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Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax 1503.2 ng/mL vs 1521.4, Tmax 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13–113.6), 98.08% (88.04–109.2), and 97.52% (84.9–112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration. [ABSTRACT FROM AUTHOR]

Background and aims: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when β-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early β-cell damage. Materials and methods: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. Results: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early β-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. Conclusions: RIAO level increases as the number of complications rises; RIAOs > 3.35 μg/ml is a predictor of changes in the current indicators of β-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making. [ABSTRACT FROM AUTHOR]

Conformational diseases represent a new aspect of proteomic medicine where diagnostic and therapeutic paradigms are evolving. In this context, the early biomarkers for target cell failure (neurons, β-cells, etc.) represent a challenge to translational medicine and play a multidimensional role as biomarkers and potential therapeutic targets. This systematic review, which follows the PICO and Prisma methods, analyses this new-fangled multidimensionality, its strengths and limitations, and presents the future possibilities it opens up. The nuclear diagnosis methods are immunoassays: ELISA, immunodot, western blot, etc., while the therapeutic approach is focused on pharmaco- and molecular chaperones. [ABSTRACT FROM AUTHOR]

Background: In recent years, medical practice has followed two different paradigms: evidence-based medicine (EBM) and values-based medicine (VBM). There is an urgent need to promote medical education that strengthens the relationship between these two paradigms. This work is designed to establish the foundations for a continuing medical education (CME) program aimed at encouraging the dialogue between EBM and VBM by determining the values relevant to everyday medical activities. Methods: A quasi-experimental, observational, comparative, prospective and qualitative study was conducted by analyzing through a concurrent triangulation strategy the correlation between healthcare personnel-patient relationship, healthcare personnel's life history, and ethical judgments regarding dilemmas that arise in daily clinical practice. In 2009, healthcare personnel working in Mexico were invited to participate in a free, online clinical ethics course. Each participant responded to a set of online survey instruments before and after the CME program. Face-to-face semi-structured interviews were conducted with healthcare personnel, focusing on their views and representations of clinical practice. Results: The healthcare personnel's core values were honesty and respect. There were significant differences in the clinical practice axiology before and after the course (P < 0.001); notably, autonomy climbed from the 10th (order mean (OM) = 8.00) to the 3rd position (OM = 5.86). In ethical discernment, the CME program had an impact on autonomy (P = 0.0001). Utilitarian autonomy was reinforced in the participants (P = 0.0001). Regarding work values, significant differences due to the CME intervention were found in openness to change (OC) (P < 0.000), selftranscendence (ST) (P < 0.001), and self-enhancement (SE) (P < 0.019). Predominant values in life history, ethical discernment and healthcare personnel-patient relation were beneficence, respect and compassion, respectively. Conclusions: The healthcare personnel participating in a CME intervention in clinical ethics improved high-order values: Openness to change (OC) and Self Transcendence (ST), which are essential to fulfilling the healing ends of medicine. The CME intervention strengthened the role of educators and advisors with respect to healthcare personnel. The ethical values developed by healthcare professionals arise from their life history and their professional formation. [ABSTRACT FROM AUTHOR]

The modulators that diminish appetite and increase metabolic calorie needs at hypothalamus level are synthesized in different tissues: gastrointestinal system (glucagons-like peptide-1, pancreatic polypeptide, peptide YY, cholecystokinin and oxyntomodulin), the endocrine system (insulin, beta effects of adrenalin, and estrogens), adipose tissue (leptin, visfatin and omentin-1), peripheral nervous system (noradrenaline beta effects) and central nervous system (corticotropin released hormone, melanocortin, agouti protein, cocacine-amphetamine-regulated transcript and MCH). Those factors increasing appetite and lower basal metabolism comes from gastrointestinal system (ghrelin and growth hormone re lease hormone from pancreas), and central nervous system (neuropeptide Y, orexins and cannabinoids). In the hypothalamus, the neural and neuroendocrine afferents are integrated with the purpose of regulate appetite (hunger or satiety signals), and metabolic needs (increasing or decreasing basal metabolism and brown adipose tissue thermoregulation efficacy) according to body energy balance. The arcuate nucleus contains 2 main cellular systems: one rich in proopiomelanocortin (precursor of alpha melanocytes stimulating hormone and agonist of melanocortin 3 and 4 receptors), which decreases appetite, and other rich in neuropeptide Y and agouti-related peptide which increase appetite. [ABSTRACT FROM AUTHOR]

