To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory ...flows in endotoxic shock.
Animal experimental study.
University translational research laboratory.
Fifteen Landrace pigs.
Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance.
Hypotension was significantly shorter in i-NE group (7.5 min 5.5-22.0 min vs 49.3 min 29.5-60.0 min; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively).
In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment.
We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and ...explored potential genetic and epigenetic mechanisms involved.
β-Catenin gene expression and nuclear levels were analyzed by real time PCR and confocal immunofluorescence. Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99±4 units vs. 76±12, p=0.01, n=10), without differences in gene transcription, which is consistent with a post-translational down-regulation of β-catenin and decreased Wnt pathway activity.
Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 patients. The genotypic frequencies were similar in both groups of patients, with no significant differences.
Methylation of Wnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteoarthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down-regulated other 16 genes.
In conclusion, Wnt activity is reduced in patients with hip fractures, in comparison with those with osteoarthritis. It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other hand, methylation differences between both groups could contribute to explain the differences in Wnt activity.
•Wnt pathway plays a critical role in bone homeostasis.•Nuclear β-catenin is higher in cells from osteoarthritis than in osteoporosis.•Some Wnt-related genes are differentially methylated in both disorders.•DNA demethylation modulated the expression of several genes.•DNA methylation may participate in the pathogenesis of skeletal disorders.
Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as ...promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with "high" expression levels of CCN2 had higher overall survival than those with "low" levels (
= 0.042), and this gene might be an independent prognostic biomarker in pediatric B-ALL. These findings provide one of the first detailed descriptions of lncRNA expression profiles in pediatric B-ALL and indicate that these potential biomarkers could help in the classification of leukemia subtypes and that CCN2 expression could predict the survival outcome of pediatric B-cell acute lymphoblastic leukemia patients.
Genes explaining the susceptibility to osteoporosis have not been fully elucidated. Our objective was to explore the association of polymorphisms capturing common variations of the lipoprotein ...receptor-related protein (LRP) 5 and 6 genes, encoding two Wnt receptors, with femoral neck bone mineral density (BMD) and osteoporotic fractures of the spine and the hip.
Cross-sectional, case-control, and replication genetic association study.
Thirty-nine tagging and functional single nucleotide polymorphisms (SNPs) were analyzed in a group of 1043 postmenopausal women and 394 women with hip fractures. The results were replicated in a different group of 342 women.
Three SNPs of the LRP6 gene were associated with BMD (nominal uncorrected P values <0.05) in the discovery cohort. One showed a significant association after multiple test correction; two of them were also associated in the replication cohort, with a combined standardized mean difference of 0.51 (P=0.009) and 0.47 (P<0.003) across rs11054704 and rs2302685 genotypes. In the discovery cohort, several LRP5 SNPs were associated with vertebral fractures (odds ratio (OR) 0.67; P=0.01), with hip fractures (unadjusted ORs between 0.59 and 1.21; P=0.005-0.033, but not significant after multiple test adjustment or age adjustment), and with height and the projected femoral neck area, but not with BMD. Transcripts of LRP5 and LRP6 were similarly abundant in bone samples.
In this study, we found common polymorphisms of LRP5 associated with osteoporotic fractures, and polymorphisms of the LRP6 gene associated with BMD, thus suggesting them as likely candidates to contribute to the explaination of the hereditary influence on osteoporosis.
Plants are a source of multiple antineoplastic treatments. However, the effect of many species used in traditional medicine has yet to be demonstrated. In this work, the taxonomic identification of ...Agave mapisagawas made and a high-performance liquid chromatography-mass spectrometry (HPLC-MS) study suggested the presence of the aglycone hecogenin, which is part of compounds such as agavoside C and cantalasaponin 4. The antineoplastic activity of an aqueous extract was tested in vitroand in vivoon PEC-Src epithelial murine prostate cancer cells. In vitrostudy revelead a significant chemosensivity at 0.125mg/100μL(p=0.0001). Also, in in vivo, using an isotransplantation model with 1x106cells subcutaneously, it was observed that the group treated with 50 mg/kg presented a lower tumor implantation compared with the control without treatment (p=0.04).
