To evaluate incidence of subclinical and overt hyperthyroidism and hypothyroidism.
The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study of 15,105 civil ...servants, examined at baseline and over a 4-year follow-up. This analysis included 9,705 participants with normal thyroid function at baseline, follow-up information about thyroid function and with no report of using drugs that may interfere in the thyroid function. Thyroid function was defined by TSH/FT4 levels or routine use of thyroid hormones/anti-thyroid medications. Annual and cumulative (over 4-year) incidence rates were presented as percentages (95% Confidence Intervals).
The incidence of all overt and subclinical thyroid disease was 6.7% (1.73%/year): 0.19% for overt hyperthyroidism (0.048%/year), 0.54% for subclinical hyperthyroidism (0.14%/year), 1.98% for overt hypothyroidism (0.51%/year), and 3.99% for subclinical hypothyroidism (1.03%/year). The incidence of all thyroid diseases was higher in women, when compared to men, with a low women:men ratio (1.36). For Blacks the highest incidence was for overt hyperthyroidism, while for Whites, the highest incidence was for overt hypothyroidism. However, the highest incidence of overt hyperthyroidism was detected in Asian descendants. The presence of antithyroperoxidase antibodies at baseline was associated with higher incidence of overt thyroid diseases.
These results showed a high incidence of hypothyroidism, which is compatible with a country with a more-than-adequate iodine intake. The low women:men ratio of the incidence of thyroid dysfunction highlights the importance of the diagnosis of thyroid diseases among men in Brazil.
Background Obesity hypoventilation syndrome (OHS) is associated with a high burden of cardiovascular morbidity (CVM) and mortality. The majority of patients with OHS have concomitant OSA, but there ...is a paucity of data on the association between CVM and OSA severity in patients with OHS. The objective of our study was to assess the association between CVM and OSA severity in a large cohort of patients with OHS. Methods In a cross-sectional analysis, we examined the association between OSA severity based on tertiles of oxygen desaturation index (ODI) and CVM in 302 patients with OHS. Logistic regression models were constructed to quantify the independent association between OSA severity and prevalent CVM after adjusting for various important confounders. Results The prevalence of CVM decreased significantly with increasing severity of OSA based on ODI as a continuous variable or ODI tertiles. This inverse relationship between OSA severity and prevalence of CVM was seen in the highest ODI tertile and it persisted despite adjustment for multiple confounders. Chronic heart failure had the strongest negative association with the highest ODI tertile. No significant CVM risk change was observed between the first and second ODI tertiles. Patients in the highest ODI tertile were younger, predominantly male, more obese, more hypersomnolent, had worse nocturnal and daytime gas exchange, lower prevalence of hypertension, better exercise tolerance, and fewer days hospitalized than patients in the lowest ODI tertile. Conclusions In patients with OHS, the highest OSA severity phenotype was associated with reduced risk of CVM. This finding should guide the design of future clinical trials assessing the impact of interventions aimed at decreasing cardiovascular morbidity and mortality in patients with OHS. Trial Registry Clinicaltrial.gov; No.: NCT01405976 ; URL: www.clinicaltrials.gov
The Body Mass Index (BMI) and Waist Circumference (WC) are well-used anthropometric predictors for cardiovascular diseases (CVD), but their validity is regularly questioned. Recently, A Body Shape ...Index (ABSI) and Body Roundness Index (BRI) were introduced as alternative anthropometric indices that may better reflect health status.
This study assessed the capacity of ABSI and BRI in identifying cardiovascular diseases and cardiovascular disease risk factors and determined whether they are superior to BMI and WC.
4627 Participants (54±12 years) of the Nijmegen Exercise Study completed an online questionnaire concerning CVD health status (defined as history of CVD or CVD risk factors) and anthropometric characteristics. Quintiles of ABSI, BRI, BMI, and WC were used regarding CVD prevalence. Odds ratios (OR), adjusted for age, sex, and smoking, were calculated per anthropometric index.
