Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3-7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8-10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10-14, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy15,16. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

Automated assays for trace elements and ferritin measurement in saliva of pigs: Analytical validation and a pilot application to evaluate different iron status.

The aim of this study was to validate automated methods to measure iron (Fe), zinc (Zn), copper (Cu) and ferritin in pig saliva samples. A complete analytical validation was performed of all assays. In addition, these methods were applied to saliva of Fe supplemented (n = 22) and non-supplemented (n = 20) piglets. All assays were able to measure these biomarkers in pig saliva with adequate precision, accuracy and high sensitivity and, in case of trace elements without needing a deproteinization pre-process. The group of piglets supplemented with Fe presented significantly higher levels of ferritin and Zn in saliva. In conclusion, the automated assays evaluated were able to measure Fe, Zn, Cu and ferritin in saliva of pigs, and in case of trace elements, they have the advantage of not needing a deproteinization pre-treatment and thus these analytes can be measured in a simple and fast manner.

The impacts of changing climate and streamflow on nutrient speciation in a large Prairie reservoir.

Climate mediated warming water temperature, drought and extreme flooding are projected to shift the phenology of nutrients in receiving lakes and reservoirs further intensifying eutrophication and algal blooms, especially in temperate reservoirs. An emerging issue in reservoir management is the prediction of climate change impacts, a necessity for sound decision making and sustainable management. Lake Diefenbaker is a large multipurpose reservoir in the Canadian Prairies. In this study, the impact of climate change on nutrient speciation in Lake Diefenbaker is examined using loosely linked SpAtially Referenced Regression On Watershed attributes (SPARROW) and CE-QUAL-W2 models. Two climate mediated scenarios, RCP 8.5 representing the most extreme climate change, and climate induced streamflow were modelled. Nutrient levels are anticipated to double under the climate change and streamflow scenarios. Winter and spring were identified as hot moments for nitrogen pollution with a plausible saturation of nitrous oxides in the future. Of concern is a plausible recycling of nitrate through dissimilatory nitrate reduction to ammonium. Summer and fall on the other hand represent the period for phosphorus enrichment and internal loading with a probable succession of cyanobacteria in the summer.

Gestational vitamin D and offspring risk of multiple sclerosis: a systematic review and meta-analysis.

PURPOSE: Our objective was to systematically review and meta-analyze studies that assessed the association between gestational vitamin D levels and risk of multiple sclerosis (MS) in offspring. METHODS: Embase and Pubmed databases were searched from inception to May 2018. Original, observational studies that investigated both clinically defined MS (in offspring) and vitamin D levels in utero or shortly after birth were included. Two reviewers independently abstracted data and assessed the quality of studies using the Newcastle-Ottawa Quality Assessment Scale. Summary effect estimates and 95% confidence intervals were calculated with random effects models using inverse variance weighting. Determinants of heterogeneity were evaluated. RESULTS: Four case-control studies of moderate to low risk of bias were included. Summary effect estimates of the effect of higher levels of gestational vitamin D on risk of offspring MS demonstrated a significant protective effect in random effects (OR: 0.63, 95% CI: 0.47, 0.84) models and in a stratified analysis based on study quality. Factors identified as determinants of heterogeneity were the definitions of vitamin D deficiency, the characteristics of study participants, and the quality of the study. CONCLUSIONS: Sufficient levels of vitamin D during pregnancy may be protective against offspring's development of multiple sclerosis later in life.

Antitumoral gene-based strategy involving nitric oxide synthase type III overexpression in hepatocellular carcinoma.

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoblastoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. The first-generation adenoviruses were designed to overexpress NOS-3 or green fluorescent protein, and luciferase complementary DNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenovirus and Hepa 1-6 cells were used for in vitro and in vivo experiments. Adenoviruses were administered through the tail vein 2 weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8, -9 and -3 activities in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by Nω-nitro-l-arginine methyl ester hydrochloride, p53 and CD95 small interfering RNA. AFP-NOS-3/RSV-luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

Actividad bactericida de extractos acuosos de Lippia alba (Mill.) N.E. Brown contra Helicobacter pylori / Antibacterial activity of aqueous extracts of Lippia alba (Mill.) N.E. Brown against Helicobacter pylori

Lippia alba (Mill) N.E. Brown es una planta medicinal conocida en Colombia como "prontoalivio" y que se emplea para el tratamiento de múltiples dolencias gastrointestinales. El aceite esencial, los extractos acuosos y alcohólicos obtenidos de la planta han mostrado poder antibacteriano, antiviral, antiparasitario y antimicótico. En el presente estudio, se determinó el efecto antibacteriano in vitro del extracto acuoso de las hojas de Lippia alba contra tres aislados de Helicobacter pylori. Se requieren estudios adicionales que permitan establecer el potencial uso clínico del extracto acuoso en combinación con los tratamientos antibióticos.

