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Aim: The objective of this study was to analyze the antitumor effect of BisBAL NP in a mouse melanoma model. Material and Methods: The antitumor activity of BisBAL NP on murine B16-F10 melanoma cells was determined both in vitro (PrestoBlue cell viability assay and Live/Dead fluorescence) and in vivo, in a mouse model, with the following 15-day treatments: BisBAL NP, negative control (PBS), and cell-death control (docetaxel; DTX). Mouse survival and weight, as well as the tumor volume, were recorded daily during the in vivo study. Results: BisBAL NP were homogeneous in size (mean diameter, 14.7 nm) and bismuth content. In vitro, 0.1 mg/mL BisBAL NP inhibited B16-F10 cell growth stronger (88%) than 0.1 mg/mL DTX (82%) (*p Conclusion: BisBAL NP decreased the tumor growing in a mouse melanoma model without secondary effects, constituting an innovative low-cost alternative to treat melanoma.

Background . Voluntary post-mortem donation to science (PDS) is the most appropriate source for body dissection to medical education and training, and highly useful for biomedical research. In Mexico, unclaimed bodies are no longer a legal source, but PDS is legally possible, though scarcely facilitated, and mostly ignored by the general population. Therefore, we aimed to evaluate the attitude and willingness for PDS and to identify a sociodemographic profile of people with willingness towards PDS. Methods . A validated on-line survey was distributed by the convenience method via the social networks of a Catholicism-inspired, private university in northern Mexico. Frequency analyses of all variables and coded free comments were complemented with association studies. Results . Although the responder cohort (n = 143) was too small and biased to be representative for the university community (n = 13,500), willingness to post-mortem organ donation was 90.7% and to PDS 70.7%. In this cohort, PDS willingness had the strongest association with mature age (> 40 years old; P, 0.0008). Among young adults, willingness to PDS was the lowest among volunteers from technical and business schools and the highest among those from the social sciences (P, 0.009). Respondents from the social sciences were also the most consistent between attitude and behavior with respect to organ donation. A free comment option revealed respondents were interested in the unusual taboo topic. Conclusions . A small, but sufficiently large proportion expressed willingness towards DPS. Therefore, the authors invite Mexican medical schools and biomedical research institutes to organize PDS programs in favor of medical teaching and biomedical research.

Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT- rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out. Fil: León Cachón, Rafael B. R.. Universidad de Monterrey.; México Fil: Bamford, Aileen Diane. Universidad de Monterrey.; México Fil: Meester, Irene. Universidad de Monterrey.; México Fil: Barrera Saldaña, Hugo Alberto. Vitagenesis S.A.; México. Innbiogem S.C.; México Fil: Gómez Silva, Magdalena. Universidad Autonoma de Nuevo Leon.; México Fil: Garcia Bustos, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina

The fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbances, fatigue, and cognitive alterations. A limited efficacy of targeted treatment and a high FMS prevalence (2-5% of the adult population) sums up to high morbidity. Although, altered nociception has been explained with the central sensitization hypothesis, which may occur after neuropathy, its molecular mechanism is not understood. The marked female predominance among FMS patients is often attributed to a psychosocial predisposition of the female gender, but here we will focus on sex differences in neurobiological processes, specifically those of the immune system, as various immunological biomarkers are altered in FMS. The activation of innate immune sensors is compatible with a neuropathy or virus-induced autoimmune diseases. Considering sex differences in the immune system and the clustering of FMS with autoimmune diseases, we hypothesize that the female predominance in FMS is due to a neuropathy-induced autoimmune pathophysiology. We invite the scientific community to verify the autoimmune hypothesis for FMS.

The objective of this study was to analyze the antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on human cervical, prostate, and colon cancer cell lines. The effect of lipophilic bismuth nanoparticles on the viability of cancer cell lines (HeLa, DU145, and HCT-116) and non-cancer lung fibroblasts (HLF; LL 47[MaDo]) was determined with the MTT cell viability assay and compared with known antineoplastic drugs. The biocompatibility at an organismal level was verified in a murine model by histological examination. A lipophilic bismuth nanoparticle hydrogel at 50 µM time-dependently inhibited the growth of the three cancer cell lines, in a time-dependent way. A 1-hour exposure to 250 µM lipophilic bismuth nanoparticle hydrogel, inhibited the growth of the three cancer cell lines. The in-vitro efficacy of lipophilic bismuth nanoparticle was similar to the one of docetaxel and cisplatin, but without inhibiting the growth of non-cancer control cells. Histology confirmed the biocompatibility of lipophilic bismuth nanoparticles as there were no signs of cytotoxicity or tissue damage in any of the evaluated organs (kidney, liver, brain, cerebellum, heart, and jejunum). In conclusion, a lipophilic bismuth nanoparticle hydrogel is an innovative, low-cost alternative for the topical treatment of cervicouterine, prostate, and colon human cancers.

