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To better understand the energetic status of proliferating cells, we have measured the intracellular pH (pHi) and concentrations of key metabolites, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) in normal and cancer cells, extracted from fresh human colon tissues. Cells were sorted by elutriation and segregated in different phases of the cell cycle (G0/G1/S/G2/M) in order to study their redox (NAD, NADP) and bioenergetic (ATP, pHi) status. Our results show that the average ATP concentration over the cell cycle is higher and the pHi is globally more acidic in normal proliferating cells. The NAD+/NADH and NADP+/NADPH redox ratios are, respectively, five times and ten times higher in cancer cells compared to the normal cell population. These energetic differences in normal and cancer cells may explain the well-described mechanisms behind the Warburg effect. Oscillations in ATP concentration, pHi, NAD+/NADH, and NADP+/NADPH ratios over one cell cycle are reported and the hypothesis addressed. We also investigated the mitochondrial membrane potential (MMP) of human and mice normal and cancer cell lines. A drastic decrease of the MMP is reported in cancer cell lines compared to their normal counterparts. Altogether, these results strongly support the high throughput aerobic glycolysis, or Warburg effect, observed in cancer cells.

Sleep changes have been associated with increased risks of developing cognitive disturbances and Alzheimer's disease (AD). A bidirectional relation is underlined between amyloid-beta (Aß) and sleep disruptions. The sleep profile in participants at risk to develop AD is not fully deciphered. We aim to investigate sleep-wake changes with objective sleep measurements in elderly participants without cognitive impairment depending on their brain amyloid status, positive (Aß+) or negative (Aß-) based on standard absorption ratios (SUVr) positron emission tomography-florbetapir imaging. Sixty-eight participants without cognitive impairment who have accepted to be involved in the sleep ancillary study from the InveStIGation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-pre AD) cohort, aiming to record sleep profile based on the analyses of an ambulatory accelerometer-based assessment (seven consecutive 24-hour periods). Neuropsychological tests were performed and sleep parameters have been individualized by actigraph. Participants also underwent a magnetic resonance imaging scan to assess their hippocampal volume. Based on SUVr PET-florbetapir imaging, two groups Aß+ and Aß- were compared. Participants were divided into two groups: Aß+ (n = 24) and Aß- (n = 44). Except for the SUVr, the two subgroups were comparable. When looking to sleep parameters, increased sleep latency, sleep fragmentation (wake after sleep onset [WASO] score and awakenings) and worst sleep efficiency were associated with cortical brain amyloid load. Actigraphic sleep parameters were associated with cortical brain amyloid load in participants at risk to develop AD. The detection of sleep abnormalities in those participants may be of interest to propose some preventive strategies.

The different phases of the eukaryotic cell cycle are exceptionally well-preserved phenomena. DNA decompaction, RNA and protein synthesis (in late G 1 phase) followed by DNA replication (in S phase) and lipid synthesis (in G 2 phase) occur after resting cells (in G 0 ) are committed to proliferate. The G 1 phase of the cell cycle is characterized by an increase in the glycolytic metabolism, sustained by high NAD + /NADH ratio. A transient cytosolic acidification occurs, probably due to lactic acid synthesis or ATP hydrolysis, followed by cytosolic alkalinization. A hyperpolarized transmembrane potential is also observed, as result of sodium/potassium pump (NaK-ATPase) activity. During progression of the cell cycle, the Pentose Phosphate Pathway (PPP) is activated by increased NADP + /NADPH ratio, converting glucose 6-phosphate to nucleotide precursors. Then, nucleic acid synthesis and DNA replication occur in S phase. Along with S phase, unpublished results show a cytosolic acidification, probably the result of glutaminolysis occurring during this phase. In G 2 phase there is a decrease in NADPH concentration (used for membrane lipid synthesis) and a cytoplasmic alkalinization occurs. Mitochondria hyperfusion matches the cytosolic acidification at late G 1 /S transition and then triggers ATP synthesis by oxidative phosphorylation. We hypothesize here that the cytosolic pH may coordinate mitochondrial activity and thus the different redox cycles, which in turn control the cell metabolism.