Lippia alba (Mill) N.E. Brown is a medicinal plant known in Colombia as "prontoalivio" (= fast relief). It is used for the treatment of multiple gastro-intestinal ailments. The essential oil, the aqueous and alcoholic extracts obtained from the plant have demonstrated antibacterial, antiviral, anti-parasitic and antimycotic power. In the current in vitro study of the aqueous extracts from Lippia alba leaves against three isolated Helicobacter pylori cultures, it was determined that there was an antibacterial effect. There are needed additional studies that allow to establish the potential clinical use of the aqueous extracts in combination with the antibiotic treatment.

Impact of empiric antimicrobial therapy on outcomes in patients with Escherichia coli and Klebsiella pneumoniae bacteremia: a cohort study.

BACKGROUND: It is unclear whether appropriate empiric antimicrobial therapy improves outcomes in patients with bacteremia due to Escherichia coli or Klebsiella. The objective of this study is to assess the impact of appropriate empiric antimicrobial therapy on in-hospital mortality and post-infection length of stay in patients with Escherichia coli or Klebsiella bacteremia while adjusting for important confounding variables. METHODS: We performed a retrospective cohort study of adult patients with a positive blood culture for E. coli or Klebsiella between January 1, 2001 and June 8, 2005 and compared in-hospital mortality and post-infection length of stay between subjects who received appropriate and inappropriate empiric antimicrobial therapy. Empiric therapy was defined as the receipt of an antimicrobial agent between 8 hours before and 24 hours after the index blood culture was drawn and was considered appropriate if it included antimicrobials to which the specific isolate displayed in vitro susceptibility. Data were collected electronically and through chart review. Survival analysis was used to statistically assess the association between empiric antimicrobial therapy and outcome (mortality or length of stay). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Among 416 episodes of bacteremia, 305 (73.3%) patients received appropriate empiric antimicrobial therapy. Seventy-one (17%) patients died before discharge from the hospital. The receipt of appropriate antimicrobial agents was more common in hospital survivors than in those who died (p = 0.04). After controlling for confounding variables, there was no association between the receipt of appropriate empiric antimicrobial therapy and in-hospital mortality (HR, 1.03; 95% CI, 0.60 to 1.78). The median post-infection length of stay was 7 days. The receipt of appropriate antimicrobial agents was not associated with shortened post-infection length of stay, even after controlling for confounding (HR, 1.11; 95% CI 0.86 to 1.44). CONCLUSION: Appropriate empiric antimicrobial therapy for E. coli and Klebsiella bacteremia is not associated with lower in-hospital mortality or shortened post-infection length of stay. This suggests that the choice of empiric antimicrobial agents may not improve outcomes and also provides data to support a randomized trial to test the hypothesis that use (and overuse) of broad-spectrum antibiotics prior to the availability of culture results is not warranted.

Dialysis outcomes in Colombia (DOC) study: a comparison of patient survival on peritoneal dialysis vs hemodialysis in Colombia.