The formation of amyloid oligomers and fibrils of the human islet amyloid polypeptide (hIAPP) has been linked with β- cell failure and death which causes the onset, progression, and comorbidities of diabetes. We begin to unpack the aggregation-oligomerization-fibrillization process of these oligomers taken from sera of pediatric patients. The naturally occurring or real hIAPP (not synthetic) amyloid oligomers (RIAO) were successfully isolated, we demonstrated the presence of homo (dodecamers, hexamers, and trimers) and hetero-RIAO, as well as several biophysical characterizations which allow us to learn from the real phenomenon taking place. We found that the aggregation/oligomerization process is active in the sera and showed that it happens very fast. The RIAO can form fibers and react with anti-hIAPP and anti-amyloid oligomers antibodies. Our results opens the epistemic horizon and reveal real differences between the four groups (Controls vs obesity, T1DM or T2DM) accelerating the process of understanding and discovering novel and more efficient prevention, diagnostic, transmission and therapeutic pathways. [ABSTRACT FROM AUTHOR]

OBJETIVE: To describe the performance in neurocognitive processes and executive functions related to age, start of treatment and type of CH in Mexican school children. MATERIALS AND METHODS: Observational, cross-sectional, prospective and comparative study. 33 children with CH participated, aged 8 and 9, female cases predominated, the attention process and executive functions were evaluated with the Neuropsychological Assessment Child (ENI). RESULTS: 58% of the children presented agenesis and 42% other dysgenesis, with early onset of treatment (EoT) in 18% and late onset treatment (LoT) in 82%. All children presented low performance in both visual and auditory attention. Children with agenesis and EoT presented low performance in executive functions and execution processing speed. CONCLUSIONS: The LoT and type of CH (agenesis) have an impact on the development of neurocognitive functions related to school learning, however, not all domains present the same level of competence. [ABSTRACT FROM AUTHOR]

Background: In recent years, medical practice has followed two different paradigms: evidence-based medicine (EBM) and values-based medicine (VBM). There is an urgent need to promote medical education that strengthens the relationship between these two paradigms. This work is designed to establish the foundations for a continuing medical education (CME) program aimed at encouraging the dialogue between EBM and VBM by determining the values relevant to everyday medical activities.Methods: A quasi-experimental, observational, comparative, prospective and qualitative study was conducted by analyzing through a concurrent triangulation strategy the correlation between healthcare personnel-patient relationship, healthcare personnel's life history, and ethical judgments regarding dilemmas that arise in daily clinical practice.In 2009, healthcare personnel working in Mexico were invited to participate in a free, online clinical ethics course. Each participant responded to a set of online survey instruments before and after the CME program. Face-to-face semi-structured interviews were conducted with healthcare personnel, focusing on their views and representations of clinical practice.Results: The healthcare personnel's core values were honesty and respect. There were significant differences in the clinical practice axiology before and after the course (P <0.001); notably, autonomy climbed from the 10th (order mean (OM) = 8.00) to the 3rd position (OM = 5.86). In ethical discernment, the CME program had an impact on autonomy (P ≤0.0001). Utilitarian autonomy was reinforced in the participants (P ≤0.0001). Regarding work values, significant differences due to the CME intervention were found in openness to change (OC) (P <0.000), self-transcendence (ST) (P <0.001), and self-enhancement (SE) (P <0.019). Predominant values in life history, ethical discernment and healthcare personnel-patient relation were beneficence, respect and compassion, respectively.Conclusions: The healthcare personnel participating in a CME intervention in clinical ethics improved high-order values: Openness to change (OC) and Self Transcendence (ST), which are essential to fulfilling the healing ends of medicine. The CME intervention strengthened the role of educators and advisors with respect to healthcare personnel. The ethical values developed by healthcare professionals arise from their life history and their professional formation. [ABSTRACT FROM AUTHOR]

We analyze the health normativity for the denomination of non caloric edulcorants in Mexico, and the authorization for the use of natural and synthetic non caloric edulcorants in newborn and until puberty. Special emphasis was given to the consecutive points of safety required in order to assure that they are free of secondary effects. For each non caloric edulcorant available in Mexico, we looked into the studies which mention their side effects in terms of growth and overall. [ABSTRACT FROM AUTHOR]

