is formed and regulated by the orchestrated action of a complex array of cells including chondrocytes, osteoblasts, osteocytes, and osteoclasts. The interactions between cells, proteins, and minerals are essential for the bone functions under physiological loading conditions, trauma, and fractures. The organization of the bone's organic and inorganic phases stands out for its mechanical and biological properties and has inspired materials research. The objective of this review is to fill the gaps between the physical and biological characteristics that must be achieved to fabricate scaffolds for bone tissue engineering with enhanced performance. We describe the organization of bone tissue highlighting the characteristics that have inspired the development of 3D cell-laden collagenous scaffolds aimed at replicating the mechanical and biological properties of bone after implantation. The role of noncollagenous macromolecules in the organization of the collagenous matrix and mineralization ability of entrapped cells has also been reviewed. Understanding the modulation of cell activity by the extracellular matrix will ultimately help to improve the biological performance of 3D cell-laden collagenous scaffolds used for bone regeneration and repair as well as for in vitro studies aimed at unravelling physiological and pathological processes occurring in the bone.

ß-defensin 1 Gene Polymorphisms are Associated with Kidney Disease in Northwestern Mexicans with Type 2 Diabetes.

Diabetic kidney disease (DKD) is one of the more limiting complications to the quality of life of diabetes mellitus patients. Studies including cultured cells, animal models, and case-control studies highlight the role of human ß-defensin-1 (hBD-1) in diabetes.This study assessed the association of hBD-1 gene (DEFB1) functional variations -52 G/A (rs1799946), -44 C/G (rs1800972) and -20 G/A (rs11362) with type 2 diabetes mellitus (T2DM) in order to investigate its effects on genetic susceptibility and progression to DKD in a Mexican population. A total of 214 T2DM patients with and without DKD (n = 102 and n = 112, respectively) and 117 healthy subjects participated in this case-control study. Genotyping was made by PCR-RFLPs. Clinical and biochemical parameters of all patients were measured. There was no statistically significant difference in genotype or allele frequencies between patients and healthy individuals. Nevertheless, compared with patients without DKD, DKD patients have a reduced prevalence of AA genotype of -52 G/A (OR = 0.307, 95% CI = 0.104-0.905, p =.026), as well as a higher frequency of GA genotype of -20 G/A variant (OR = 1.875, 95%CI = 1.031-3.409, p = .038). Our results suggest that rs1799946 and rs11362 could be useful variants to stratify T2DM Mexican patients in order to prescribe closer follow-up to prevent or retard DKD. Further tests in different ethnic groups are encouraged.

Blood Biomarker Profile Alterations in Newborn Canines: Effect of the Mother's Weight.

This study aims to determine the effect of the weight of bitches on liveborn and stillbirth puppies from eutocic births, and physiological blood alterations during the first minute postpartum. A total of 52 female dogs were evaluated and distributed in four categories: C1 (4.0-8.0 kg, n = 19), C2 (8.1-16.0 kg, n = 16), C3 (16.1-32.0 kg, n = 11), and C4 (32.1-35.8 kg, n = 6). The dams produced 225 liveborn puppies and 47 were classified as stillbirth type II. Blood samples were taken from the umbilical vein to evaluate the concentration of gases, glucose, lactate, calcium, hematocrit levels, and blood pH. The liveborn puppies in C2, C3, and C4 had more evident physiological alterations (hypercapnia, acidosis) than those in C1 (p < 0.05). These signs indicate a process of transitory asphyxiation. The stillborn pups in all four categories had higher weights than their liveborn littermates. C3 and C4 had the highest mean weights (419.86 and 433.79 g, respectively) and mortality rates (C3 = 20.58%, C4 = 24.58%). Results suggest that if the weight of the bitch is >16.1 kg in eutocic births, there is a higher risk of intrapartum physiological alterations and death. The results of this study allowed us to identify that the weight of dams before birth determines the weight of the puppies at birth.

