Aberrant expression of N-glycolyl GM3 ganglioside is associated with the aggressive biological behavior of human sarcomas. Pilco-Janeta D, De la Cruz Puebla M, Soriano J, Osorio M, Caballero I, Pérez AC, et al. BMC Cancer. 2019 Jun 10;19(1):556.
Background The aberrant expression of N-glycolyl GM3 ganglioside (NeuGcGM3) in patients with sarcomas was reevaluated by assessing the relation of this molecule with some clinicopathological features and overall survival (OS) of patients. Methods Fifty formalin-fixed and paraffin-embedded specimens from patients diagnosed with sarcomas were included. For the evaluation of NeuGcGM3, the 14F7 monoclonal antibody followed by a peroxidase avidin-biotin system was used. Clinicopathological features were obtained from patient records. Survival rates were estimated by the Kaplan-Meier method and compared with the log-rank test. For multivariate analyses, the Cox regression model was used to identify independent prognostic factors for OS. Results The majority of samples had high levels of NeuGcGM3 expression (66.0%) that showed statistical correlation with age (p = 0.014), TNM stage (p = 0.022), histological grade (p = 0.013) and proliferation rates (p = 0.012). In addition, a tendency for association with tumor depth (p = 0.070) was evidenced. In univariate survival analysis, TNM stage (p = 0.000), occurrence of metastasis (p = 0.000) and expression of NeuGcGM3 (p = 0.034) were significant prognostic factors for OS, while a tendency for association was evidenced for histological grade (p = 0.091). Among these variables, only the presence of metastasis (p = 0.001) was an independent prognostic factor on multivariate analysis. Conclusions The present research suggests the evaluation of NeuGcGM3 expression as a complementary prognostic factor in sarcoma, although our results need to be validated in a larger series and prospective studies. Moreover, our results could support the use of this molecule as a target for immunotherapy.
Antitumor effects of the GM3(Neu5Gc) ganglioside-specific humanized antibody 14F7hT against Cmah-transfected cancer cells. Dorvignit D, Boligan KF, Relova-Hernández E, Clavell M, López A, Labrada M, et al. Sci Rep. 2019 Jul 9;9(1):9921.
The GM3(Neu5Gc) ganglioside represents a tumor-specific antigen that is considered a promising target for cancer immunotherapy. We previously demonstrated that the humanized antibody 14F7hT, specific for this ganglioside, exhibited significant antitumor effects in preclinical hematological tumor models. As this antibody recognizes human tumor tissues from several origins, we addressed its potential effect on different tumor types. The use of cell lines for testing GM3(Neu5Gc)-targeting strategies, in particular for human malignancies, is complicated by the absence in humans of functional cytidine monophospho-N-acetyl-neuraminic acid hydroxylase (CMAH), the enzyme required for Neu5Gc sialic acid biosynthesis. Quantitative flow cytometry revealed the absence of surface GM3(Neu5Gc) in several human but also mouse cell lines, in the last case due to low expression of the enzyme. Hypoxia-induced expression of this ganglioside on human SKOV3 cells was observed upon culture in Neu5Gc-containing medium without evidence for CMAH-independent biosynthesis. However, only transfection of the mouse Cmah gene into human SKOV3 and mouse 3LL cells induced a stable expression of GM3(Neu5Gc) on the cancer cell surface, resulting in effective models to evaluate the antitumor responses by 14F7hT in vitro and in vivo. This antibody exerted antibody-dependent cell-mediated cytotoxicity (ADCC) and in vivo antitumor effects on these Cmah-transfected non-hematological tumors from both mouse and human origin. These results contribute to validate GM3(Neu5Gc) as a relevant target for cancer immunotherapy and reinforces the value of 14F7hT as a novel anti-cancer drug.
