Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: Studies using Mössbauer spectroscopy and mathematical modeling.

The neurodegenerative disease Friedreich's ataxia arises from a deficiency of frataxin, a protein that promotes iron-sulfur cluster (ISC) assembly in mitochondria. Here, primarily using Mössbauer spectroscopy, we investigated the iron content of a yeast strain in which expression of yeast frataxin homolog 1 (Yfh1), oxygenation conditions, iron concentrations, and metabolic modes were varied. We found that aerobic fermenting Yfh1-depleted cells grew slowly and accumulated FeIII nanoparticles, unlike WT cells. Under hypoxic conditions, the same mutant cells grew at rates similar to WT cells, had similar iron content, and were dominated by FeII rather than FeIII nanoparticles. Furthermore, mitochondria from mutant hypoxic cells contained approximately the same levels of ISCs as WT cells, confirming that Yfh1 is not required for ISC assembly. These cells also did not accumulate excessive iron, indicating that iron accumulation into yfh1-deficient mitochondria is stimulated by O2. In addition, in aerobic WT cells, we found that vacuoles stored FeIII, whereas under hypoxic fermenting conditions, vacuolar iron was reduced to FeII. Under respiring conditions, vacuoles of Yfh1-deficient cells contained FeIII, and nanoparticles accumulated only under aerobic conditions. Taken together, these results informed a mathematical model of iron trafficking and regulation in cells that could semiquantitatively simulate the Yfh1-deficiency phenotype. Simulations suggested partially independent regulation in which cellular iron import is regulated by ISC activity in mitochondria, mitochondrial iron import is regulated by a mitochondrial FeII pool, and vacuolar iron import is regulated by cytosolic FeII and mitochondrial ISC activity.

Vitamin supplementation increases the virulence of Entamoeba histolytica grown axenically.

As a consequence of axenic growth and the elimination of accompanying bacterial flora, Entamoeba histolytica virulence decreases rapidly, and pathogenicity is lost. This paper evaluated the impact of vitamin supplementation on the pathogenicity of E. histolytica. Growth of E. histolytica trophozoites, cultured axenically in PEHPS (a Spanish acronym for the main ingredients - casein peptone, liver, pancreas extract and bovine serum) medium, with or without vitamins, exhibited a similar growth rate. However, the vitamin-enriched PEHPS preparations expressed 2.65 times more haemolytic activity (at 60 min: 98 vs 48%, P < 0.05), 2.5 times more phospholipase A2 activity at 150 min of incubation and generated more hepatic abscesses (88 vs 60%, P = 0.05) than the preparations without vitamins. The haemolytic and phospholipase A2 activity for the PEHPS - V preparations were restored following vitamin supplementation with A and D. These data highlight, for the first time, that vitamins and specifically vitamin A and D were essential for the recovery of amoebic virulence, lost through axenic growth.

Relationship between TNF-α, MMP-8, and MMP-9 levels in gingival crevicular fluid and the subgingival microbiota in periodontal disease.

Periodontitis is modulated by a complex dysbiotic microbiota, these species stimulate upward the production of pro-inflammatory cytokines such as TNF-α, which, in turn, upregulates the production of bone resorption molecules. Enzymes such as MMP-8 and 9 have been associated with the destructive disease. This study evaluated the composition of periodontal microbiota with the checkerboard hybridization technique and its correlation with TNF-α, MMP-8, and MMP-9 evaluated with ELISA, of 80 patients (45 healthy, and 35 with chronic periodontitis). The frequency of the 18 species evaluated was higher in patients with bone loss compared with control group. TNF-α in gingival crevicular fluid was significantly higher in bone loss group (p < 0.01); MMP-8 (p = 0.34) by MMP-9 (p < 0.05) in bone loss group obtained lower values than in control group. Positive correlation of TNF-α was obtained with Aggregatibacter actinomycetemcomitans (rho = 0.38; p < 0.01), Fusobacterium nucleatum (rho = 0.25; p < 0.05) and Porphyromonas gingivalis (rho = 0.26; p < 0.05); negative correlation of MMP-8 with A. actinomycetemcomitans (rho = 0.26; p < 0.01), Capnocytophaga sputigena (rho = 0.33; p < 0.01), and F. nucleatum (rho = 0.21; p < 0.05); also negative correlation of MMP-9 with F. nucleatum (rho = 0.23; p < 0.05), P. gingivalis (rho = 0.23; p < 0.05), and Tannerella forsythia (rho = 0.26; p < 0.01). TNF-α increased due to the increase in each count of A. actinomycetemcomitans (ß = 0.57; p = 0.00). The presence of A. actinomycetemcomitans (ß = 1.88; p = 0.00), Campylobacter rectus (ß = 0.78; p = 0.01), F. nucleatum (ß = 0.65; p = 0.04), and P. gingivalis (ß = 0.65; p = 0.04) significantly increases TNF-α levels. TNF-α in gingival crevicular fluid, despite the minimal amounts collected, is a good biomarker of periodontal disease; since levels of TNF-α increases with the increase of the most harmful species to the periodontium.

