Análisis de la concentración sérica del ADN tumoral en el cáncer de pulmón no microcítico y avanzado: ¿es útil como factor pronóstico?

INTRODUCTION: Presence of circulating DNA in the serum of patients with cancer makes detection of tumour-specific genetic alterations feasible. OBJECTIVE: To study serum DNA concentration in patients diagnosed as having advanced Non-Small Cell Lung Cancer (NSCLC) and to evaluate its relationship with age, histology, stage, response, time-to-progression (TTP), and survival. METHODS: Serum DNA from 78 patients was purified and spectrophotometrically quantified. RESULTS: No significant correlations were found between serum DNA concentration and age, histology, response and survival. There was a significant correlation with respect to stage (IIIB = 408.75 ng/ml; IV = 478.74 ng/ml; p = 0.02). When patients were grouped according to DNA concentration, significant correlation with TTP was found; establishing a cut-off point at 500 ng/ml ([DNA] < 500 ng/ml TTP = 7.25 months, 95%CI: 3.5-5.25; [DNA ] > or = 500 ng/ml TTP = 4.25 months, 95%CI: 2-6.5; p = 0.05). CONCLUSIONS: Using the present method, DNA concentration quantification appears to be simple, but with certain deficiencies due to inter-sample variability and low specificity. This is because total DNA concentration is measured without distinguishing as to whether it is tumour-related. We suggest that there is a correlation between DNA concentration and prognosis which enables an analysis of the natural history of the disease.     

Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstr?m's macroglobulinemia.

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.     

Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis.

The purpose was to investigate the in vivo skin penetration of four 14C-salicylic compounds using microdialysis and to relate dermal concentrations to structural features. Furthermore, to compare two in vivo retrodialysis recovery methods for estimation of true unbound extracellular concentrations. Microdialysis probes were inserted in the dermis of hairless rats. Equimolal 14C-salicylic formulations were applied topically and dialysate sampled consecutively for 4h. True extracellular concentrations were estimated by retrodialysis by drug method (the 14C-salicylic compounds themselves) and by retrodialysis by calibrator method (3H-salicylic acid as internal standard). Probe depth was measured by ultrasound scanning. High dermal concentrations were found after application of 14C-salicylamide (low protein-binding) and the lipophilic ester 14C-butyl salicylate, which was completely hydrolysed to 14C-salicylic acid during skin diffusion. Protein binding and dissociation may explain the lower dermal concentrations of 14C-salicylic acid and 14C-diethylamine salicylate, respectively. Probe depth did not significantly influence dialysate concentrations. The two in vivo recovery correction methods did not reduce the variation in concentration-time curves. In conclusion, differentiated penetration kinetics was found ranking: 14C-salicylamide >/= 14C-butyl salicylate > 14C-salicylic acid > 14C-diethylamine salicylate. Dermal concentrations were related to structural features of the model compounds. The two correction methods performed alike; however, the calibrator method has the advantage of serving as a quality control during experiments.     

SARS-CoV-2 Variants in Paraguay: Detection and Surveillance with an Economical and Scalable Molecular Protocol

SARS-CoV-2 variant detection relies on resource-intensive whole-genome sequencing methods. We sought to develop a scalable protocol for variant detection and surveillance in Paraguay, pairing rRT-PCR for spike mutations with Nanopore sequencing. A total of 201 acute-phase nasopharyngeal samples were included. Samples were positive for the SARS-CoV-2 N2 target and tested with the Spike SNP assay to detect mutations associated with the following variants: alpha (501Y), beta/gamma (417variant/484K/501Y), delta (452R/478K), and lambda (452Q/490S). Spike SNP calls were confirmed using amplicon (Sanger) sequencing and whole-genome (Nanopore) sequencing on a subset of samples with confirmed variant lineages. Samples had a mean N2 Ct of 20.8 (SD 5.6); 198/201 samples (98.5%) tested positive in the Spike SNP assay. The most common genotype was 417variant/484K/501Y, detected in 102/198 samples (51.5%), which was consistent with the P.1 lineage (gamma variant) in Paraguay. No mutations (K417 only) were found in 64/198 (32.3%), and K417/484K was identified in 22/198 (11.1%), consistent with P.2 (zeta). Seven samples (3.5%) tested positive for 452R without 478K, and one sample with genotype K417/501Y was confirmed as B.1.1.7 (alpha). The results were confirmed using Sanger sequencing in 181/181 samples, and variant calls were consistent with Nanopore sequencing in 29/29 samples. The Spike SNP assay could improve population-level surveillance for mutations associated with SARS-CoV-2 variants and inform the judicious use of sequencing resources.     