Case Report: Severe Craniofacial Coccidioidomycosis in a Pregnant Woman.

Coccidioidomycosis is a systemic fungal disease caused by Coccidioides immitis and Coccidioides posadasii. The lungs are the most common and often the initial site of involvement, and the non-pulmonary presentation is infrequent. We describe an unusual case of primary craniocutaneous coccidioidomycosis in a pregnant woman with infected bilateral periorbital nodules, intense pain at paranasal sinuses, and several osteolytic skull lesions. The analysis of 54 cases available in the literature makes us suggest that the area between the United States and Mexico is a risk zone for primary cutaneous coccidioidomycosis.

Phosphatidylserine controls calcium phosphate nucleation and growth on lipid monolayers: A physicochemical understanding of matrix vesicle-driven biomineralization.

Bone biomineralization is an exquisite process by which a hierarchically organized mineral matrix is formed. Growing evidence has uncovered the involvement of one class of extracellular vesicles, named matrix vesicles (MVs), in the formation and delivery of the first mineral nuclei to direct collagen mineralization. MVs are released by mineralization-competent cells equipped with a specific biochemical machinery to initiate mineral formation. However, little is known about the mechanisms by which MVs can trigger this process. Here, we present a combination of in situ investigations and ex vivo analysis of MVs extracted from growing-femurs of chicken embryos to investigate the role played by phosphatidylserine (PS) in the formation of mineral nuclei. By using self-assembled Langmuir monolayers, we reconstructed the nucleation core - a PS-enriched motif thought to trigger mineral formation in the lumen of MVs. In situ infrared spectroscopy of Langmuir monolayers and ex situ analysis by transmission electron microscopy evidenced that mineralization was achieved in supersaturated solutions only when PS was present. PS nucleated amorphous calcium phosphate that converted into biomimetic apatite. By using monolayers containing lipids extracted from native MVs, mineral formation was also evidenced in a manner that resembles the artificial PS-enriched monolayers. PS-enrichment in lipid monolayers creates nanodomains for local increase of supersaturation, leading to the nucleation of ACP at the interface through a multistep process. We posited that PS-mediated nucleation could be a predominant mechanism to produce the very first mineral nuclei during MV-driven bone/cartilage biomineralization.

Matrix vesicle biomimetics harboring Annexin A5 and alkaline phosphatase bind to the native collagen matrix produced by mineralizing vascular smooth muscle cells.

BACKGOUND: Vascular smooth muscle cells (VSMCs) transdifferentiated ectopically trigger vascular calcifications, contributing to clinical cardiovascular disease in the aging population. AnxA5 and TNAP play a crucial role in (patho)physiological mineralization. METHODS: We performed affinity studies between DPPC and 9:1 DPPC:DPPS-proteoliposomes carrying AnxA5 and/or TNAP and different types of collagen matrix: type I, II, I + III and native collagenous extracellular matrix (ECM) produced from VSMCs with or without differentiation, to simulate ectopic calcification conditions. RESULTS: AnxA5-proteoliposomes had the highest affinity for collagens, specially for type II. TNAP-proteoliposomes bound poorly and the simultaneous presence of TNAP in the AnxA5-proteoliposomes disturbed interactions between AnxA5 and collagen. DPPC AnxA5-proteoliposomes affinities for ECM from transdifferentiating cells went up 2-fold compared to that from native VSMCs. The affinities of DPPC:DPPS-proteoliposomes were high for ECM from VSMCs with or without differentiation, underscoring a synergistic effect between AnxA5 and DPPS. Co-localization studies uncovered binding of proteoliposomes harboring AnxA5 or TNAP+AnxA5 to various regions of the ECM, not limited to type II collagen. CONCLUSION: AnxA5-proteoliposomes showed the highest affinities for type II collagen, deposited during chondrocyte mineralization in joint cartilage. TNAP in the lipid/protein microenvironment disturbs interactions between AnxA5 and collagen. These findings support the hypothesis that TNAP is cleaved from the MVs membrane just before ECM binding, such facilitating MV anchoring to ECM via AnxA5 interaction. GENERAL SIGNIFICANCE: Proteoliposomes as MV biomimetics are useful in the understanding of mechanisms that regulate the mineralization process and may be essential for the development of novel therapeutic strategies to prevent or inhibit ectopic mineralization.