Purpose The purpose of this study was to describe diabetes self-management behaviors, diabetes health care access, and health perception for Mexican adults and Hispanics residing in the Mexico-US border region. Methods This study used data from the Behavior Risk Factor Surveillance System (BRFSS) survey diabetes items (n = 26) to assess characteristics of Hispanics in 4 Arizona border counties (n = 216) and cross-sectional data from a modified BRFSS in a convenience sample of adults residing in Monterrey, Mexico (n = 351). Data were analyzed for descriptive statistics with SPSS. Results The Mexico cohort was younger than the Arizona cohort (59.36 [11.5] vs 65.54 [11.1], respectively) and the mean length of time with type 2 diabetes was similar. Less than 10% (9.7%) of the Arizona cohort reported never monitoring blood glucose compared to 22.5% of the Mexico cohort. The mean (SD) number of times in the past 12 months the Mexico cohort saw their health care provider was 9.09 (6.8) vs 4.49 (8.3) for the Arizona cohort. Despite provider access, there were differences in self-management behaviors between the cohorts. Conclusions Due to environmental and policy factors in the Mexico-US border region, there continues to be a gap in evidence-based practice and uptake of self-management behaviors for adults with diabetes. Resources such as the BRFSS and shared practice guidelines would bridge this gap.

A ventricular aneurysm entails well-known risks for the patient such as heart failure, potentially lethal arrhythmias, and systemic embolic phenomena. The submitral or posterolateral ventricular aneurysm is a very rare variety, usually of congenital etiology, which may also have other causes, including ischemic heart disease. The present case is about a 76-year-old male with the antecedent of an acute myocardial infarction 3 years ago. He presented with intermittent, brief, and self-limiting episodes of severe dyspnea, intense desperation, and accelerated palpitations, with a nonspecific electrocardiogram. An echocardiography revealed a large submitral aneurysm, with a good clinical response to the specific treatment of heart failure, antiarrhythmics, and oral anticoagulation therapy. We analyze the implications of an aneurysm in the context of an ischemic etiology, with special attention to the limitations of the electrocardiogram in the diagnosis of occlusions of the circumflex artery that irrigates the posterolateral region of the heart. We suspect that a greater number of patients with a culprit circumflex artery could receive appropriate coronary interventionism or thrombolysis if decision-making in the emergency room would not depend mainly on the electrocardiogram. Better stratification tools are needed to prevent late complications of infarction, such as those observed in this patient.

Objective As sex bias in immune function has been contributed partly to a preponderance of immune system-related genes (ISRG) on the X-chromosome, we performed a comparative study to verify this viewpoint. Methods The comparative study consisted of three complementary strategies: Results The X chromosome had less ISRG than the median of the autosomal chromosomes. Among X-linked genes, ISRG ranked 4th after genes dedicated to the reproductive and nervous systems or to development, proliferation and apoptosis (not ranking genes dedicated to basal metabolism nor genes of unknown function). On the Y chromosome, ISRG ranked 2nd, and at the pseudoautosomal region 1st. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention with respect to a possible role in sex biased expression or its neutralisation. Conclusions The X chromosome is not enriched for ISRG. Thus, gene-related causes for sex bias in immune responses cannot be due to the X-linked ISRG number, but may be due to 1) particular sex chromosome-linked genes, 2) sex-biased regulation of the expression of ISRG in leukocytes and/or lymphoid organs. (Funding: UDEM, UIN19592)