A zinc oxide-modified hydroxyapatite-based cement favored sealing ability in endodontically treated teeth. Toledano M, Muñoz-Soto E, Aguilera FS, Osorio E, González-Rodríguez MP, Pérez-Álvarez MC, et al. J Dent. 2019 Jul 5. pii: S0300-5712(19)30133-2. DOI: 10.1016/j.jdent.2019.06.009. [Epub ahead of print]
Objectives To evaluate the effectiveness of different endodontic canal sealers for dentin permeability reduction and to determine the viscoelastic performance of root dentin after their application. Methods Cervical, medial and apical root dentin surfaces were treated with two experimental hydroxyapatite-based cements, containing sodium hydroxide (calcypatite) or zinc oxide (oxipatite); an epoxy resin- based canal sealer, AH Plus; and gutta-percha. Root dentin was evaluated for fluid filtration. Field emission scanning electron microscopy, energy dispersive analysis, AFM, Young’s modulus and Nano-DMA analysis were also performed, at the inner and outer zones of dentin. Results Dentin treated with oxipatite showed the lowest microleakage among groups with hermetically sealed tubules and zinc-based salt formations. Samples treated with oxipatite showed the highest Ei at the cervical dentin third among groups, at 6 m of storage. Oxipatite promoted the highest complex modulus and tan delta values at the inner zone of both cervical and medial root dentin. Calcypatite favored the lowest tan delta outcomes at the inner zone of apical dentin at 6 m. Conclusions Specimens treated with oxipatite showed the highest sealing ability, based on the highest Young’s modulus and dentin mineralization, achieved by closing dentinal tubules, voids and pores that reinforced the inner zone of root dentin. The homogeneity of viscoelastic properties among the different root dentin thirds favored the energy dissipation without creating zones of stress concentration and micro-cracking which would have challenge micropermeability. Thereby, among the tested materials oxipatite is proposed as canal filling material and sealer in endodontics. Clinical Significance Oxipatite could be considered a good candidate for root canal filling material and sealer due to its improved long-term sealing ability and to the advanced remineralization, and so to the enhanced energy dissipation achieved at the inner zone of the radicular dentin.
Biomodulina T partially restores immunosenescent CD4 and CD8 T cell compartments in the elderly. Saavedra D, Fuertes SA, Suárez GM, González A, Lorenzo-Luaces P, García B, et al. Exp Gerontol. 2019 Sep;124:110633. DOI: 10.1016/j.exger.2019.110633. [Epub ahead of print]
The changes that occur in the immune system with aging are commonly termed immunosenescence. Immunosenescence affects almost all components and functions of the immune response. The most commonly described change is a decrease in numbers and proportions of naïve T cells combined with the increase of terminally differentiated T lymphocytes, mainly affecting CD8+ T cells. The changes in the naïve T cell compartment are principally attributed to thymic involution and lifelong chronic antigen stimulation, among other triggers. Several strategies such as hormonal products, thymic peptides, or cytokines have been proposed for the restoration of the immune system. Here we show the effects of Biomodulina T (BT) on several populations of the immune system when administered to elderly patients diagnosed with recurrent respiratory infections. BT is a polypeptide fraction of bovine thymus, a Cuban product that obtained sanitary registration in 1994 for its immunomodulatory effects. We found that CD4+ naïve T, CD8+ stem cell-like memory (SCM) T, CD4+ recent thymic emigrants (RTE) T and CD4+ CD31+ naïve T cells increased with the administration of BT, whereas CD4+ and CD8+ T cells expressing PD1 decreased after the treatment with BT. Additionally, the proliferative capacity of CD4+ T cells measured by Ki67 expression, and the CD4+ T cell ability to produce IFN-γ were also improved by BT. Moreover, BT did not increase CD4+ Tregs. Altogether, these findings suggest that BT administration is a promising strategy for immune restoration in elderly patients and improvement of immunotherapeutic potential in cancer patients.
Can neuromodulation techniques optimally exploit cerebello-thalamo-cortical circuit properties to enhance motor learning post-stroke? Israely S, Leisman G. Rev Neurosci. 2019 Jun 5. pii: /j/revneuro.ahead-of-print/revneuro-2019-0008/revneuro-2019-0008.xml. DOI: 10.1515/revneuro-2019-0008. [Epub ahead of print]
Individuals post-stroke sustain motor deficits years after the stroke. Despite recent advancements in the applications of non-invasive brain stimulation techniques and Deep Brain Stimulation in humans, there is a lack of evidence supporting their use for rehabilitation after brain lesions. Non-invasive brain stimulation is already in use for treating motor deficits in individuals with Parkinson’s disease and post-stroke. Deep Brain Stimulation has become an established treatment for individuals with movement disorders, such as Parkinson’s disease, essential tremor, epilepsy, cerebral palsy and dystonia. It has also been utilized for the treatment of Tourette’s syndrome, Alzheimer’s disease and neuropsychiatric conditions such as obsessive-compulsive disorder, major depression and anorexia nervosa. There exists growing scientific knowledge from animal studies supporting the use of Deep Brain Stimulation to enhance motor recovery after brain damage. Nevertheless, these results are currently not applicable to humans. This review details the current literature supporting the use of these techniques to enhance motor recovery, both from human and animal studies, aiming to encourage development in this domain.