Effectiveness of an educational intervention to improve the safety culture in primary care: a randomized trial.

BACKGROUND: Fostering a culture of safety is an essential step in ensuring patient safety and quality in primary care. We aimed to evaluate the effectiveness of an educational intervention to improve the safety culture in the family and community medicine teaching units in an Atlantic European Region. METHODS: Randomized study conducted in family and community medicine teaching units in Galicia (Spain). Participants were all fourth-year residents and their tutors (N = 138). Those who agreed to participate were randomized into one of two groups (27 tutors/26 residents in the intervention group, 23 tutors/ 23 residents in the control one).All were sent the Survey on Patient Safety Culture. After that, the intervention group received specific training in safety; they also recorded incidents over 15 days, documented them following a structured approach, and had feedback on their performance. The control group did not receive any action. All participants completed the same survey four months later. Outcome measures were the changes in safety culture as quantified by the results variables of the Survey: Patient Safety Grade and Number of events reported. We conducted bivariate and adjusted analyses for the outcome measures. To explore the influence of participants' demographic characteristics and their evaluation of the 12 dimensions of the safety culture, we fitted a multivariate model for each outcome. RESULTS: Trial followed published protocol. There were 19 drop outs. The groups were comparable in outcome and independent variables at start. The experiment did not have any effect on Patient safety grade (- 0.040) in bivariate analysis. The odds of reporting one to two events increased by 1.14 (0.39-3.35), and by 13.75 (2.41-354.37) the odds of reporting 3 or more events. Different dimensions had significant independent effects on each outcome variable. CONCLUSION: A educational intervention in family and community medicine teaching units may improve the incidents reported. The associations observed among organizational dimensions and outcomes evidence the complexity of patient safety culture measurement and, also, show the paths for improvement. In the future, it would be worthwhile to replicate this study in teaching units from different settings and with different health professionals engaged. TRIAL REGISTRATION: It was retrospectively registered with ( ISRCTN41911128 , 31/12/2010).

National Clinical Practice Guidelines for the management of non-small cell lung cancer in early, locally advanced and metastatic stages. Extended version. / Guía de Práctica Clínica Nacional para el manejo del cáncer de pulmón de células no pequeñas en estadios tempranos, localmente avanzados y metastásicos.

OBJECTIVE: Lung cancer is one the leading causes of mortality worldwide. Symptomatic manifestations of the disease generally occur in the advanced-stage setting, and therefore an important number of patients have advanced or metastatic disease by the time they are diagnosed. This situation contributes to a poor prognosis in the treatment of lung cancer. Evidencebased clinical recommendations are of great value to support decision-making for daily practice, and thus improving health care quality and patient outcomes. MATERIALS AND METHODS: This document was an initiative of the Mexican Society of Oncology (SMEO) in collaboration with Mexican Center of Clinical Excellence (Cenetec) according to Interna- tional Standards. Such standards included those described by the IOM, NICE, SIGN and GI-N. An interdisciplinary Guideline Development Group (GDG) was put together which included medical oncologists, surgical oncologistsc, radiation therapists, and methodologists with expertise in critical appraisal, sys- tematic reviews and clinical practice guidelines development. RESULTS: 62 clinical questions were agreed among members of the GDG. With the evidence identified from systematic reviews, the GDG developed clinical recommendations using a Modified Delphi Panel technique. Patients' representatives validated them. CONCLUSIONS: These Clinical Practice Guideline aims to support the shared decision-making process for patients with different stages of non-small cell lung cancer. Our goal is to improve health-care quality on these patients.