1332 participants (27.7%) reported presence of CVD or CVD risk factors. The prevalence of CVD increased across quintiles for BMI, ABSI, BRI, and WC. Comparing the lowest with the highest quintile, adjusted OR (95% CI) for CVD were significantly different for BRI 3.2 (1.4-7.2), BMI 2.4 (1.9-3.1), and WC 3.0 (1.6-5.6). The adjusted OR (95% CI) for CVD risk factors was for BRI 2.5 (2.0-3.3), BMI 3.3 (1.6-6.8), and WC 2.0 (1.6-2.5). No association was observed for ABSI in both groups.
BRI, BMI, and WC are able to determine CVD presence, while ABSI is not capable. Nevertheless, the capacity of BRI as a novel body index to identify CVD was not superior compared to established anthropometric indices like BMI and WC.
Background. Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus ...bacteremia, and recent data point to a similar effect on methicillin-susceptible S. aureus bacteremia. We aimed to evaluate the effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin. Methods. We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (<1.5 μg/mL) and high vancomycin MIC (≥1.5 μg/mL). The primary endpoint was in-hospital mortality. Results. We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC < 1.5 μg/mL and 40 (43%) a vancomycin MIC ≥ 1.5 μg/mL. In-hospital mortality was 30% (n = 16/53) in patients with a low vancomycin MIC and 53% (n = 21/40) in those with a high vancomycin MIC (P = .03). No correlation was found between oxacillin MIC and vancomycin or daptomycin MIC. Logistic regression analysis showed that higher vancomycin MIC increased in-hospital mortality 3-fold (odds ratio, 3.1; 95% confidence interval, 1.2–8.2) after adjustment for age, year of diagnosis, septic complications, and nonseptic complicated endocarditis. Conclusions. Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of antibiotics.
Summary Background New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel ...CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. Methods In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3–6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response PR + very good PR + complete response CR + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov , number NCT01985126. Findings The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2–14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29·2%, 95% CI 20·8–38·9)—three (2·8%, 0·6–8·0) had a stringent CR, ten (9·4%, 4·6–16·7) had a very good PR, and 18 (17·0%, 10·4–25·5) had a PR. The median time to first response was 1·0 month (range 0·9–5·6). Median duration of response was 7·4 months (95% CI 5·5–not estimable) and progression-free survival was 3·7 months (95% CI 2·8–4·6). The 12-month overall survival was 64·8% (95% CI 51·2–75·5) and, at a subsequent cutoff, median overall survival was 17·5 months (95% CI 13·7–not estimable). Daratumumab was well tolerated; fatigue (42 40% patients) and anaemia (35 33%) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. Interpretation Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. Funding Janssen Research & Development.
ABSTRACT
In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)‐23. Abnormal regulation of the FGFR1‐Klotho receptor complex may cause a ...resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)‐1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a highphosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti‐FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β‐cateniv together with a reduction in Klotho. Wnt/β‐catenin inhibition with Dkk‐1 prevented the P‐induced down‐regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β‐catenin pathway.—Muñoz‐Castañeda, J. R., Herencia, C., Pendón‐Ruiz de Mier M. V., Rodriguez‐Ortiz, M. E., Diaz‐Tocados, J. M., Vergara, N., Martínez‐Moreno, J. M., Salmerón M. D., Richards, W. G., Felsenfeld, A., Kuro‐O, M., Almadén Y., Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. FASEB J. 31, 3858–3867 (2017). www.fasebj.org—Muñoz‐Castañeda, Juan R., Herencia, Carmen, Pendón‐Ruiz de Mier, Maria Victoria, Rodriguez‐Ortiz, Maria Encarnación, Diaz‐Tocados, Juan M., Vergara, Noemi, Martínez‐Moreno, Julio M., Salmerón, Maria Dolores, Richards, William G., Felsenfeld, Arnold, Kuro‐O, Makoto, Almadén, Yolanda, Rodríguez, Mariano Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. FASEB J. 31, 3858–3867 (2017)