The objective of this study was to compare the antitumor activity of lipophilic bismuth nanoparticles (BisBAL NPs) and chlorhexidine (CHX) on human squamous cell carcinoma. BisBAL NPs were synthesized by colloidal method and characterized by energy dispersive X-ray spectroscopy in conjunction with scanning electron microscopy (EDS-SEM). The effect of BisBAL NPs and CHX on oral cancer cell line (CAL-27) and nontumor control cell human gingival fibroblasts (HGFs) was determined by MTT cell viability assay. The obtained results showed selective inhibition of CAL-27 cell growth by BisBAL nanoclusters. A 24 h exposition to 25 μM BisBAL NP decreased 91% of CAL-27 cell growth, while nontumor HGFs cells were unaffected by BisBAL NPs showing 90% of cell viability. In contrast, CHX kills both CAL-27 and HGFs with the same efficacy. 25 μM of CHX decreased 97% and 80% of tumor and nontumoral cell growth. BisBAL NP and CHX alter cell permeability suggesting that action mechanism may include loss of cell membrane integrity. Also, CHX and not BisBAL NP presented genotoxicity on genomic DNA of tumor cells. As conclusion, BisBAL NPs have a selective antitumor activity on human squamous cell carcinoma, unlike CHX which was cytotoxic for both tumoral and nontumoral control cells.

Amebiasis remains a major health problem in Mexico. Therefore, the search for better culture media and low-cost diagnostic and therapeutic tools is fundamental. We present a new culture medium forEntamoeba histolyticawhich allows the microbe to preserve its virulence factors and ability to induce hepatic abscesses in animal models. The novel CLUPS medium is an improved version of the PEHPS medium, previously designed in our laboratory. The main difference is the substitution of raw beef liver in PEHPS by raw beef lung in the CLUPS medium. To compare the performance of three-culture media (traditional TYI-S-33, PEHPS, and CLUPS),E. histolyticatrophozoites were cultured in quintuplicate, followed by the evaluation of phospholipase activity and the induction of liver abscesses in golden hamsters.E. histolyticatrophozoites grew significantly better in CLUPS medium than in TYI-S-33. Likewise, CLUPS-cultured trophozoites produced significantly more phospholipases than TYI-S-33-cultured trophozoites. Finally, trophozoites grown in any of the three tested media had similar potential to induce liver abscesses.

Recessive dystrophic epidermolysis bullosa (R-DEB) is caused by mutations in the COL7A1 gene. The most common mutation reported in Mexican families is the c.2470insG mutation, normally detected by DNA sequencing. We report a faster and more economical high-throughput genotyping method to detect the c.2470insG mutation using specific TaqMan probes in a real-time polymerase chain reaction (RT-PCR) that facilitates genotype analysis with allelic discrimination plots. Our new method correctly genotyped 45 samples that had previously been sequenced as 41 wild-type homozygous (−/−), 1 heterozygous (−/G) and three mutant homozygous (G/G) (100% specificity). This new method allows high-throughput screening and furthermore is economical ($3 US/sample), fast (2 h), and sensitive as it requires only 20 ng input DNA. We used the new test to genotype 89 individuals from 32 unrelated Mexican families with R-DEB. The observed genotypic frequencies were 93.3% for the homozygous wild-type and 6.7% for the heterozygous genotype. The homozygous mutant genotype was not found. In conclusion, the allelic discrimination assay by RT-PCR is a sensitive, specific and effective high-throughput test for detecting the c.2470insG mutation.

[No abstract available]

OBJECTIVE. The purpose of this study was to assess esophageal damage in patients with recessive dystrophic epidermolysis bullosa (RDEB) with or without dysphagia. SUBJECTS AND METHODS. Fourteen patients with either severe generalized or another generalized form of RDEB recruited through a research and support foundation were evaluated for obstructive esophageal lesions by means of barium esophagography. RESULTS. All patients, even those without dysphagia, had at least one stenosis; five patients had two stenoses. Stenotic lesions occurred most often (74%) in the upper third of the esophagus. CONCLUSION. Esophageal stenosis is a common complication in patients with RDEB, even when they do not have dysphagia. We recommend regular esophagographic examinations of all patients with RDEB.