Causal attribution for mental illness in Cuba: A thematic analysis. Nohr L, Steinhäuser T, Ruiz AL, Ferrer JES, Lersner UV. Transcult Psychiatry. 2019 Jun 10:1363461519853649. DOI: 10.1177/1363461519853649. [Epub ahead of print]
Explanatory models (EMs) for illness are highly relevant for patients, and they are also important for clinical diagnoses and treatment. EMs serve to capture patients’ personal illness narratives and can help reveal how culture influences these narratives. While much research has aimed to understand EMs in the Western hemisphere, less research has been done on other cultures. Therefore, we investigated local causal attributions for mental illness in Cuba because of its particular history and political system. Although Cuban culture shares many values with Latin American cultures because of Spanish colonization, it is unique because of its socialist political and economic context, which might influence causal attributions. Thus, we developed a qualitative interview outline based on the Clinical Ethnographic Interview and administered interviews to 14 psychiatric patients in Havana. We conducted a thematic analysis to identify repeated patterns of meaning. Six patterns of causal attribution for mental illness were identified: (1) Personal shortcomings, (2) Family influences, (3) Excessive demands, (4) Cultural, economic, and political environment in Cuba, (5) Physical causes, and (6) Symptom-related explanations. In our sample, we found general and Cuba-specific patterns of causal attributions, whereby the Cuba-specific themes mainly locate the causes of mental illness outside the individual. These findings might be related to Cubans’ socio-centric personal orientation, the cultural value of familismo and common daily experiences within socialist Cuban society. We discuss how the findings may be related to social stigma and help-seeking behavior.
Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data. Haase R, Schlattmann P, Gueret P, Andreini D, Pontone G, Alkadhi H, et al. BMJ. 2019 Jun 12;365:l1945.
DOI: 10.1136/bmj.l1945.
Objective To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. Design Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. Data sources Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. Eligibility criteria for selecting studies Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. Results Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). Conclusions In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients
Does VEGF-targeted active immunotherapy induce complete abrogation of platelet VEGF levels? Sánchez Ramírez J, Bequet-Romero M, Morera Díaz Y, Hernández-Bernal F, Ayala Ávila M. BMC Res Notes. 2019 Jun 10;12(1):323. DOI: 10.1186/s13104-019-4368-z.
Objectives Vascular endothelial growth factor (VEGF) is involved in physiological angiogenesis, but also is considered one of the key factors that promotes tumor angiogenesis. CIGB-247 is a VEGF-based vaccine that has been evaluated in phase I clinical trial patients with advanced solid tumors. This specific active immunotherapy is able to reduce platelet VEGF levels; however it is unknown whether this effect leads to a decrease in VEGF below the levels that can be observed in healthy individuals. The objective of the present study is to investigate platelet VEGF levels in cancer patients vaccinated with CIGB-247, and then compare these values with those obtained in healthy individuals. To achieve this, platelet VEGF levels of 62 cancer patients and 93 healthy individuals were compared. Cancer patients were those individuals recruited in CENTAURO and CENTAURO-2 clinical trials. Results Before vaccination, platelets of cancer patients carried more VEGF than the levels seen in platelet of healthy individuals. However, after vaccination, cancer patients had platelet VEGF values within the range established by healthy individuals, indicating that the antibody response elicited by CIGB-247 is not able to induce a complete suppression of VEGF. Vaccination with CIGB-247 helps to normalize VEGF levels within platelets.