Localization of Annexin A6 in Matrix Vesicles During Physiological Mineralization.

Annexin A6 (AnxA6) is the largest member of the annexin family of proteins present in matrix vesicles (MVs). MVs are a special class of extracellular vesicles that serve as a nucleation site during cartilage, bone, and mantle dentin mineralization. In this study, we assessed the localization of AnxA6 in the MV membrane bilayer using native MVs and MV biomimetics. Biochemical analyses revealed that AnxA6 in MVs can be divided into three distinct groups. The first group corresponds to Ca2+-bound AnxA6 interacting with the inner leaflet of the MV membrane. The second group corresponds to AnxA6 localized on the surface of the outer leaflet. The third group corresponds to AnxA6 inserted in the membrane's hydrophobic bilayer and co-localized with cholesterol (Chol). Using monolayers and proteoliposomes composed of either dipalmitoylphosphatidylcholine (DPPC) to mimic the outer leaflet of the MV membrane bilayer or a 9:1 DPPC:dipalmitoylphosphatidylserine (DPPS) mixture to mimic the inner leaflet, with and without Ca2+, we confirmed that, in agreement with the biochemical data, AnxA6 interacted differently with the MV membrane. Thermodynamic analyses based on the measurement of surface pressure exclusion (πexc), enthalpy (ΔH), and phase transition cooperativity (Δt1/2) showed that AnxA6 interacted with DPPC and 9:1 DPPC:DPPS systems and that this interaction increased in the presence of Chol. The selective recruitment of AnxA6 by Chol was observed in MVs as probed by the addition of methyl-ß-cyclodextrin (MßCD). AnxA6-lipid interaction was also Ca2+-dependent, as evidenced by the increase in πexc in negatively charged 9:1 DPPC:DPPS monolayers and the decrease in ΔH in 9:1 DPPC:DPPS proteoliposomes caused by the addition of AnxA6 in the presence of Ca2+ compared to DPPC zwitterionic bilayers. The interaction of AnxA6 with DPPC and 9:1 DPPC:DPPS systems was distinct even in the absence of Ca2+ as observed by the larger change in Δt1/2 in 9:1 DPPC:DPPS vesicles as compared to DPPC vesicles. Protrusions on the surface of DPPC proteoliposomes observed by atomic force microscopy suggested that oligomeric AnxA6 interacted with the vesicle membrane. Further work is needed to delineate possible functions of AnxA6 at its different localizations and ways of interaction with lipids.

Factores asociados con mal pronóstico en embarazadas con diagnóstico de SARS-CoV-2 / Factors associated with poor forecasting in pregnant women with SARS-Cov-2 diagnosis

Resumen OBJETIVO: Describir los factores asociados con mal pronóstico en embarazadas con diagnóstico de infección por virus SARS-CoV-2. MATERIALES Y MÉTODOS: Estudio transversal, descriptivo y comparativo de los datos abiertos reportados por la Secretaría de Salud de México de pacientes COVID-19 hasta el 26 de abril de 2020. Se incluyeron mujeres embarazadas, con reporte positivo para infección por SARS-CoV-2. El grupo control se integró con mujeres en edad reproductiva. Se excluyeron las mujeres en quienes el estado puerperal se reportó desconocido o sin correspondencia. En ambos grupos se analizaron la severidad de la enfermedad y las comorbilidades asociadas con la severidad. RESULTADOS: Se registraron 84 mujeres embarazadas con infección por SARS-CoV-2 vs 2836 con infección por SARS-CoV-2 en edad reproductiva. El 33% de las embarazadas requirió hospitalización vs 17% de las no embarazadas; fue mayor la necesidad de intubación (2.4 vs 0.08%), ingreso a la unidad de cuidados intensivos (3.6 vs 1.3%) y letalidad en las embarazadas (7.14 vs 0.7%). Éstas tuvieron mayor probabilidad de llegar a la forma severa de la infección (7%) vs las no embarazadas en edad reproductiva (2.8%). Las comorbilidades asociadas con mayor severidad fueron diabetes (50%) y tabaquismo (33%). CONCLUSIÓN: Las mujeres embarazadas tienen mayor probabilidad de experimentar una forma severa ante la infección por SARS-CoV-2 vs las mujeres en edad reproductiva. Los principales factores asociados con la infección fueron la coexistencia de diabetes y el antecedente de tabaquismo.