Modulation of lipid metabolism is a well-established cancer hallmark, and SCD1 has been recognized as a key enzyme in promoting cancer cell growth, including in glioblastoma (GBM), the deadliest ...brain tumor and a paradigm of cancer resistance. The central goal of this work was to identify, by MS, the phospholipidome alterations resulting from the silencing of SCD1 in human GBM cells, in order to implement an innovative therapy to fight GBM cell resistance. With this purpose, RNAi technology was employed, and low serum-containing medium was used to mimic nutrient deficiency conditions, at which SCD1 is overexpressed. Besides the expected increase in the saturated to unsaturated fatty acid ratio in SCD1 silenced-GBM cells, a striking increase in polyunsaturated chains, particularly in phosphatidylethanolamine and cardiolipin species, was noticed and tentatively correlated with an increase in autophagy (evidenced by the increase in LC3BII/I ratio). The contribution of autophagy to mitigate the impact of SCD1 silencing on GBM cell viability and growth, whose modest inhibition could be correlated with the maintenance of energetically associated mitochondria, was evidenced by using autophagy inhibitors. In conclusion, SCD1 silencing could constitute an important tool to halt GBM resistance to the available treatments, especially when coupled with a mitochondria disrupter chemotherapeutic.
Pentylenetetrazole (PTZ) is a common convulsant agent used in animal models to investigate the mechanisms of seizures. Although adult zebrafish have been recently used to study epileptic seizures, a ...thorough characterization of the PTZ-induced seizures in this animal model is missing. The goal of this study was to perform a detailed temporal behavior profile characterization of PTZ-induced seizure in adult zebrafish. The behavioral profile during 20 min of PTZ immersion (5, 7.5, 10, and 15 mM) was characterized by stages defined as scores: (0) short swim, (1) increased swimming activity and high frequency of opercular movement, (2) erratic movements, (3) circular movements, (4) clonic seizure-like behavior, (5) fall to the bottom of the tank and tonic seizure-like behavior, (6) death. Animals exposed to distinct PTZ concentrations presented different seizure profiles, intensities and latencies to reach all scores. Only animals immersed into 15 mM PTZ showed an increased time to return to the normal behavior (score 0), after exposure. Total mortality rate at 10 and 15 mM were 33% and 50%, respectively. Considering all behavioral parameters, 5, 7.5, 10, and 15 mM PTZ, induced seizures with low, intermediate, and high severity, respectively. Pretreatment with diazepam (DZP) significantly attenuated seizure severity. Finally, the brain PTZ levels in adult zebrafish immersed into the chemoconvulsant solution at 5 and 10 mM were comparable to those described for the rodent model, with a peak after a 20-min of exposure. The PTZ brain levels observed after 2.5-min PTZ exposure and after 60-min removal from exposure were similar. Altogether, our results showed a detailed temporal behavioral characterization of a PTZ epileptic seizure model in adult zebrafish. These behavioral analyses and the simple method for PTZ quantification could be considered as important tools for future investigations and translational research.
Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be ...electrographic‐only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic‐only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non‐motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.
A direct and practical method for photocatalyzed hydrodecarboxylation of fatty acids is reported herein. The catalytic system consists of a commercially available acridinium salt as the photocatalyst ...and thiophenol as the Hydrogen Atom Transfer (HAT) co-catalyst. Results evidenced that C
n
−1
alkanes were obtained in yields up to 77%. Furthermore, the protocol was employed for a complex mixture of fatty acids bio-derived from a real sample of licuri oil to obtain hydrocarbons in the range of C
9
-C
17
with high selectivity and excellent conversion (>90%). This work provides a powerful strategy for producing drop-in biofuels under mild conditions. Finally, an energetic assessment of our proposed protocol (∼22.9 kW h) reveals the benefit of a sustainable production of renewable hydrocarbons.
A direct and practical method for photocatalyzed hydrodecarboxylation of fatty acids is reported herein.
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