This is a descriptive review of the elaboration routes, the physical and chemical characteristics, metabolism and clearance, sweetener level, residual flavor, maximal recommended ingestion, security levels and the assessment of growth and development problems in children (from newborns, including prematures, to the end of puberty), of the main no caloric edulcorants used in Mexico. The no caloric edulcorants included in this review are: aspartame, acesulfame-K, sucralose, sacarin, ciclamates, thaumatin, D-tagatose, estevia and alitame. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene–gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The primary congenital hypothyroidism (PCH) persists with alterations in processes cognitive. OBJECTIVE: to evaluate the cognitive functions of children with PCH as a response to a comprehensive transfunctional treatment. MATERIAL AND METHODS: An observational, analytical, prospective and longitudinal study of a 2003-2004 cohort of children with PCH, treated in the Service of Endocrinology and incorporated in a neurodevelopmental follow-up program at the Laboratory of the National Institute of Pediatrics. The cases were assessed using the Wechsler Intelligence Scale for pre-school and primary (WPPSI) at 4, 5 and 6 years. We obtained the total intelligence quotient (IQ), and verbal and executive quotients by direct scores. Standardized and scalar ages of the cognitive processes of attention, memory and conceptualization were also assessed. RESULTS: 32 (71.8% female) patients with PHC, [53% for thyroid agenesis and 47% with thyroid ectopy, on treatment with levothyroxine According to the IQ at the age of four, 12% patients had limited scores that persisted up to 6 years and 12% showed mental deficiency that improved at 6 years. In two-thirds of them the IQ was normal, finding that the IQ of one-third of these patients was normal brilliant or higher, depending on the classification of WPPSI. The auditory memory and conceptualization functions were the most affected regarding the cognitive trajectory. Scalar estimated ages were found lower than the chronological age. Was possible to predict cognitive path up to the 6 years at 4 years. The overall risk factors of the PHC outcomes were thyroid agenesis, delayed onset of treatment and higher hormonal doses. Maternal participation, higher stimulation at home and better socioeconomically condition was considered as protective factors. CONCLUSIONS: The variability of the cognitive evolution in cases with PHC allowed characterizing both the risk and protective factors to define early cognitive intervention in children with PHC. [ABSTRACT FROM AUTHOR]

Human islet amyloid peptide (hIAPP1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A–F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities. [ABSTRACT FROM AUTHOR]

Background: Recent scientific developments, along with growing awareness of cultural and social diversity, have led to a continuously growing range of available treatment options; however, such developments occasionally lead to an undesirable imbalance between science, technology and humanism in clinical practice. This study explores the understanding and practice of values and value clusters in real-life clinical settings, as well as their role in the humanization of medicine and its institutions. The research focuses on the values of clinical practice as a means of finding ways to enhance the pairing of Evidence-Based Medicine (EBM) with Values-based Medicine (VBM) in daily practice. Methods and findings: The views and representations of clinical practice in 15 pre-CME and 15 post-CME interviews were obtained from a random sampling of active healthcare professionals. These views were then identified and qualitatively analyzed using a three-step hermeneutical approach. A clinical values space was identified in which ethical and epistemic values emerge, grow and develop within the biomedical, ethical, and socio-economic dimensions of everyday health care. Three main values—as well as the dynamic clusters and networks that they tend to form—were recognized: healthcare personnel-patient relationships, empathy, and respect. An examination of the interviews suggested that an adequate conceptualization of values leads to the formation of a wider axiological system. The role of clinician-as-consociate emerged as an ideal for achieving medical excellence. Conclusions: By showing the intricate clusters and networks into which values are interwoven, our analysis suggests methods for fine-tuning educational interventions so they can lead to demonstrable changes in attitudes and practices. [ABSTRACT FROM AUTHOR]

The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro, the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aβ17–42 and Aβ16–21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20–29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes. [ABSTRACT FROM AUTHOR]