Abstract OBJECTIVE: To describe the associated factors with the degree of severity in pregnant Mexican women reported with SARS-CoV-2 virus infection. MATERIAL AND METHODS: Descriptive, transversal and comparative study of free dates reported by Mexico's Health Secretary of COVID-19 patients until April 26th, 2020. Pregnant women positive to SARS-CoV-2 infection were included. Control group were women in reproductive age. Exclusion criteria were women with puerperal status reported as unknown or does not apply. Infection was analyzed by severity in both groups, then comorbidities associated to degree of severity were determined with descriptive statistic. RESULTS: 84 pregnant women were positive to SARS-CoV-2 vs 2,836 non-pregnant infected women in reproductive age. 33% of pregnant women required hospitalization vs 17% of control group. 2.4% vs 0.08% required intubation, 3.6% vs 1.3% were admitted to critical care unit and lethality was 7.14% vs 0.7% in pregnant vs control group respectively. Main comorbidities associated with severity in pregnant women were diabetes (50%) and tobacco use (33%). CONCLUSION: Pregnant women have greater probability to develop a severe form of SAR-CoV-2 infection compared to women in reproductive age. The main associated factors to severe forms were diabetes and tobacco use.

Genetic Screening of the Usher Syndrome in Cuba.

BACKGROUND: Usher syndrome (USH) is a recessive inherited disease characterized by sensorineural hearing loss, retinitis pigmentosa, and sometimes, vestibular dysfunction. Although the molecular epidemiology of Usher syndrome has been well studied in Europe and United States, there is a lack of studies in other regions like Africa or Central and South America. METHODS: We designed a NGS panel that included the 10 USH causative genes (MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN, and CLRN1), four USH associated genes (HARS, PDZD7, CEP250, and C2orf71), and the region comprising the deep-intronic c.7595-2144A>G mutation in USH2A. RESULTS: NGS sequencing was performed in 11 USH patients from Cuba. All the cases were solved. We found the responsible mutations in the USH2A, ADGRV1, CDH23, PCDH15, and CLRN1 genes. Four mutations have not been previously reported. Two mutations are recurrent in this study: c.619C>T (p.Arg207∗) in CLRN1, previously reported in two unrelated Spanish families of Basque origin, and c.4488G>C (p.Gln1496His) in CDH23, first described in a large Cuban family. Additionally, c.4488G>C has been reported two more times in the literature in two unrelated families of Spanish origin. CONCLUSION: Although the sample size is very small, it is tempting to speculate that the gene frequencies in Cuba are distinct from other populations mainly due to an "island effect" and genetic drift. The two recurrent mutations appear to be of Spanish origin. Further studies with a larger cohort are needed to elucidate the real genetic landscape of Usher syndrome in the Cuban population.

Catalase but not vitamin D receptor gene polymorphisms are associated with nonsegmental vitiligo in Northwestern Mexicans.