OBJETIVO: El cáncer de pulmón es una de las principales causas de mortalidad alrededor del mundo. Su historia natural, con la manifestación de síntomas en etapas avanzadas y el retraso en su diagnóstico hacen que una gran proporción de pacientes se diagnostiquen en estadios tardíos de la enfermedad, lo que hace muy complicado el tratamiento exitoso de la misma. De esto deriva la importancia de dar origen a recomendaciones basadas en evidencia para soportar la toma de decisiones clínicas por parte de los grupos interdisicplinarios que se encargan del manejo de este padecimiento. MATERIAL Y MÉTODOS: Este documento se desarrolló por parte de la Sociedad Mexicana de Oncología en colaboración con el Centro Nacional de Excelencia Tec- nológica de México (Cenetec) a través de la dirección de integración de Guías de Práctica Clínica en cumplimiento a estándares internacionales como los descritos por el Ins- tituto de Medicina de EUA (IOM, por sus siglas en inglés), el Instituto de Excelencia Clínica de Gran Bretaña (NICE, por sus siglas en inglés), la Red Colegiada para el Desarrollo de Guías de Escocia (SIGN, por sus siglas en inglés), la Red Internacional de Guías (G-I-N, por sus siglas en inglés); entre otros. Se integró en representación de la Sociedad Mexicana de Oncología un Grupo de Desarrollo de la Guía (GDG) de manera interdisciplinaria, considerando oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos, y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. RESULTADOS: Se consensuaron 62 preguntas cllínicas que abarcaron lo establecido previamente por el GDG en el documento de alcances de la Guía. Se identificó la evidencia científica que responde a cada una de estas preguntas clínicas y se evaluó críticamente la misma, antes de ser incorporada en el cuerpo de evidencia de la Guía. El GDG acordó mediante la técnica de consenso formal de expertos Panel Delphi la redacción final de las recomendaciones clínicas. C. CONCLUSIONES: Esta Guía de Práctica Clínica pretende proveer recomendaciones clínicas para el manejo de los distintos estadios de la enfermedad y que asistan en el proceso de toma de decisiones compartida. El GDG espera que esta guía contribuya a mejorar la calidad de la atención clínica en las pacientes con cáncer de pulmón de células no pequeñas.

Nomogram and Validity of a Model for Predicting Malnutrition in Patients on Liver Transplant Lists.

BACKGROUND: Malnutrition is associated with increased morbimortality in liver transplant patients, and it is important to identify factors related to nutritional status in these patients. AIMS: Determine variables associated with malnutrition and create a nomogram in liver transplant candidates. METHODS: Cross-sectional study (n = 110). VARIABLES: demographic variables, imbalances due to the disease, transplant aetiology and analytical parameters. Physical examination was performed and degree of hepatic dysfunction calculated. Nutritional status was assessed: Controlling Nutritional Status, Spanish Society of Parenteral and Enteral Nutrition criteria, Nutritional Risk Index, Prognostic Nutritional Index or Onodera Index and The Subjective Global Assessment. Logistic regression analysis was performed. A predictive nomogram (discrimination and calibration analysis) was generated. RESULTS: Malnourishment was defined according to at least 4 or more of the methods studied. Patients with ascites, encephalopathy and portal hypertension presented malnourishment more frequently. Malnutrition was associated with greater liver dysfunction and lower grip strength. Variables independently associated with malnourishment were encephalopathy and lower albumin values. A nomogram was created to predict malnourishment, with good discriminatory power and calibration. CONCLUSIONS: A score was developed for evaluating malnutrition risk. This would provide a tool that makes it possible to quickly and easily identify the risk of malnutrition in liver transplant candidates.

Neuromuscular function of the soft palate and uvula in snoring and obstructive sleep apnea: A systematic review.

OBJECTIVE: A collapsible upper airway is a common cause of obstructive sleep apnea. The exact pathophysiology leading to a more collapsible airway is not well understood. A progressive neuropathy of the soft palate and pharyngeal dilators may be associated with the progression of snoring to OSA. The purpose of this study is to systematically review the international literature investigating the neurophysiologic changes in the soft palate and uvula that contribute to progression from snoring to OSA. METHODS: PubMed/MEDLINE and 4 other databases were systematically searched through July 4, 2017. Eligibility: (1) Patients: controls, snoring or OSA patients (2) Intervention: neuromuscular evaluation of the palate and/or uvula (3) Comparison: differences between controls, snoring and OSA patients (4) Outcomes: neuromuscular outcomes (5) Study design: Peer reviewed publications of any design. RESULTS: 845 studies were screened, 76 were downloaded in full text form and thirty-one studies met criteria. Histological studies of the soft palate demonstrated diffuse inflammatory changes, muscular changes consistent with neuropathy, and neural aberrancies. Sensory testing studies provided heterogeneous outcomes though the majority favored neuronal dysfunction. Studies have consistently demonstrated that increasing severity of snoring and sleep apnea is associated with worsening sensory nerve function of the palate in association with atrophic histological changes to the nerves and muscle fibers of the soft palate and uvula. CONCLUSIONS: Recent evidence highlighted in this systematic review implicates the role of neurogenic pathology underlying the loss of soft palate and/or uvular tone in the progression of snoring to sleep apnea.