Doc number: 127 Abstract Background: Enzymatic hydrolysis is a crucial step of biomass conversion into biofuels and different pretreatments have been proposed to improve the process efficiency. Amongst the various factors affecting hydrolysis yields of biomass samples, porosity and water accessibility stand out due to their intimate relation with enzymes accessibility to the cellulose and hemicellulose fractions of the biomass. In this work, sugarcane bagasse was subjected to acid and alkali pretreatments. The changes in the total surface area, hydrophilicity, porosity and water accessibility of cellulose were investigated by scanning electron microscopy (SEM) and nuclear magnetic resonance (NMR). Results: Changes in chemical and physical properties of the samples, caused by the partial removal of hemicellulose and lignin, led to the increase in porosity of the cell walls and unwinding of the cellulose bundles, as observed by SEM. 1 H NMR relaxation data revealed the existence of water molecules occupying the cores of wide and narrow vessels as well as the cell wall internal structure. Upon drying, the water molecules associated with the structure of the cell wall did not undergo significant dynamical and partial moisture changes, while those located in the cores of wide and narrow vessels kept continuously evaporating until reaching approximately 20% of relative humidity. This indicates that water is first removed from the cores of lumens and, in the dry sample, the only remaining water molecules are those bound to the cell walls. The stronger interaction of water with pretreated bagasse is consistent with better enzymes accessibility to cellulose and higher efficiency of the enzymatic hydrolysis. Conclusions: We were able to identify that sugarcane bagasse modification under acid and basic pretreatments change the water accessibility to different sites of the sample, associated with both bagasse structure (lumens and cell walls) and hydrophilicity (lignin removal). Furthermore, we show that the substrates with increased water accessibility correspond to those with higher hydrolysis yields and that there is a correlation between experimentally NMR-measured transverse relaxation times and the efficiency of enzymatic hydrolysis. This might allow for semiquantitative estimates of the enzymatic hydrolysis efficiency of biomass samples using inexpensive and non-destructive low-field 1 H NMR relaxometry methods.

Background The treatment of refractory status epilepticus (RSE) remains largely empirical. Lacosamide (LCM) is a new anticonvulsant available in intravenous (IV) form, but its optimal dosing regimen for the treatment of RSE is unknown. We compared safety and efficacy of two loading doses: 200 and 400 mg. Methods Prospective observational study of all patients who received IV LCM for RSE or seizure clusters between October 2010 and December 2012. A first group received an IV load of 200 mg of LCM. After the initial part of the study, and due to poor results with this dosage, a second group received a loading dose of 400 mg. Outcome measures included response rate, time to response, and adverse events. Results There was a trend in favor of a higher response rate to LCM in the 400 mg group [7/14 (50 %) vs. 2/11 (18 %), respectively; p  = 0.2]. Early responses (occurring within 3 h of initiation of LCM) were significantly more frequent in the 400 mg group [4/14 (28 %) vs. 0/11 (0 %); p  = 0.026]. Overall, 9/25 patients (36 %) responded to LCM and seizures were terminated in eight more patients (32 %), by adding other anticonvulsants. The following adverse events were attributed to LCM: myoclonus and confusion, increase in seizure frequency, vertigo, ataxia, and an asymptomatic increase in liver enzymes level. All occurred in the 200 mg group. No skin rash, renal, cardiac, or hemodynamic side effects were observed in any group. Conclusions In this small prospective observational study, an initial dose of 400 mg of IV LCM was associated with a higher proportion of early termination of RSE and with a trend toward a higher response rate.

Studies investigating the association between functional capacity and quality of life (QoL) in individuals with chronic Chagas cardiomyopathy (CCC) usually do not include a gold-standard evaluation of functional capacity, limiting the validity and the interpretation of the results. The present study is a cross-section analysis aiming to evaluate the association between functional capacity (quantified by cardiopulmonary exercise test [CPET]) and QoL in individuals with CCC. QoL was assessed using the SF-36 questionnaire. Sociodemographic, anthropometric, clinical, cardiac function and maximal progressive CPET variables were obtained from PEACH study. Generalized linear models adjusted for age, sex, and left ventricular ejection fraction were performed to evaluate the association between CPET variables and QoL. After adjustments, VO 2 peak and VO 2 AT were both associated with physical functioning (β = +0.05 and β = +0.05, respectively) and physical component summary (β = +0.03 and β = +0.03, respectively). Double product was associated with physical functioning (β = +0.003), general health perceptions (β = +0.003), physical component summary (β = +0.002), and vitality (β = +0.004). HRR≤12bpm was associated with physical functioning (β = -0.32), role limitations due to physical problems (β = -0.87), bodily pain (β = -0.26), physical component summary (β = -0.21), vitality (β = -0.38), and mental health (β = -0.19). VE/VCO 2 slope presented association with all mental scales of SF-36: vitality (β = -0.028), social functioning (β = -0.024), role limitations due to emotional problems (β = -0.06), mental health (β = -0.04), and mental component summary (β = -0.02). The associations between CPET variables and QoL demonstrate the importance of CPET inclusion for a more comprehensive evaluation of individuals with CCC. In this setting, intervention strategies aiming to improve functional capacity may also promote additional benefits on QoL and should be incorporated as a treatment strategy for patients with CCC.