BACKGROUND: Vitiligo is an acquired pigmentation disorder characterized by melanocyte loss via autoimmune mechanisms triggered by oxidative stress. Gene polymorphisms in antioxidant enzymes and immunomodulators such as catalase (CAT) and vitamin D receptor (VDR), respectively, have been linked to vitiligo in European and Asian populations. Our aim was to evaluate the role of CAT and VDR gene polymorphisms as well as CAT and vitamin D in nonsegmental vitiligo in Northwestern Mexicans. METHODS: A total of 357 subjects, 173 nonsegmental vitiligo patients and 184 age-gender matched healthy controls, were genotyped by PCR-restriction fragment length polymorphism. CAT activity was determined in 39 patients and in 39 controls and vitamin D (VitD) levels in 35 individuals per group. RESULTS: CAT 419 C/T gene polymorphism was not informative, -89 A/T was associated with risk (P = 0.02), and 389 C/T conferred protection against vitiligo along with AT haplotype (P < 0.01 in both cases). VDR BsmI, ApaI, and TaqI gene polymorphisms were not associated with vitiligo, but BsmI was more prevalent in patients with Koebner phenomenon (P = 0.02). Serum CAT activity and VitD levels were lower in patients than in controls, but they showed no association with any vitiligo clinical characteristics neither with their gene polymorphisms. CONCLUSIONS: Our results suggest a role for CAT gene polymorphisms in vitiligo susceptibility in the Mexican population and a lack of association with VDR gene polymorphisms.

Is alkaline phosphatase biomimeticaly immobilized on titanium able to propagate the biomineralization process?

Tissue-nonspecific alkaline phosphatase (TNAP) is a key enzyme in the biomineralization process as it produces phosphate from a number of phospho-substrates stimulating mineralization while it also inactivates inorganic pyrophosphate, a potent mineralization inhibitor. We have previously reported on the reconstitution of TNAP on Langmuir monolayers as well as proteoliposomes. In the present study, thin films composed of dimyristoylphosphatidic acid (DMPA) were deposited on titanium supports by the Langmuir-Blodgett (LB) technique, and we determined preservation of TNAP's phosphohydrolytic activity after incorporation into the LB films. Increased mineralization was observed after exposing the supports containing the DMPA:TNAP LB films to solutions of phospho-substrates, thus evidencing the role of TNAP on the growth of calcium phosphates after immobilization. These coatings deposited on metallic supports can be potentially applied as osteoconductive materials, aiming at the optimization of bone-substitutes integration in vivo.

[Fatal invasive pulmonary aspergillosis in a patient with multiple non-classic risk factors]. / Aspergilosis pulmonar invasiva fatal en un paciente con factores de riesgo no clásicos.

BACKGROUND: Pulmonary aspergillosis is a severe invasive infection that mainly affects immunocompromised patients, causing a great mortality. CLINICAL CASE: We present a male patient with chronic ethilism, diabetes mellitus, and work exposure of inhalated harmful chemicals, who had a fatal outcome, that even when not presenting typical risk factors, developed a clinical presentation compatible, and mycological evaluation that support the diagnosis of a probably invasive pulmonary aspergillosis. CONCLUSION: The effect of the combination of the described non-typical situations as predisposing factors for pulmonary aspergillosis requires further research, given that they are non-typical factors.

INTRODUCCIÓN: la aspergilosis pulmonar es una infección invasiva severa que afecta principalmente a pacientes inmunocomprometidos y representa una causa importante de mortalidad. CASO CLÍNICO: presentamos un paciente con antecedentes de etilismo crónico, diabetes mellitus y exposición laboral recurrente a sustancias químicas nocivas inhaladas, quien tuvo un desenlace fatal, y que, incluso al no presentar factores de riesgo típicos, desarrolló una presentación clínica compatible y tuvo estudios micológicos que apoyan el diagnóstico de una probable aspergilosis invasiva. CONCLUSIÓN: el efecto de la combinación de tales situaciones no típicas como factores predisponentes de aspergilosis pulmonar amerita mayor investigación, dado que se trata de factores de riesgo no típicos.