Oropharyngeal and tongue exercises (myofunctional therapy) for snoring: a systematic review and meta-analysis.

PURPOSE: Oropharyngeal and tongue exercises (myofunctional therapy) have been shown to improve obstructive sleep apnea. However, to our knowledge, a systematic review has not been performed for snoring. The study objective is to perform a systematic review, with a meta-analysis, dedicated to snoring outcomes after myofunctional therapy. METHODS: PubMed/MEDLINE and three other databases were searched through November 25, 2017. Two authors independently searched the literature. Eligibility (1) patients: children or adults with snoring, (2) intervention: oropharyngeal and/or tongue exercises, (3) comparison: pre and post-treatment data for snoring, (4) outcomes: snoring frequency and snoring intensity, (5) study design: publications of all study designs. RESULTS: A total of 483 articles were screened, 56 were downloaded in their full text form, and nine studies reported outcomes related to snoring. There were a total of 211 patients (all adults) in these studies. The snoring intensity was reduced by 51% in 80 patients from pre-therapy to post-therapy visual analog scale values of 8.2 ± 2.1 (95% CI 7.7, 8.7) to 4.0 ± 3.7 (95% CI 3.2, 4.8). Berlin questionnaire snoring intensity reduced by 36% in 34 patients from 2.5 ± 1.0 (95% CI 2.2, 2.8) to 1.6 ± 0.8 (95% CI 1.3, 1.9). Finally, time spent snoring during sleep was reduced by 31% in 60 patients from 26.3 ± 18.7% (95% CI 21.6, 31.0) to 18.1 ± 20.5% (95% CI 12.9, 23.3) of total sleep time. CONCLUSIONS: This systematic review demonstrated that myofunctional therapy has reduced snoring in adults based on both subjective questionnaires and objective sleep studies.

Predictive factors of satisfaction and quality of life after immediate breast reconstruction using the BREAST-Q©.

AIMS AND OBJECTIVES: To analyse quality of life and satisfaction after immediate breast reconstruction due to cancer and its determining factors. BACKGROUND: Studying breast reconstruction is important because of its frequency and variability. In addition to the surgical results, it is necessary to analyse the quality of life and patient satisfaction using a specific tool. DESIGN METHODS: An ambispective design was used (n = 101; α = 0.05; precision = 10%), studying anthropometric, sociocultural data, Fagerström test and the BREAST-Q© questionnaire. A logistic regression analysis was performed to identify variables associated with quality of life and satisfaction. RESULTS: Mean age of the patients on diagnosis was 44.87 ± 8.5 years. Forty-one of the patients were carried out a skin-sparing mastectomy (42.7%). Immediate reconstruction was performed with implant in 73 (74.5%). The domains on the BREAST-Q© for quality of life with the lowest scores were physical well-being chest (74) and sexual well-being (61.5). The satisfaction domain with the lowest score was with the breast (59). The variables associated with the worst quality of life in the physical well-being chest domain were the skin-sparing mastectomy (OR, 4.2; 95% confidence interval (CI), 1.2-14.1) and lymphedema (OR, 12.9; 95% CI, 1.0-159.9). Antibody treatment was associated with a worse score on the psychosocial well-being domain (OR, 4.25; 95% CI, 1.0-18.0) and sexual well-being domain (OR, 7.34; 95% CI, 0.9-54.6). Satisfaction was associated with nicotine dependence on the breast and outcome scale. The higher the dependence on nicotine, the greater the dissatisfaction with the breasts (OR, 2.41; 95% CI, 1.1-5.3) and with the result (OR, 2.45; 95% CI, 1.0-5.9). CONCLUSIONS: The type of treatment and lymphedema modify the patients' quality of life. Nicotine dependence is associated with lower satisfaction with the breast and with the outcome. RELEVANCE TO CLINICAL PRACTICE: This study suggests the need for multidisciplinary attention during the first year of adjuvant treatment despite the benefits of immediate reconstruction. It shows the need for preoperative assessment of the level of nicotine dependence, anxiety and depression of smoking patients before preoperative counselling.