To achieve WHO's goal of eliminating hepatitis C virus (HCV), innovative strategies must be designed to diagnose and treat more patients. Therefore, we aimed to describe an implementation strategy to ...identify patients with HCV who were lost to follow‐up (LTFU) and offer them re‐linkage to HCV care. We conducted an implementation study utilizing a strategy to contact patients with HCV who were not under regular follow‐up in 13 countries from Latin America. Patients with HCV were identified by the international classification of diseases (ICD‐9/10) or equivalent. Medical records were then reviewed to confirm the diagnosis of chronic HCV infection defined by anti‐HCV+ and detectable HCV‐RNA. Identified patients who were not under follow‐up by a liver specialist were contacted by telephone or email, and offered a medical reevaluation. A total of 10,364 patients were classified to have HCV. After reviewing their medical charts, 1349 (13%) had undetectable HCV‐RNA or were wrongly coded. Overall, 9015 (86.9%) individuals were identified with chronic HCV infection. A total of 5096 (56.5%) patients were under routine HCV care and 3919 (43.5%) had been LTFU. We were able to contact 1617 (41.3%) of the 3919 patients who were LTFU at the primary medical institution, of which 427 (26.4%) were cured at a different institutions or were dead. Of the remaining patients, 906 (76.1%) were candidates for retrieval. In our cohort, about one out of four patients with chronic HCV who were LTFU were candidates to receive treatment. This strategy has the potential to be effective, accessible and significantly impacts on the HCV care cascade.
To examine homicide rates in Cali, Colombia, during the 1993-2018 period, using information derived from an interagency surveillance system.
We used homicide data from Cali's Epidemiological ...Surveillance System to examine homicide trends by victim's age and sex, time, and type of method used. We estimated trend changes and the annual percentage changes using joinpoint regression analyses.
Homicide rates per 100 000 inhabitants dropped from 102 in 1993 to 47.8 in 2018. We observed reductions in homicide rates across age and sex groups. Most homicide victims were men aged 20 to 39 years from poor, marginalized areas. Firearms were used in 84.9% of all cases. The average annual percentage change for the entire period was -3.6 (95% confidence interval = -6.7, -0.4).
Fluctuations in homicide rates in Cali show a clear epidemic pattern, occurring concurrently with the "crack epidemic" in different countries. Reliable and timely information provided by an Epidemiological Surveillance System allowed opportune formulation of public policies to reduce the impact of violence in Cali.
After a study of ICA prevalence among relatives of Type-1 diabetics (DM1) in Santiago, Chile, parents of those who tested positive asked us to go on forward with an intervention study.
We had ...screened 1021 relatives, of which 30 had shown ICA
≥
20
JDF units (2.9%). Among the 26/30 who participated in the intervention study, the baseline screening showed normal glucose tolerance in all, and the first-phase insulin response (FPIR) was normal in 24/26 individuals, which were randomized into Nicotinamide (
n
=
12; oral Nicotinamide, 1200
mg
m
−2
day
−1) and Placebo (
n
=
12) groups. The FPIRs and ICAs were monitored yearly. Compliance was monitored by urine Nicotinamide.
The 1.5, 3.0 and 5-year life-table estimates of keeping the FPIR
≥
10th centile were, for Nicotinamide group 100% in all time points, and for Placebo these were 90.0% (c.i.
=
100–71.4), 72.0% (c.i.
=
100–37.1) and 0.0% (c.i.
=
0.0–0.0) (
p
=
0.0091). The 5-year life-table estimates of remaining diabetes-free were 100% for Nicotinamide and 62.5% for Placebo (
p
=
0.0483). No adverse effects were observed.
Oral Nicotinamide protected beta-cell function and prevented clinical disease in ICA-positive first-degree relatives of type-1 diabetes.
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