Alzheimer’s disease (AD) is characterized by a progressive decay of cognitive abilities, most remarkably (spatial) memory and learning. AD is diagnosed by clinical mental tests, often combined with the detection of neurobiological markers, mainly brain imaging studies and a decreased amyloid beta (Aβ) level and/or increased total and hyper-phosphorylated Tau protein (tau-P) in cerebral spinal fluid (Hampel et al., 2008; Alzheimer’s Association, 2014). The diagnosis is confirmed post-mortem by histopathological detection of senile plaques, composed of Aβ accumulations, and tau-P-containing neurofibrillary tangles (Jellinger and Bancher, 1998). However, non-demented, aged patients may have a histopathology that is indistinguishable from AD (Price and Morris, 1999; Nelson et al., 2012). Furthermore, the brains of AD may have additional changes, such as (micro)vascular changes (Scheibel et al., 1989; de la Torre, 2002; Bell and Zlokovic, 2009; Hommet et al., 2011), white matter hyperintensities (Kandiah et al., 2015), and vacuolar cells, which are not considered as pathognomonic features under current standards (Nelson et al., 2012).

Foamy cells have been described in various infectious diseases, for example in actinomycetoma induced by Nocardia brasiliensis. These cells are generally considered to be macrophages, although they present dendritic cell (DC)-specific surface markers. In this study, we determined and confirmed the lineage of possible precursors of foamy cells in vitro and in vivo using an experimental actinomycetoma model in BALB/c mice. Bone marrow-derived macrophages (BMDM) or DC (BMDC) were infected in vitro with N. brasiliensis or labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). Both, macrophages and DC, differentiated into foamy cells after in vitro infection. CFSE-labeled BMDM or BMDC were tested for phagocytosis and CD11c/CD11b receptors markers expression before being transferred into the actinomycetoma lesion site of infected mice. In vivo studies showed that BMDM and BMDC were traced at the site where foamy cells are present in the experimental actinomycetoma. Interestingly, many of the transferred BMDM and BMDC were stained with the lipid-droplet fluorophore Nile Red. In conclusion, macrophages and DC cells can be differentiated into foamy cells in vitro and in vivo during N. brasiliensis infection.

Nocardia brasiliensis (Nb) is a facultative intracellular pathogen that may cause actinomycetoma when immune response is unable to control the pathogenic invasion. We used comparative real-time PCR to evaluate the expression level of molecules indicative of either classical or alternative activation of macrophages, as well as of cytokines involved in macrophage polarization, during the experimental infection in BALB/c mice. We found induction or increased expression of the pro-inflammatory markers csf2/GM-CSF, interferon-gamma, and nos2/iNOS. The expression of Ym1 and IL-13, which are usually related with alternative activation of macrophage, was also increased. However, retnla/FIZZ1 expression decreased sharply during the infection. We concluded that Nb infection induces both a pro-inflammatory and anti-inflammatory environment, in which there is a strong inverse correlation between IL-13 and retnla expression.

In the pond snail Lymnaea stagnalis, the growth regulating system consists of (1) about 200 neuroendocrine light green cells, located in four clusters in the cerebral ganglia, and (2) the paired canopy cells, located in the lateral lobes. These cells express genes encoding the molluscan insulin-related peptides (MIPs). Six MIP genes have previously been identified. Four of these (I, II, III and V) are expressed in the light green cells and the canopy cells. The MIP-VI gene is a pseudogene. In the present in situ hybridization study, using oligonucleotide probes specific to the transcripts of MIP-I, -II, -III, -IV and -V, no signal was obtained with the MIP-IV probe, indicating that gene IV is also a pseudogene. With the other four probes, two types of light green cells were distinguished. Type-A cells express all four MIP genes, whereas type-B cells do not (or only faintly) express the MIP-I gene. Gene III is relatively strongly expressed in type-B cells. Genes II and V are moderately expressed in both cell types. Type-A cells are mainly located in the periphery of the clusters, whereas type-B cells are present in the center. The canopy cell resembles type-A light green cells. The expression levels of the MIP-II and MIP-V genes are low in the canopy cell. The expression pattern of the MIP genes correlates with the staining pattern of the anti-MIP-C antibody, which has been raised to a synthetic C-fragment shared by MIP-I, -II and -V. Type-A cells stain more intensely with the antibody than type-B cells.