Bone marrow mesenchymal stem cells: improving transgene expression level, transfection efficiency and cell viability.

PURPOSE: Advanced cancer is a catastrophic medical condition that is generally treated with surgery and conventional anticancer drugs, which are very toxic and often fail. A promising alternative is using genetically engineered mesenchymal stem cells. A popular method for genetically engineering mesenchymal stem cells (MSCs) is by employing transfection reagents. Nevertheless, a serious limitation of this procedure is its consistently low transfection efficiency. Therefore, the utility of transfection reagents in regenerative medicine - including cancer treatment - might increase strikingly by increasing their transfection efficiency and maintaining, to the greatest extent possible, cell viability and transgene expression levels. The purpose of this study was to analyze various effects on gene expression level, transfection efficiency, and cell viability by increasing the volume of transfection reagents and the plasmid DNA mass. METHODS: Mouse bone marrow MSCs were transfected with trademarked Xfect®, Turbofect® or Lipofectamine 3000® and the plasmid pTracer-EF-His-A® expressing the green fluorescent protein (GFP). Additionally, we tested a protocol modification recommended by the Xfect manufacturer. The GFP expression level, transfection efficiency, and cell viability were evaluated together using a performance index. RESULTS: By doubling the quantities recommended by the manufacturers (reagent volume), plasmid DNA mass or both variables and by following a modified Xfect method, the transfection efficiency improved to 70%, the cell viability did not diminish, and the performance index increased to 47.7% with respect to the values determined using the original Xfect protocol. CONCLUSION: Transgene expression levels, transfection efficiency, and cell viability may be strikingly improved, by increasing the volume of the transfectant agent, the plasmid DNA mass or both, beyond those recommended by transfection kit manufacturers.

Incidence of cardiovascular events and associated risk factors in kidney transplant patients: a competing risks survival analysis.

BACKGROUND: The high prevalence of cardiovascular risk factors among the renal transplant population accounts for increased mortality. The aim of this study is to determine the incidence of cardiovascular events and factors associated with cardiovascular events in these patients. METHODS: An observational ambispective follow-up study of renal transplant recipients (n = 2029) in the health district of A Coruña (Spain) during the period 1981-2011 was completed. Competing risk survival analysis methods were applied to estimate the cumulative incidence of developing cardiovascular events over time and to identify which characteristics were associated with the risk of these events. Post-transplant cardiovascular events are defined as the presence of myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances, peripheral vascular disease and cardiovascular disease and death. The cause of death was identified through the medical history and death certificate using ICD9 (390-459, except: 427.5, 435, 446, 459.0). RESULTS: The mean age of patients at the time of transplantation was 47.0 ± 14.2 years; 62% were male. 16.5% had suffered some cardiovascular disease prior to transplantation and 9.7% had suffered a cardiovascular event. The mean follow-up period for the patients with cardiovascular event was 3.5 ± 4.3 years. Applying competing risk methodology, it was observed that the accumulated incidence of the event was 5.0% one year after transplantation, 8.1% after five years, and 11.9% after ten years. After applying multivariate models, the variables with an independent effect for predicting cardiovascular events are: male sex, age of recipient, previous cardiovascular disorders, pre-transplant smoking and post-transplant diabetes. CONCLUSIONS: This study makes it possible to determine in kidney transplant patients, taking into account competitive events, the incidence of post-transplant cardiovascular events and the risk factors of these events. Modifiable risk factors are identified, owing to which, changes in said factors would have a bearing of the incidence of events.

Concordance among methods of nutritional assessment in patients included on the waiting list for liver transplantation.