EECoG-Comp: An Open Source Platform for Concurrent EEG/ECoG Comparisons-Applications to Connectivity Studies. Wang Q, Valdés-Hernández PA, Paz-Linares D, Bosch-Bayard J, Oosugi N, Komatsu M, et al. Brain Topogr. 2019 Jul;32(4):550–68. DOI: 10.1007/s10548-019-00708-w. [Epub ahead of print]
Electrophysiological Source Imaging (ESI) is hampered by lack of “gold standards” for model validation. Concurrent electroencephalography (EEG) and electrocorticography (ECoG) experiments (EECoG) are useful for this purpose, especially primate models due to their flexibility and translational value for human research. Unfortunately, there is only one EECoG experiments in the public domain that we know of: the Multidimensional Recording (MDR) is based on a single monkey ( www.neurotycho.org ). The mining of this type of data is hindered by lack of specialized procedures to deal with: (1) Severe EECoG artifacts due to the experimental produces; (2) Sophisticated forward models that account for surgery induced skull defects and implanted ECoG electrode strips; (3) Reliable statistical procedures to estimate and compare source connectivity (partial correlation). We provide solutions to the processing issues just mentioned with EECoG-Comp: an open source platform ( https://github.com/Vincent-wq/EECoG-Comp ). EECoG lead fields calculated with FEM (Simbio) for MDR data are also provided and were used in other papers of this special issue. As a use case with the MDR, we show: (1) For real MDR data, 4 popular ESI methods (MNE, LCMV, eLORETA and SSBL) showed significant but moderate concordance with a usual standard, the ECoG Laplacian (standard partial [Formula: see text]); (2) In both monkey and human simulations, all ESI methods as well as Laplacian had a significant but poor correspondence with the true source connectivity. These preliminary results may stimulate the development of improved ESI connectivity estimators but require the availability of more EECoG data sets to obtain neurobiologically valid inferences.
Efficacy and tolerability of Roystonea regia lipid extract (D-004) and terazosin in men with symptomatic benign prostatic hyperplasia: a 6-month study. Guzmán R, Fernández JC, Pedroso M, Fernández L, Illnait J, Mendoza S, et al. Ther Adv Urol. 2019 Jun 11;11:1756287219854923. DOI: 10.1177/1756287219854923. eCollection 2019 Jan–Dec.
Background Benign prostatic hyperplasia (BPH), a common urological disease in aging men, frequently produces lower urinary tract symptoms (LUTS). Clinical studies have shown that terazosin relaxes the smooth muscle of the prostate and bladder, facilitates bladder emptying, improves LUTS, increases maximum urinary flow, and reduces the residual volume of urine. D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia), presents a similar efficacy to Saw palmetto. Clinical studies have demonstrated its efficacy and safety in short- and medium-term trials in patients with BPH. The objective of this study was to compare the efficacy and tolerability of D-004 with terazosin for 6 months on LUTS in patients with BPH. Methods The present phase III study had an open, randomized, comparative design, with two parallel groups who received D-004 (320 mg/day) or terazosin (5 mg/day) for 6 months. The study included men at least 50 years of age, with evidence of the LUTS of moderate intensity according to the International Symptoms of the Prostate (IPSS). The effects on the IPSS Scale was the primary efficacy variable. The effects on the size of the prostate and the residual volume were secondary variables. The subjective self-perception of symptom relief at trial completion was a collateral outcome. Analysis was done by intention-to-treat. Results The study included 100 men with a diagnosis of BPH, confirmed by digital rectal examination and ultrasonography, and moderate LUTS (IPSS score >7, <19). Baseline characteristics were similar in both groups. Nine patients did not continue the study: one from group D-004 (due to protocol violation) and eight from the terazosin group (six due to adverse events and two due to protocol violation; p < 0.01). D-004 and terazosin significantly reduced the IPSS scores at the end of the 6 months of therapy by 74.2% and 66.1%, respectively, with respect to baseline values. Comparisons between groups performed showed that, at the end of the treatment, D-004 was more effective (p < 0.05) than terazosin in reducing the IPSS score. Although the average size of the prostate was reduced in both groups, this reduction reached statistical significance only for D-004. On the other hand, postvoid residual volume was significantly and similarly reduced in both groups. Both treatments were safe, while D-004 was better tolerated than terazosin. Conclusions D-004 administered at a dose of 320 mg/day for 6 months showed comparable efficacy with terazosin (5 mg/day) in reducing the LUTS (IPSS score), producing a significant decrease in prostate volume and postvoid residual volume. Both treatments were safe, with better tolerability for D-004 as compared with terazosin.
Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort. Pimentel-Quiroz VR, Ugarte-Gil MF, Harvey GB, Wojdyla D, Pons-Estel GJ, Quintana R, et al. Lupus. 2019 Jul 10:961203319860579. DOI: 10.1177/0961203319860579. [Epub ahead of print]
Aim The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). Methods A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. Results Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. Conclusions Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.