A cDNA clone encoding molluscan insulin-related peptide V (MIP V) was isolated from a cDNA library of the central nervous system (CNS) of the freshwater snail, Lymnaea stagnalis, using a heterologous screening with a previously identified MIP II cDNA. The MIP V cDNA encodes a preprohormone resembling the organization of preproinsulin, with a putative signal sequence, and an A and B chain, however, in this case connected by two distinct C peptide, C alpha and C beta, instead of one single C peptide. This phenomenon, which is shared by the MIP II precursor, represents a new development in the prohormone organization of peptides belonging to the insulin superfamily. The A and B chains of MIPs V, I and II, differ remarkably in primary structure; in contrast, the C alpha peptide domains are almost identical. MIP V has only limited sequence similarity with insulins and related peptides. Both MIP V and I exhibit structural features, which make them a unique class of the insulin superfamily. The MIP I, II and V genes are expressed in a single type of neuron: the growth controlling neuroendocrine light green cells of the Lymnaea CNS.

Actinomycetoma, caused by the intracellular bacterium Nocardia brasiliensis, is characterized by an infiltration of several inflammatory cell populations. To explore aspects of the immune response in the pathogenesis of these bacteria we injected 10(6) CFU in footpads of BALB/c mice. After 1, 2, 3, 4, 7, 30 and 90 days immunohistochemistry was performed to compare presence and distribution of the inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, IFN-gamma, IL-4, IL-10, and TGF-beta. Analysis of serial paraffin tissue sections showed strong participation and differences in distribution of cytokine-producing cells during the course of infection. Several TNF-alpha immunoreactive lymphocytes of the dermis were present during the course of the infection, but absent in the site of inflammation. During the first 4 days, IL-1 beta immunoreactivity was observed in dendritic epidermal cells and in cells surrounding the neutrophils around the grain. In later stages of infection, immunoreactive cells to this cytokine were mainly in the periphery of the microabscesses. Strong immunoreactivity was observed with IL-6 during the course of infection. Some cells in the epidermis and dermis, as well as muscle cells and several cells at the periphery of the microabscesses, showed strong IL-6 immunoreactivity. Cells immunoreactive to IL-4, IL-10, IFN-gamma and TGF-beta were present at the site of infection and, in later stages, in cells at the periphery of the microabscesses. In conclusion a mix of proinflammatory and antiinflammatory cytokines are produced at the same time by host cells. According to their distribution, inflammatory cytokines seems to have different functions during the course of infection with the intracellular bacterium N. brasiliensis.

Foamy cells (FC) have been described in various infectious diseases, and can be usurped by intracellular pathogens for survival. In a mouse model of experimental actinomycetoma induced by Nocardia brasiliensis, FC have been observed at day 3 after inoculation, remaining constant during acute inflammation, and expanding in surface area during chronic disease. These FC seem to be monocytes/macrophages and/or dendritic cells (DC) that accumulate lipid droplets upon infection. Our aim was to elucidate the levels of cytokines known to be involved in the differentiation of macrophages or DC (IL-4, IL-13, M-CSF, and GM-CSF). Female BALB/c mice (8-12 wk) were infected with N. brasiliensis in the left hind foot pad and sacrificed at 0, 0.5, 1, 3, 7, 15, 30 and 60 days of infection (n=5). Biopsies of the left foot pads were homogenized in PBS or Trizol to determine the cytokine concentrations at both the protein and the transcript level by means of ELISA and RT-PCR. We found the highest M-CSF and IL-13 levels during chronic inflammation, when the major expansion of CF occurs. M-CSF and IL-13 have been related with the alternative activation of macrophages. In conclusion: high M-CSF and IL-13 levels coincide with the expansion of CF in an experimental model of actinomycetoma.

A cDNA clone encoding molluscan insulin-related peptide (MIP) II was isolated from a cDNA library of the central nervous system (CNS) of the freshwater snail, Lymnaea stagnalis, using a heterologous screening with a previously identified MIP cDNA (renamed MIP-I cDNA). The MIP-II cDNA encodes a preprohormone resembling the organization of preproinsulin, with a putative signal sequence, and A and B chains; however, in this case connected by two distinct C peptides, C alpha and C beta, instead of a single C peptide, a phenomenon which represents a new development in the prohormone organization of peptides belonging to the insulin superfamily. The A and B chains of MIP II and I differ remarkably in primary structure; in contrast, the C alpha peptide domains are fully identical. MIP II has only limited sequence similarity with insulins and related peptides. Both MIP II and I exhibit structural features, which make them a unique class of the insulin superfamily. The MIP I and II genes are expressed in a single type of neuron: the growth-controlling neuroendocrine light green cells of the Lymnaea CNS.

Background The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. Methods A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. Results Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. Conclusion Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2062-2) contains supplementary material, which is available to authorized users.