BACKGROUND: The aim of the present study was to determine the extent of malnutrition in patients waiting for a liver transplant. The agreement among the methods of nutritional assessment and their diagnostic validity were evaluated. METHODS: Patients on the waiting list for liver transplantation (n = 110) were studied. The variables were: body mass index, analytical parameters, liver disease etiology, and complications. Liver dysfunction was evaluated using the Child-Pugh Scale. Nutritional state was studied using the Controlling Nutritional Status (CONUT), the Spanish Society of Parenteral and Enteral Nutrition (SENPE) criteria, the Nutritional Risk Index (NRI), the Prognostic Nutritional Index (PNI-O), and the Subjective Global Assessment (SGA). Agreement was determined using the Kappa index. Area under receiver operator characteristic curves (AUCs), the Youden index (J), and likelihood ratios were computed. RESULTS: Malnutrition varied depending on the method of evaluation. The highest value was detected using the CONUT (90.9%) and the lowest using the SGA (50.9%). The pairwise agreement among the methods ranged from K = 0.041 to K = 0.826, with an overall agreement of each criteria with the remaining methods between K = 0.093 and K = 0.364. PNI-O was the method with the highest overall agreement. Taking this level of agreement into account, we chose the PNI-O as a benchmark method of comparison. The highest positive likelihood ratio for the diagnosis of malnutrition was obtained from the Nutritional Risk Index (13.56). CONCLUSIONS: Malnutrition prevalence is high and prevalence estimates vary according the method used, with low concordance among methods. PNI-O and NRI are the most consistent methods to identify malnutrition in these patients.

Hallux valgus in a random population in Spain and its impact on quality of life and functionality.

The aim of this study was to determine the prevalence of Hallux valgus (HV) and the association between the presence thereof and quality of life, dependence for basic and instrumental activities of daily living and foot function. Prevalence study was carried out in a random population sample (n = 1837) (α = 0.05; Precision = ±2.2%). Informed consent and ethical review board were obtained (code 2008/264). We studied anthropometric variables, Charlson Comorbidity Index, function and state of foot [Foot Function index (FFI), Foot Health Status Questionnaire (FHSQ)], quality of life (SF-36), and dependence for activities of daily living (Barthel and Lawton index). Degree of HV was determined using Manchester scale. Descriptive and multivariate logistic regression analyses were performed. Hence, the prevalence of HV is 39%. Patients with HV are significantly older (64.6 ± 11.7 vs 60.1 ± 12.6 years old). HV prevalence is greater in females (48.1 vs. 28.3%), subjects with flat foot (48.1 vs. 36.1%) or hammer toes (48.2 vs. 30.9%). Moreover, with regard to the presence or not of HV, statistically significant differences were neither noted in the SF-36 questionnaire nor in the Barthel and Lawton Index. For FHSQ and FFI questionnaires, significant differences were observed between patients who presented HV and those who did not. HV is associated with age, gender, flat foot and hammer toes. The SF-36 and Barthel and Lawton questionnaires remained unaltered by the presence of HV. The presence of Hallux valgus was associated with reduced quality of life and increases foot pain, disability and functional limitation.

Tongue retaining devices for obstructive sleep apnea: A systematic review and meta-analysis.

OBJECTIVE: Tongue Retaining Devices (TRD) anteriorly displace the tongue with suction forces while patients sleep. TRD provide a non-surgical treatment option for patients with Obstructive Sleep Apnea (OSA). Our objective was to conduct a systematic review of the international literature for TRD outcomes as treatment for OSA. METHODS: Three authors independently and systematically searched four databases (including PubMed/MEDLINE) through June 26, 2016. We followed guidelines set within the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Sixteen studies with 242 patients met criteria. The overall means±standard deviations (M±SD) for apnea-hypopnea index (AHI) decreased from 33.6±21.1/h to 15.8±16.0/h (53% reduction). Seven studies (81 patients) reported lowest oxygen saturation (LSAT), which improved from 79.8±17.5% to 83.9±8.6%. Four studies (93 patients) reported Epworth sleepiness scale (ESS), which decreased from 10.8±4.8 to 8.2±4.5, p <0.0001. Four studies (31 patients) reported Oxygen Desaturation Index (ODI) which decreased from 29.6±32.1 to 12.9±8.7, a 56.4% reduction. CONCLUSION: Current international literature demonstrates that tongue retaining devices reduce apnea-hypopnea index by 53%, increase lowest oxygen saturation by 4.1 oxygen saturation points, decrease oxygen desaturation index by 56% and decrease Epworth sleepiness scale scores by 2.8 points. Tongue retaining devices provide a statistically effective alternative treatment option for obstructive sleep apnea.