Background: Dystrophic calcinosis is associated with juvenile dermatomyositis and systemic sclerosis. Clinical diagnosis is performed through the detection of subcutaneous, hard nodules. Conventional radiographic studies may demonstrate calcium deposits, however, with very early lesions X-rays may prove insufficient. There are a few studies where scintilliography has been used to identify dystrophic calcinosis. Objectives: To estimate the frequency of dystrophic calcinosis in patients with juvenile dermatomyositis and systemic sclerosis/CREST syndrome. To estimate the concordance between the diagnoses of dystrophic calcinosis obtained by physical examination and scintigraphy. Patients and Methods: Observational, transversal and comparative study in which patients of both genders, between 5 and 7 years of age with the diagnoses of juvenile dermatomyositis and systemic sclerosis/CREST syndrome were included in order to detect dystrophic calcinosis by physical examination and scintigraphy. Fisher's exact test was used to evaluate the association between both diagnostic methods, Kappa test was used to evaluate the level of concordance between both methods and a distribution by group analysis was used to analyze the extent of dystrophic calcinosis with both methods. Sensitivity and specificity for scintigraphic findings in soft tissues, bony protrusions , ribs and vertebrae was also estimated. Results: The frequency of dystrophic calcinosis was 80%. Dystrophic calcinosis was detected through physical examination in 16 patients and through scintigraphy in 9 patients. No association or concordance was found between the clinical and the scintigraphic findings. Scintigraphy has a 37.5% sensitivity for the detection of dystrophic calcinosis in soft tissues and 43.8% in bony protrusions, but is ideal for its detection in the ribs. Conclusions: Both, physicial examination and scintigraphy are complementary tools for the detection of dystrophic calcinosis. [ABSTRACT FROM AUTHOR]

Introduction: Cardiology is characterized by its state-of-the-art biomedical technology and the predominance of Evidence-Based Medicine. This predominance makes it difficult for healthcare professionals to deal with the ethical dilemmas that emerge in this subspecialty. This paper is a first endeavor to empirically investigate the axiological foundations of the healthcare professionals in a cardiology hospital. Our pilot study selected, as the target population, cardiology personnel not only because of their difficult ethical deliberations but also because of the stringent conditions in which they have to make them. Therefore, there is an urgent need to reconsider clinical ethics and Value-Based Medicine. This study proposes a qualitative analysis of the values and the virtues of healthcare professionals in a cardiology hospital in order to establish how the former impact upon the medical and ethical decisions made by the latter. Results: We point out the need for strengthening the roles of healthcare personnel as educators and guidance counselors in order to meet the ends of medicine, as well as the need for an ethical discernment that is compatible with our results, namely, that the ethical values developed by healthcare professionals stem from their life history as well as their professional education. Conclusion: We establish the kind of actions, communication skills and empathy that are required to build a stronger patient-healthcare professional relationship, which at the same time improves prognosis, treatment efficiency and therapeutic adhesion. [ABSTRACT FROM AUTHOR]

Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug. [Display omitted] • Frequency of L125F MATE1 variant in Mexican population suggests an Amerindian origin. • This is the first pharmacogenetic study in a L125F homozygous individual. • L125F MATE1 has an additive effect on metformin plasma accumulation. • The L125F homozygous patient showed hyperlactatemia after metformin administration. • Molecular dynamics showed that L125F reduces the permeability of the transporter. [ABSTRACT FROM AUTHOR]

Introduction: Cardiology is characterized by its state-of-the-art biomedical technology and the predominance of Evidence-Based Medicine. This predominance makes it difficult for healthcare professionals to deal with the ethical dilemmas that emerge in this subspecialty. This paper is a first endeavor to empirically investigate the axiological foundations of the healthcare professionals in a cardiology hospital. Our pilot study selected, as the target population, cardiology personnel not only because of their difficult ethical deliberations but also because of the stringent conditions in which they have to make them. Therefore, there is an urgent need to reconsider clinical ethics and Value-Based Medicine. This study proposes a qualitative analysis of the values and the virtues of healthcare professionals in a cardiology hospital in order to establish how the former impact upon the medical and ethical decisions made by the latter.Results: We point out the need for strengthening the roles of healthcare personnel as educators and guidance counselors in order to meet the ends of medicine, as well as the need for an ethical discernment that is compatible with our results, namely, that the ethical values developed by healthcare professionals stem from their life history as well as their professional education.Conclusion: We establish the kind of actions, communication skills and empathy that are required to build a stronger patient-healthcare professional relationship, which at the same time improves prognosis, treatment efficiency and therapeutic adhesion. [ABSTRACT FROM AUTHOR]