The goal of the Dialysis Outcomes in Colombia (DOC) study was to compare the survival of patients on hemodialysis (HD) vs peritoneal dialysis (PD) in a network of renal units in Colombia. The DOC study examined a historical cohort of incident patients starting dialysis therapy between 1 January 2001 and 1 December 2003 and followed until 1 December 2005, measuring demographic, socioeconomic, and clinical variables. Only patients older than 18 years were included. As-treated and intention-to-treat statistical analyses were performed using the Kaplan-Meier method and Cox proportional hazard model. There were 1094 eligible patients in total and 923 were actually enrolled: 47.3% started HD therapy and 52.7% started PD therapy. Of the patients studied, 751 (81.3%) remained in their initial therapy until the end of the follow-up period, death, or censorship. Age, sex, weight, height, body mass index, creatinine, calcium, and Subjective Global Assessment (SGA) variables did not show statistically significant differences between the two treatment groups. Diabetes, socioeconomic level, educational level, phosphorus, Charlson Co-morbidity Index, and cardiovascular history did show a difference, and were less favorable for patients on PD. Residual renal function was greater for PD patients. Also, there were differences in the median survival time between groups: 27.2 months for PD vs 23.1 months for HD (P=0.001) by the intention-to-treat approach; and 24.5 months for PD vs 16.7 months for HD (P<0.001) by the as-treated approach. When performing univariate Cox analyses using the intention-to-treat approach, associations were with age > or =65 years (hazard ratio (HR)=2.21; confidence interval (CI) 95% (1.77-2.755); P<0.001); history of cardiovascular disease (HR=1.96; CI 95% (1.58-2.90); P<0.001); diabetes (HR=2.34; CI 95% (1.88-2.90); P<0.001); and SGA (mild or moderate-severe malnutrition) (HR=1.47; CI 95% (1.17-1.79); P=0.001); but no association was found with gender (HR=1.03, CI 95% 0.83-1.27; P=0.786). Similar results were found with the as-treated approach, with additional associations found with Charlson Index (0-2) (HR=0.29; Cl 95% (0.22-0.38); P<0.001); Charlson Index (3-4) (HR=0.61; Cl 95% (0.48-0.79); P<0.001); and SGA (mild-severe malnutrition) (HR=1.43; Cl 95% (1.15-1.77); P<0.001). Similarly, the multivariate Cox model was run with the variables that had shown association in previous analyses, and it was found that the variables explaining the survival of patients with end-stage renal disease in our study were age, SGA, Charlson Comorbidity Index 5 and above, diabetes, healthcare regimes I and II, and socioeconomic level 2. The results of Cox proportional risk model in both the as-treated and intention-to-treat analyses showed that there were no statistically significant differences in survival of PD and HD patients: intention-to-treat HD/PD (HR 1.127; CI 95%: 0.855-1.484) and as-treated HD/PD (HR 1.231; CI 95%: 0.976-1.553). In this historical cohort of incident patients, there was a trend, although not statistically significant, for a higher (12.7%) adjusted mortality risk associated with HD when compared to PD, even though the PD patients were poorer, were more likely to be diabetic, and had higher co-morbidity scores than the HD patients. The variables that most influenced survival were age, diabetes, comorbidity, healthcare regime, socioeconomic level, nutrition, and education.

Reflexiones para considerar en una política pública de salud para las personas mayores: Thoughts for action / Health policies for older adults: Thoughts for action

The speed of growth of the population of older adults has been much faster than expected in every country. In Chile today one out of ten persons is an older adult and in the next twenty years this proportion will duplicate. Population aging is a success of development but also presents a medical and social challenge. The health issues of the National Policy addressing the needs of the older population in Chile are severely delayed in their implementation due to the lack of human resources trained in medicine of older adults and geriatric services. The consensus evidence on how to develop appropriate geriatric health services for older adults should include services coordinated in a continuum, including health promotion and disease prevention targeting older people to achieve "healthy aging" in the majority of the older population; outpatient health care services; acute care in hospitals with physicians trained in geriatrics; special services for geriatric rehabilitation and restoration of function (short term care) and a variety of settings and services offering long term care ranging from home to institutions. To be able to implement this vision of appropriate, coordinated and integrated health and social services for older people, the country needs a minimum number of geriatricians (at least 260), health care teams trained in the basics of geriatrics and continuing development of human resources to meet the increasing demand on health services by the fast growing older population.

Estimulaçäo elétrica nervosa transcutânea no controle da dor pós-laparotomia: estudo preliminar / Post-laparotomy pain control by transcutaneous eletrical nerve stimulation: preliminary report

A dor é um problema freqüente dos quadros pós-operatórios. O objetivo foi introduzir, de forma controlada, um programa de TENS para verificar a efetividade no alívio da dor aguda pós-laparotomia, observando a reduçäo da demanda de analgésicos, o índice de dor presente, a permanência do paciente no hospital e suas atividades no leito e as complicaçös pós-operatórias. Pacientes submetidos a laparotomia foram distribuídos num grupo controle (n = 31) que recebeu apenas analgésicos convencionais, e num grupo experimental (n = 31) que recebeu estimulaçäo transcutânea e analgésicas quando necessário. O programa de TENS incluiu: disposiçäo pericicatricial e cruzada dos eletrodos, início da estimulaçäo quando o paciente relatava dor, ajuste da intensidade conforme sensaçäo do paciente, estimulaçäo contínua por 17 h em média, avaliaçäo subjetiva da intensidade da dor (escala de 0 a 10) e registro diário dos dados em ficha padräo. O grupo experimental apresentou uma reduçäo de 63% na quantidade de analgésicos requisitados e 22% na queixa de dor. Os melhores resultados foram alcançados nas histerectomias e os piores nas gastrectomias. O tempo de permanência hospitalar e as atividades no leito näo foram diferentes para os dois grupos. Nenhuma complicaçäo foi observada em ambos os grupos. Subjetivamente avaliou-se que a TENS teve importante papel na reduçäo da quantidade de analgésicos, em cerca de 50% do grupo experimental. Embora os resultados sejam encorajadores, os autores acreditam que estudos posteriores devam ser realizados