Genetic Diversity of Trichomonas Vaginalis Clinical Isolates According to Restriction Fragment Length Polymorphism Analysis of the 60-kDa Proteinase Gene. Hernández H, Fraga J, Marcet R, Alba A, Figueredo M, Alfonso Y, et al. Acta Parasitol. 2019 Jun;64(2):300–7.
Introduction Trichomonas vaginalis is a highly prevalent parasitic that causes the sexually transmitted disease trichomoniasis with some serious health complications. More understanding about genetic features of the parasite can be helpful in the study of the pathogenesis, epidemiology of the infection and drug susceptibility. For this end, we conducted analysis of a fragment (23 kDa) of the p60 of T. vaginalis gene. Material and methods The restriction fragment length polymorphism (RFLP) methods was used. Results and discussion RFLP analysis showed the difference between T. vaginalis isolates from symptomatic and asymptomatic patients, suggesting a relation between the genetic identity of the isolates and their clinical manifestations.
Left ventricular mechanical dyssynchrony in patients with chest pain and normal epicardial coronary arteries. Peix A, Padrón K, Cabrera LO, Pardo L, Sánchez J. J Nucl Cardiol. 2019 Jul 2. DOI: 10.1007/s12350-019-01804-x. [Epub ahead of print]
Background To detect ischemia in patients with angina and normal coronaries frequently represents a complex diagnosis. Methods To investigate whether left ventricular mechanical dyssynchrony by phase analysis contributes in the evaluation of patients with chest pain and normal coronaries, gated-SPECT myocardial perfusion imaging (MPI) at rest and 30 minutes post-stress was performed in 218 patients with normal epicardial coronaries, who were divided into two groups: those with summed difference score (SDS) ≥ 4 (54 patients, Group 1), and those with SDS < 4 (164 patients, Group 2). Intraventricular synchronism-phase standard deviation (PSD) and histogram bandwidth (HBW)-was evaluated by phase analysis. Results Women were significantly more frequent in Group 2 (those without ischemia in SPECT MPI): 113 (69%) vs 25 (46%), P = .00001. In males, left ventricular ejection fraction (LVEF) and ventricular volumes were not significantly different between patients with or without ischemia. However, ischemic females showed significantly higher ventricular volumes, minor post-stress LVEF and more negative delta LVEF (- 3.9 vs 0.34, P = .0008) than the non-ischemic ones. There was a significant post-stress increase of PSD and HBW among males, although not among females. According to SSS (≥ 4, with ischemia/necrosis; < 4, without ischemia/necrosis), post-stress PSD and HBW significantly increase both in male and female, and PSD and HBW were significantly higher in females with SSS ≥ 4 compared to those with SSS < 4 (PSD rest: 19.04° vs 11.72°, P < .0001; HBW rest: 58.85° vs 38.21°, P < .0001). PSD and HBW were also higher among males with SSS ≥ 4 compared to those with SSS < 4, although not significantly. Conclusion Higher ventricular volumes in females and dyssynchrony are associated with inducible ischemia in MPI in patients with chest pain and normal coronaries. Stress-induced ischemia increases degree of dyssynchrony.
Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations. Lona-Durazo F, Hernández-Pacheco N, Fan S, Zhang T, Choi J, Kovacs MA, et al. BMC Genet. 2019 Jul 17;20(1):59.
Background Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. Results We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. Conclusions Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.
Numerical processing profiles in children with varying degrees of arithmetical achievement. Estévez-Pérez N, Castro-Cañizares D, Martínez-Montes E, Reigosa-Crespo V. Acta Psychol (Amst). 2019 Jun 17;198:102849. DOI: 10.1016/j.actpsy.2019.05.001. [Epub ahead of print]
Recent studies show basic cognitive abilities such as the rapid and precise apprehension of small numerosities in object sets (“subitizing”), verbal counting and numerical magnitude comparison significantly influence the acquisition of arithmetic and continues to modulate more advanced stages of mathematical cognition. Additionally, children with low arithmetic achievement (LAA) and Developmental Dyscalculia (DD) exhibit significant deficits in these cognitive processes. Nevertheless, the different cognitive profiles of children with varying degrees of numerical and arithmetic processing deficits have not been sufficiently characterized, despite its potential relevance to the stimulation of numerical cognition and the design of appropriate intervention strategies. Here, the cognitive profiles of groups of typically developing children, children with low arithmetical achievement and DD, exhibiting typical and atypical subitizing ability were contrasted. The results suggest that relatively independent neurocognitive mechanisms may produce distinct profiles at the behavioral level and suggest children with low arithmetic performance exhibiting atypical subitizing abilities are not only significantly slower, but rely on compensatory mechanisms and strategies compared to typical subitizers. The role of subitizing as a correlate of arithmetic fluency is revised in the light of the present findings.