Tongue surgeries for pediatric obstructive sleep apnea: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the international literature for studies reporting outcomes for obstructive sleep apnea (OSA) in children undergoing isolated tongue surgeries. METHODS: Two authors searched from inception through November 14, 2016 in four databases including PubMed/MEDLINE. RESULTS: 351 studies were screened. Eleven studies (116 children) met criteria. Most children were syndromic and had craniofacial disorders, co-morbidities, or other serious medical issues. Surgeries included base-of-tongue (BOT) reduction (n = 114), tongue suspension (n = 1), and hypoglossal nerve stimulation (n = 1). The pre- and post-BOT reduction surgeries decreased apnea-hypopnea index (AHI) from a mean (M) and standard deviation (SD) of 16.9 ± 12.2/h to 8.7 ± 10.6/h (48.5% reduction) in 114 patients. Random effects modeling (109 patients) demonstrated a standardized mean difference for AHI of -0.78 (large magnitude of effect) [95% CI -1.06, -0.51], p value <0.00001. For BOT surgery in 53 non-syndromic children, the AHI decreased 59.2% from 14.0 ± 11.4 to 5.7 ± 6.7/h, while in 55 syndromic children, the AHI decreased 40.0% from 20.5 ± 19.1 to 12.3 ± 18.2/h. BOT reduction improved lowest oxygen saturation from M ± SD of 84.7 ± 7.4-87.9 ± 6.5% in 113 patients. Hypoglossal nerve stimulation and tongue-base suspension are limited to case reports. CONCLUSIONS: Most children undergoing tongue surgeries in the literature were syndromic and had craniofacial disorders, co-morbidities, or other serious medical issues. Children with a body mass index <25 kg/m2 and non-syndromic children have had the most improvement in AHI. The specific type of surgery must be tailored to the patient. Patients with co-morbidities should undergo treatment in centers that are equipped to provide appropriate perioperative care.

How desirable and undesirable features of naïve or genetically reengineered mesenchymal stem cells are being considered in preclinical or clinical assays.

The implantation of adult mesenchymal stem cells (MSCs) has become a promising alternative in cancer treatments. Accordingly, in this article we revised the ultimate advances in the knowledge on the MSC-homing mechanism, the cancer cell and MSCs interactions and the microvesicles and exosomes used by malignant cells to transport and deliver pro-cancer cytokines or microRNA (miRNA), or by MSCs to favor or fight cancer progression. In addition, we analyzed the current knowledge generated by ongoing or terminated preclinical and clinical trials, using naive MSCs as natural anti-cancer living factors or gene-engineered MSCs as cytokine delivering vehicles, where anti-cancer cytokines were chosen and the pro-cancer factors were avoided. Finally, we present some concerns about the implantation of MSCs and anti-cancer therapies and hypothesize the MSC implantation combines with conventional or new therapies to treat cancer.

Remarkably higher efficacy and a wider safety window for nonfrontline over first-line drug combinations in the adenocarcinoma Colo 320DM cell line.

PURPOSE: To determine in vitro, the efficacy and safety window of not-front-line and first-line anti-colorectal (CRC) drug combinations. METHODS: The adenocarcinoma cell line Colo 320DM and normal human mesenchymal stem cells derived from adipose tissue were used respectively to determine the anti-CRC efficacy (% of Colo 320DM cell death [CD]) and safety window [SW] - % Colo 320DM percent cancer death (PCD)/% of mesenchymal stem cell's death) of drug combinations, using the adenosine triphosphate-based chemotherapy response assay (ATP-CRA). RESULTS: First-line anti-CRC drug combinations (5-fluorouracil [5FU]/oxaliplatin [oxa] and 5-FU/Oxa /leucovorin [Leuco]) produced 57.7% and 52.4% CD, and 1.38 and 2.44 SW, respectively. Combinations of 5-FU/Oxa and 1 to 3 non-front line drugs led to 56.3-99.8% CD and to 0.96-2.2 SW. The highest safety window corresponded to 5FU/Oxa/ carboplatin [Carbo] (93% CD and 1.4 SW) and to 5-FU/ Oxa/cisplatin [Cispl] (93.5% CD and 1.4 SW). In contrast, non-front line drugs led to 89.8-97.4% CD and to 1.1-78.2 SW. Outstandingly, those combinations containing Carbo/ Cispl/3,3'-diindolylmethane (DIM), aspirin (Asp), or 3,3'- DIM/ Asp showed a very high CD (91.9-96.9% [39.2-39.5 times higher than first-line-combined drugs]) and very wide SW (57.8-81.56 [66.6-40 times higher than the first-line drug combinations]). CONCLUSIONS: Human mesenchymal stem cells could be an excellent alternative to laboratory animals, when testing the safety profiles of drugs. The most promising combinations of non-frontline drugs to treat CRC are Carbo/Cispl/ Asp and Carbo/Cispl/DIM.