Centredness in health care: A systematic overview of reviews

IntroductionThe introduction of effective, evidence‐based approaches to centredness in health care is hindered by the fact that research results are not easily accessible. This is partly due to the large volume of publications available and because the field is closely linked to and in some ways encompasses adjoining fields of research, for example, shared decision making and narrative medicine. In an attempt to survey the field of centredness in health care, a systematic overview of reviews was conducted with the purpose of illuminating how centredness in health care is presented in current reviews.MethodsSearches for relevant reviews were conducted in the databases PubMed, Scopus, Cinahl, PsychINFO, Web of Science and EMBASE using terms connected to centredness in health care. Filters specific to review studies of all types and for inclusion of only English language results as well as a time frame of January 2017–December 2018, were applied.ResultsThe search strategy identified 3697 unique reviews, of which 31 were included in the study. The synthesis of the results from the 31 reviews identified three interrelated main themes: Attributes of centredness (what centredness is), Translation from theory into practice (how centredness is done) and Evaluation of effects (possible ways of measuring effects of centredness). Three main attributes of centeredness found were: being unique, being heard and shared responsibility. Aspects involved in translating theory into practice were sufficient prerequisites, strategies for action and tools used in safeguarding practice. Further, a variety and breadth of measures of effects were found in the included reviews.ConclusionsOur synthesis demonstrates that current synthesized research literature on centredness in health care is broad, as it focuses both on explorations of the conceptual basis and the practice, as well as measures of effects. This study provides an understanding of the commonalities identified in the reviews on centredness in healthcare overall, ranging from theory to practice and from practice to evaluation.Patient or Public ContributionPatient representatives were involved during the initiation of the project and in decisions about its focus, although no patient or public representatives made direct contributions to the review process.     

Artificial Sweeteners in Breast Milk: A Clinical Investigation with a Kinetic Perspective

Artificial sweeteners (ASs) are calorie-free chemical substances used instead of sugar to sweeten foods and drinks. Pregnant women with obesity or diabetes are often recommended to substitute sugary products with ASs to prevent an increase in body weight. However, some recent controversy surrounding ASs relates to concerns about the risk of obesity caused by a variety of metabolic changes, both in the mother and the offspring. This study addressed these concerns and investigated the biodistribution of ASs in plasma and breast milk of lactating women to clarify whether ASs can transfer from mother to offspring through breast milk. We recruited 49 lactating women who were provided with a beverage containing four different ASs (acesulfame-potassium, saccharin, cyclamate, and sucralose). Blood and breast milk samples were collected before and up to six hours after consumption. The women were categorized: BMI < 25 (n = 20), BMI > 27 (n = 21) and type 1 diabetes (n = 8). We found that all four ASs were present in maternal plasma and breast milk. The time-to-peak was 30–120 min in plasma and 240–300 min in breast milk. Area under the curve (AUC) ratios in breast milk were 88.9% for acesulfame-potassium, 38.9% for saccharin, and 1.9% for cyclamate. We observed no differences in ASs distributions between the groups.     

Parkinson’s Disease and Sugar Intake—Reasons for and Consequences of a Still Unclear Craving

Lately, studies have shown that patients with Parkinson’s disease (PD) report a strong craving for sweets and consume significantly more fast-acting carbohydrates than healthy controls. Consuming food with a high-sugar content is assumed to lead to an increase in insulin concentration, which could positively influence dopamine concentration in the brain and unconsciously be used by patients as kind of “self-medication” to compensate for a lack of dopamine in PD. On the other hand, high-sugar intake could also lead to insulin resistance and diabetes, which is discussed as a causative factor for progressive neurodegeneration in PD. In this critical appraisal, we discuss the role of sugar intake and insulin on dopamine metabolism in patients with PD and how this could influence the potential neurodegeneration mediated by insulin resistance.