Peri-implantitis at implants with different diameters: a pilot study in dogs. Morelli F, Apaza Alccayhuaman KA, Viganò P, Bengazi F, Urbizo J, Cesaretti G, et al. Int J Implant Dent. 2019 Jul 1;5(1):21. DOI: 10.1186/s40729-019-0177-3.
Aim To evaluate the progression of an induced peri-implantitis at implants with different diameters and the outcome of a corrective surgical debridement. Methods Three months after the extraction of the mandibular premolars and first molars in six dogs, non-submerged narrow implants (3.3 mm in diameter) or standard implants (3.8 mm and 4.1 mm) were installed in the molar regions, bilaterally. After 3 months, peri-implantitis lesions were induced with ligatures and plaque accumulation for 3 months. Plaque accumulation was allowed for a further month after ligatures removal. A surgical mechanical decontamination of the surfaces was subsequently performed using gauzes soaked in saline and irrigation. Five months after, biopsies were retrieved and histological slides prepared. X-rays were taken at treatment and 5 months after. Results Fourth months after peri-implantitis induction, 2.2 ± 1.0 mm at the standard implants and 3.2 ± 0.4 mm at the narrow implants were observed. Five months after treatment, a mean gain of marginal bone of 0.5 ± 0.6 mm was obtained at the standard implants and of 0.9 ± 0.4 at the narrow implants (p = 0.249). The vertical and horizontal defects were found partially closed. At the histological analysis, the coronal level of osseointegration after 5 months of healing was at 2.1 ± 0.8 mm at the standard implants, and 2.8 ± 0.3 mm at narrow implants (p = 0.116). Conclusions In conclusion, the narrow implants showed a tendency of a faster progression of the induced peri-implantitis compared to standard implants. The implant diameter did not influence the outcome of a surgical treatment of an induced peri-implantitis.
Pharmacophore model of immunocheckpoint protein PD-L1 by cosolvent molecular dynamics simulations. Mejías C, Guirola O. J Mol Graph Model. 2019 Sep;91:105–11. DOI: 10.1016/j.jmgm.2019.06.001.
Due to the clinical success of cancer immunotherapy, the design of PD-1/PD-L1 inhibitors has become an area of active research. To date, only five monoclonal antibodies are approved by FDA. Despite the great effort for the development of small molecules and peptides as inhibitors, only one of those has reached clinical trials. Pharmacophore models are a proven useful tool for drug design. The effectiveness of receptor-based pharmacophore modeling is limited due to the neglect of protein flexibility and desolvation effects. In the present application, we performed co-solvent molecular dynamics simulations of PD-L1 protein in order to obtain a pharmacophore model of PD-L1 immunecheckpoint protein. The analysis of probe molecules affinities by PD-L1 resulted in the identification of C’CFG beta strands as the zone with the highest convergence of hotspots, which corresponds to PD-1/PD-L1 interaction surface. The interactions maintained with PD-L1 residues varied from hydrophobic interactions to hydrogen bonds and salt bridges with critical residues for PD-1/PD-L1 binding (M115, A121, Y123, I54, Y56, E58, R125). The superposition of known inhibitors of PD-L1 as Peptide-57, BMS-1166 and high affinity PD-1(HAPD-1) allowed us to validate the pharmacophore model due to the good correlation with its features. The pharmacophore described herein can lead to the optimization and design of more selective and potent anti-cancer drugs.