Effect of diagnostic delay on survival in patients with colorectal cancer: a retrospective cohort study.

BACKGROUND: Disparate and contradictory results make studies necessary to investigate in more depth the relationship between diagnostic delay and survival in colorectal cancer (CRC) patients. The aim of this study is to analyse the relationship between the interval from first symptom to diagnosis (SDI) and survival in CRC. METHODS: Retrospective study of n = 942 CRC patients. SDI was calculated as the time from the diagnosis of cancer and the first symptoms of CRC. Cox regression was used to estimate five-year mortality hazard ratios as a function of SDI, adjusting for age and gender. SDI was modelled according to SDI quartiles and as a continuous variable using penalized splines. RESULTS: Median SDI was 3.4 months. SDI was not associated with stage at diagnosis (Stage I = 3.6 months, Stage II-III = 3.4, Stage IV = 3.2; p = 0.728). Shorter SDIs corresponded to patients with abdominal pain (2.8 months), and longer SDIs to patients with muchorrhage (5.2 months) and rectal tenesmus (4.4 months). Adjusting for age and gender, in rectum cancers, patients within the first SDI quartile had lower survival (p = 0.003), while in colon cancer no significant differences were found (p = 0.282). These results do not change after adjusting for TNM stage. The splines regression analysis revealed that, for rectum cancer, 5-year mortality progressively increases for SDIs lower than the median (3.7 months) and decreases as the delay increases until approximately 8 months. In colon cancer, no significant relationship was found between SDI and survival. CONCLUSIONS: Short diagnostic intervals are significantly associated with higher mortality in rectal but not in colon cancers, even though a borderline significant effect is also observed in colon cancer. Longer diagnostic intervals seemed not to be associated with poorer survival. Other factors than diagnostic delay should be taken into account to explain this "waiting-time paradox".

Leukocyte-poor platelet-rich plasma is more effective than the conventional therapy with acetaminophen for the treatment of early knee osteoarthritis.

INTRODUCTION: Knee osteoarthritis (OA) is a degenerative and progressive articular cartilage disease. Infiltration of autologous platelet-rich plasma (PRP) has been proposed as a therapeutic alternative due to the content of biologically active cytokines in PRP. We aimed to compare the clinical response of acetaminophen and intra-articular leukocyte-poor PRP (LP-PRP) in early knee OA. MATERIALS AND METHODS: A total of 65 patients with clinically and radiographically documented knee OA (grade 1-2) were analyzed. Patients were randomized into two groups: 32 were treated with acetaminophen (500 mg/8 h) over 6 weeks, and 33 received three intra-articular injections of autologous LP-PRP (once every 2 weeks). All patients were evaluated by the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities (WOMAC) score, and the SF-12 health survey at baseline and 6, 12, and 24 weeks of follow-up. All LP-PRP preparations were analyzed for the platelet, leukocyte, IL-1ra, and TGF-ß concentrations. RESULTS: The decrease in the VAS pain level in the LP-PRP group was greater than that in the acetaminophen group (p < 0.05). Patients treated with LP-PRP showed a sustained improvement in knee function at week 24 (p < 0.01). The SF-12 results only indicated an improvement in quality-of-life in the LP-PRP group at 6, 12, and 24 weeks of follow-up (p < 0.01). Both IL-1ra and TGF-ß were detected in the LP-PRP samples (313.8 ± 231.6 and 21,183.8 ± 8556.3 pg/mL, respectively). CONCLUSIONS: Treatment with LP-PRP injections resulted in a significantly better clinical outcome than did treatment with acetaminophen, with sustained lower EVA and WOMAC scores and improvement in quality-of-life (higher SF-12 score). Therapy with LP-PRP may positively modify the inflammatory joint environment by counteracting IL-1ß action.

Understanding the colon cancer stem cells and perspectives on treatment.

An area of research that has been recently gaining attention is the relationship between cancer stem cell (CSC) biology and chemo-resistance in colon cancer patients. It is well recognized that tumor initiation, growth, invasion and metastasis are promoted by CSCs. An important reason for the widespread interest in the CSC model is that it can comprehensibly explain essential and poorly understood clinical events, such as therapy resistance, minimal residual disease, and tumor recurrence. This review discusses the recent advances in colon cancer stem cell research, the genes responsible for CSC chemoresistance, and new therapies against CSCs.