Purpose To evaluate the results of combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction in patients with chronic ACL injury. It was hypothesized that patients who underwent combined ACL and ALL reconstruction would exhibit less residual laxity and better clinical outcomes. Methods Two groups of patients were evaluated and compared retrospectively. Both groups consisted only of patients with chronic (more than 12 months) ACL injuries. Patients in group 1 underwent anatomical intra-articular reconstruction of the ACL and patients in group 2 underwent anatomic intra-articular ACL reconstruction combined with ALL reconstruction. The presence of associated meniscal injury, the subjective International Knee Documentation Committee (IKDC) and Lysholm functional outcome scores in the postoperative period, KT-1000 evaluation, the presence of residual pivot shift and graft rupture rate were evaluated. Results One hundred and one patients who underwent reconstruction of chronic ACL injuries were evaluated. The median follow-up was 26 (24–29) months for group 1 and 25 (24–28) months for group 2. There were no significant differences between groups regarding gender, age, duration of injury until reconstruction, follow-up time or presence of associated meniscal injuries in the preoperative period. Regarding functional outcome scores, patients in group 2 presented better results on both the IKDC ( p  = 0.0013) and the Lysholm ( p  < 0.0001) evaluations. In addition, patients in group 2 had better KT-1000 evaluation ( p  = 0.048) and a lower pivot shift rate at physical examination, presenting only 9.1% positivity versus 35.3% in the isolated ACL reconstruction ( p  = 0.011). Regarding re-ruptures, group 1 presented 5 (7.3%) cases, and group 2 presented no cases. Conclusion The combined ACL and ALL reconstruction in patients with chronic ACL injury is an effective and safety solution and leads to good functional outcomes with no increase in complication rate. The clinical relevance of this finding is the possibility to indicate this type of procedure when patients present with more than 12 months after injury for surgery. Level of evidence Level III.

The increase in life expectancy and the migration of individuals with Chagas disease (ChD) from rural to urban centers exposes them to the development of chronic-degenerative abnormalities that may increase the prevalence of metabolic syndrome (MetS). The present study aimed to identify the prevalence of MetS and its components in individuals with chronic ChD. This is a cross-sectional study with 361 patients of both sexes, aging >18 years, followed at a national reference center (Rio de Janeiro, Brazil). MetS diagnosis followed the International Diabetes Federation 2005 criteria. The association between the variables was determined through logistic regression models. The mean age was and 60.7±10.8 years. About half (56.2%) were female and the majority self-reported their race as mulatto (59.8%). The percentage of individuals with MetS was 40.4%. The variables independently associated with MetS were age (OR 1.06; 95%CI 1.04–1.09), high education levels (OR 0.36; 95%CI 0.17–0.79) and cardiac form with heart failure (OR 0.34; 95%CI 0.17–0.68). Therefore, a high prevalence of MetS was found in this Brazilian chronic ChD cohort. The identification of the associated factors can facilitate the development of effective approaches for preventing and managing MetS in ChD patients.

This study assessed the prevalence of food insecurity (FI) in patients with Chagas Disease (CD) and its association with anthropometric measurements, comorbidities, and quality of life (QoL). This cross-sectional study included CD patients of both sexes. The FI was evaluated using the Brazilian FI scale. Anthropometric measurements included weight, height, and waist circumference. Comorbidities included hypertension, diabetes, dyslipidemia, and obesity. Lipids and plasma glucose were collected. QoL was assessed using the Portuguese version of WHOQOL-Bref questionnaire. Linear and logistic regression models were fitted to evaluate the association between FI status and outcomes. From the 359 included participants (55.9% women, median age 62 years), 22.5% had mild, 5.6% moderate, and 2.5% had severe FI. In the adjusted models, mild FI was significantly associated with an increased odds of obesity (OR=1.83, 95%CI = 1.03 to 3.25). Moreover, significant associations were observed between FI and all QoL domains, including physical health (low FI: β = −8.43 95%CI −12.36 to −4.49; moderate/severe FI: β = −8.02 95%CI −14.11 to −1.94), psychological (low FI β = −5.54 95%CI −9.11 to −1.96; moderate/severe FI β = −7.22 95%CI −12.76 to −1.68), social relationship (low FI: β = −6.62 95%CI −10.37 to −2.88), environment (low FI: β = −8.79 95%CI −11.99 to −5.60; moderate/severe FI β = −13.56 95%CI −18.51 to −8.62), and overall (low FI β = −8.10 95%CI −12.15 to −4.06; moderate/severe FI: β = −16.82 95%CI −23.08 to −10.57). FI was consistently associated with poor QoL in patients with chronic CD.

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2), ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7β-ol (3) and ent-7-oxo-pimara-8,15-diene-3β-ol (4), were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line). The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC 50 = 3.5 μ M) and L. donovani (IC 50 = 2.5 μ M) and ent-pimarane 2 against P. falciparum (IC 50 = 3.8 μ M). Both compounds returned high selectivity indices (SI >10) in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5), which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2 μ g/mL).