Quantitative Studies of Diabetic Foot Ulcer Evolution Under Treatment by Digital Stereotactic Photography. Cabal Mirabal CA, Berlanga Acosta J, Fernández Montequín J, Oramas Díaz L, González Dalmau E, Herrera Martínez L, et al. J Diabetes Sci Technol. 2019 Jun 13:1932296819853843. DOI: 10.1177/1932296819853843. [Epub ahead of print]
Background Imaging the lower extremity reproducibly and accurately remains an elusive goal. This is particularly true in the high risk diabetic foot, where tissue loss, edema, and color changes are often concomitant. The purpose of this study was to evaluate the reproducibility of a novel and inexpensive stereotaxic frame in assessment of wound healing. Methods The main idea is to keep constant and reproducible the relative position of extremities related to the sensor used for the examination during a serial studies by stereotaxic digital photographic sequence. Ten healthy volunteers were evaluated at 10 different time moments to estimate the foot position variations in the stereotaxic frame. The evolution of 40 of DFU patients under treatment was evaluated before and during the epidemical grow factor intralesional treatment. Results The wound closing and granulation speeds, the relative contribution of the contraction and tissue restauration mechanism were evaluated by stereotaxic digital photography. Conclusions The results of this study suggest that the stereotaxic frame is a robust platform for serial study of the evolution of wound healing which allow to obtain consistent information from a variety of visible and hyperspectral measurement technologies. New stereotaxic digital photography evidences related to the diabetic foot ulcer healing process under treatment has been presented.
Spontaneous Subdural Hematoma and Behavioral Changes Due to a Dural Arteriovenous Fistula. A Case Report and Literature Review. Hernández-Díaz ZM, Llíbre-Guerra JC, Arteche-Prior M, de la Paz-Bermúdez T, Águila-Ruiz AF, et al. Behav Sci (Basel). 2019 Jun 14;9(6). pii: E63. DOI: 10.3390/bs9060063.
Dural arteriovenous fistulas (DAVFs) represent 10-15% of intracranial arteriovenous malformations. Of these, only 12-29% cause intracranial hemorrhage. The presentation of DAVF as a subdural hematoma (SDH) and intraparenchymal hemorrhage (IPH) is infrequent; additionally, behavioral changes are not common among these patients. We report, for the first time in our country, the case of a 23-year-old man with no history of head injury, in which a brain computed tomography (CT) scan revealed SDH and IPH with behavioral disturbances. The angiotomography showed ecstatic venous vessels, indicating the presence of a DAVF, which was later confirmed by cerebral angiography. Endovascular therapy, which followed the clinical diagnosis, resulted in satisfactory evolution two years after treatment. A review of the literature concerning cases with DAVF and behavioral disturbances is presented. DAVF may lead to cognitive impairment, behavioral changes, and dementia as a result of diffuse white matter and thalamus modifications related to venous ischemia, and it should be considered as a reversible cause of vascular dementia.
Synthetic libraries of shark vNAR domains with different cysteine numbers within the CDR3. Cabanillas-Bernal O, Dueñas S, Ayala-Ávila M, Rucavado A, Escalante T, Licea-Navarro AF. PLoS One. 2019 Jun 17;14(6):e0213394. DOI: 10.1371/journal.pone.0213394. eCollection 2019.
The variable domain of New Antigen Receptors (vNAR) from sharks, present special characteristics in comparison to the conventional antibody molecules such as: small size (12-15 kDa), thermal and chemical stability and great tissue penetration, that makes them a good alternative source as therapeutic or diagnostic agents. Therefore, it is essential to improve techniques used for the development and selection of vNAR antibodies that recognize distinct antigens. The development of synthetic antibody libraries offers a fast option for the generation of antibodies with the desired characteristics. In this work three synthetic antibody libraries were constructed; without cysteines (Cys), with one Cys and with two Cys residues within its CDR3, with the objective of determining whether the presence or absence of Cys in the CDR3 favors the isolation of vNAR clones from a synthetic library. The libraries were validated selecting against six mammalian proteins. At least one vNAR was found for each of the antigens, and a clone coming from the library without Cys in the CDR3 was selected with all the antigens. In vitro angiogenesis assay with the isolated anti-VEGF antibodies, suggest that these vNARs are capable of inhibiting in vitro angiogenesis. In silico analysis of anti-VEGF antibodies showed that vNARs from synthetic libraries could rival antibodies with affinity maturation by in silico modeling.
TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract. Nunes FPB, Alberca-Custódio RW, Gomes E, Fonseca DM, Yokoyama NH, Labrada A, et al. J Leukoc Biol. 2019 Jul 22. DOI: 10.1002/JLB.MA1218-475RR. [Epub ahead of print]
Blomia tropicalis mite is highly prevalent in tropical and subtropical regions and it is associated with allergic diseases such as rhinitis and asthma. By using an OVA-model of allergic lung disease, we have previously shown that sensitization in the presence of toll like receptors (TLRs) agonists attenuates subsequent OVA-induced allergic responses. Here, we evaluated the effect of CpG-ODN, a specific synthetic TLR-9 agonist, on the development of experimental asthma induced by Blomia tropicalis extract, a relevant source of aeroallergens. Among different protocols of Blomia tropicalis extract sensitization, the subcutaneous sensitization in the presence of alum adjuvant induced the highest Th2 responses, including high IgE levels. Adsorption of CpG to Blomia tropicalis extract/Alum attenuated the airway hyperreactivity, the infiltration of inflammatory cells including eosinophils, and the IL-5 content in BAL. In addition, lung peribronchial inflammatory infiltrate, mucus production and IL-5-producing CD3+ CD4+ T cells were significantly reduced in the Blomia tropicalis extract/Alum+CpG group. Importantly, CpG inhibited total IgE production as well as active systemic or cutaneous anaphylaxis reactions. Inhibition of pulmonary Th2 responses was associated with increased IL-10 production but not with IFN-γ production. Notably, in IL-10-deficient mice, sensitization with OVA/Alum+CpG resulted in intense lung neutrophilia and IFN-γ production, indicating that IL-10 is necessary to inhibit subsequent Th1 immunity. Our work highlights the mechanisms of allergy attenuation by CpG and it indicates the potential use of Alum-based formulation with CpG to treat allergic processes.
Targeting Polymeric Nanobiomaterials as a Platform for Cartilage Tissue Engineering. García-Couce J, Almirall A, Fuentes G, Kaijzel E, Chan A, Cruz LJ. Curr Pharm Des. 2019 Jul 8. DOI: 10.2174/1381612825666190708184745. [Epub ahead of print]
Articular cartilage is a connective tissue structure that is found in anatomical areas that are important for the movement of the human body. Osteoarthritis is the ailment that most often affects the articular cartilage. Due to its poor intrinsic healing capacity, damage to the articular cartilage is highly detrimental and at present the reconstructive options for its repair are limited. Tissue engineering and the science of nanobiomaterials are two lines of research that together can contribute to the restoration of damaged tissue. The science of nanobiomaterials focuses on the development of different nanoscale structures that can be used as carriers of drugs / cells to treat and repair damaged tissues such as articular cartilage. This review article is an overview of the composition of articular cartilage, the causes and treatments of osteoarthritis, with a special emphasis on nanomaterials as carriers of drugs and cells, which reduce inflammation, promote the activation of biochemical factors and ultimately contribute to the total restoration of articular cartilage.
What is the association between price and economic activity with cigarette consumption in Cuba from 1980 to 2014? Varona-Pérez P, Bridges S, Lorenzo-Vázquez E, Suarez-Medina R, Venero-Fernández SJ, Langley T, et al. Public Health. 2019 Jul 2;173:126–9.
DOI: 10.1016/j.puhe.2019.05.014. Epub 2019 Jul 2.
Objectives Cuba is a tobacco-producing country that has been economically isolated as a consequence of an embargo imposed by the USA. It has also experienced a severe economic depression in the 1990s after the withdrawal of support by the former Soviet Union. These characteristics provide a unique opportunity to study the relation between large changes in economic activity, cigarette price and demand for cigarettes in a relatively isolated socialist economy. Study design This is an observational epidemiological study. Methods Data were obtained on the annual price of a packet of cigarettes and the mean number of cigarettes consumed per adult living in Cuba from 1980 to 2014. Descriptive and regression analysis were used to explore the relationship between cigarette consumption and price in Cuba. Results In 1980, the mean price of a packet of cigarettes was 1.53 Cuban pesos (CUP) in 1997 prices and the mean annual per capita consumption was 2237 cigarettes. In 2014, the mean price had increased to 5.57 CUP (1997 prices) per packet of cigarettes, and consumption had fallen to 1527 cigarettes per capita. There were significant negative associations between annual cigarette consumption and both price and living through an economic depression. The elasticity was approximately -0.31 with price, and living through an economic depression was also associated with lower consumption of cigarettes (a reduction of 9%, 95% confidence intervals -0.18 to -0.001). Conclusions Higher cigarette pricing, along with other public health interventions, are required to protect the national population from the adverse effects of tobacco smoke exposure.
