Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.

Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.

A new paradigm for regulation of protein phosphatase 2A function via Src and Fyn kinase-mediated tyrosine phosphorylation.

Protein phosphatase 2A (PP2A) is a major phospho-Ser/Thr phosphatase and a key regulator of cellular signal transduction pathways. While PP2A dysfunction has been linked to human cancer and neurodegenerative disorders such as Alzheimer's disease (AD), PP2A regulation remains relatively poorly understood. It has been reported that the PP2A catalytic subunit (PP2Ac) is inactivated by a single phosphorylation at the Tyr307 residue by tyrosine kinases such as v-Src. However, multiple mass spectrometry studies have revealed the existence of other putative PP2Ac phosphorylation sites in response to activation of Src and Fyn, two major Src family kinases (SFKs). Here, using PP2Ac phosphomutants and novel phosphosite-specific PP2Ac antibodies, we show that cellular pools of PP2Ac are instead phosphorylated on both Tyr127 and Tyr284 upon Src activation, and on Tyr284 following Fyn activation. We found these phosphorylation events enhanced the interaction of PP2Ac with SFKs. In addition, we reveal SFK-mediated phosphorylation of PP2Ac at Y284 promotes dissociation of the regulatory Bα subunit, altering PP2A substrate specificity; the phosphodeficient Y127/284F and Y284F PP2Ac mutants prevented SFK-mediated phosphorylation of Tau at the CP13 (pSer202) epitope, a pathological hallmark of AD, and SFK-dependent activation of ERK, a major growth regulatory kinase upregulated in many cancers. Our findings demonstrate a novel PP2A regulatory mechanism that challenges the existing dogma on the inhibition of PP2A catalytic activity by Tyr307 phosphorylation. We propose dysregulation of SFK signaling in cancer and AD can lead to alterations in PP2A phosphorylation and subsequent deregulation of key PP2A substrates, including ERK and Tau.

Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.

BACKGROUND: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287). PATIENTS AND METHODS: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). RESULTS: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred. CONCLUSIONS: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.

Using a robotic exoskeleton at home: An activity tolerance case study of a child with spinal muscular atrophy.

PURPOSE: Spinal Muscular Atrophy (SMA) Type II is a neurodegenerative disease that leads to progressive muscle weakness. It prevents children from walking and affects their respiratory function and their activity tolerance, among other health problems. We aimed to assess the activity tolerance showed by a child with SMA using a pediatric gait exoskeleton at home when walking and performing activities. DESIGN AND METHODS: This study presents the case of a 6-year-old boy with SMA Type II and respiratory failure who used a pediatric gait exoskeleton at home for a period of two months. A nursing assessment was done before and during the use of the device to evaluate the child's activity tolerance during the sessions. Nursing interviews, performance, vital signs, fatigue, field notes, and functional scales were analyzed. RESULTS: The nursing assessment showed a good activity tolerance of the child. Performance using the device improved over time; vital signs did not vary significantly during the sessions; fatigue perception decreased over time; and the child reached a higher score on some functional outcomes. CONCLUSIONS: A first step has been taken to evaluate the impact of exoskeleton technology in children with SMA Type II from the nursing point of view, exposing the potential of this technology for the care of children with neuromuscular diseases, and the need for more research on the topic. PRACTICE IMPLICATIONS: The information in this study will be useful to nurses to know the effects of gait exoskeletons in pediatric care of children with neuromuscular diseases like SMA.

Glycoprotein K8.1A of Kaposi's Sarcoma-Associated Herpesvirus Is a Critical B Cell Tropism Determinant Independent of Its Heparan Sulfate Binding Activity.

B lymphocytes are the major cellular reservoir in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV), and the virus is etiologically linked to two B cell lymphoproliferative disorders. We previously described the MC116 human B cell line as a KSHV-susceptible model to overcome the paradoxical refractoriness of B cell lines to experimental KSHV infection. Here, using monoclonal antibody inhibition and a deletion mutant virus, we demonstrate that the KSHV virion glycoprotein K8.1A is critical for infection of MC116, as well as tonsillar B cells; in contrast, we confirm previous reports on the dispensability of the glycoprotein for infection of primary endothelial cells and other commonly studied non-B cell targets. Surprisingly, we found that the role of K8.1A in B cell infection is independent of its only known biochemical activity of binding to surface heparan sulfate, suggesting the possible involvement of an additional molecular interaction(s). Our finding that K8.1A is a critical determinant for KSHV B cell tropism parallels the importance of proteins encoded by positionally homologous genes for the cell tropism of other gammaherpesviruses.IMPORTANCE Elucidating the molecular mechanisms by which KSHV infects B lymphocytes is critical for understanding how the virus establishes lifelong persistence in infected people, in whom it can cause life-threatening B cell lymphoproliferative disease. Here, we show that K8.1A, a KSHV-encoded glycoprotein on the surfaces of the virus particles, is critical for infection of B cells. This finding stands in marked contrast to previous studies with non-B lymphoid cell types, for which K8.1A is known to be dispensable. We also show that the required function of K8.1A in B cell infection does not involve its binding to cell surface heparan sulfate, the only known biochemical activity of the glycoprotein. The discovery of this critical role of K8.1A in KSHV B cell tropism opens promising new avenues to unravel the complex mechanisms underlying infection and disease caused by this viral human pathogen.

Post-remission therapy of adults aged 60 and older with acute myeloid leukemia in first complete remission: role of treatment intensity on the outcome.

Although complete remission (CR) is achieved in 50 to 70% of older fit patients with acute myeloid leukemia (AML), consolidation therapy in this age group remains challenging. In this retrospective study, we aimed to compare outcome in elderly patients treated with different post-remission modalities, including allogenic and autologous hematopoietic stem cell transplantation (HSCT), intensive chemotherapy, and standard-dose chemotherapy (repeated 1 + 5 regimen). We collected data of 441 patients ≥ 60 years in first CR from a single institution. Median age was 67 years. Sixty-one (14%) patients received allo-HSCT, 51 (12%) auto-HSCT, 70 (16%) intensive chemotherapy with intermediate- or high-dose cytarabine (I/HDAC), and 190 (43%) 1 + 5 regimen. Median follow-up was 6.5 years. In multivariate analysis, allo-HSCT, cytogenetics, and PS had a significant impact on OS and LFS. In spite of a more favorable-risk profile, the patients who received I/HDAC had no significantly better LFS as compared with patients treated with 1 + 5 (median LFS 8.8 months vs 10.6 months, p = 0.96). In transplanted patients, median LFS was 13.3 months for auto-HSCT and 25.8 months for allo-HSCT. Pre-transplant chemotherapy with I/HDAC had no effect on the outcome. Toxicity was significantly increased for both transplanted and non-transplanted patients treated with I/HDAC, with more units of blood and platelet transfusion and more time spent in hospitalization, but no higher non-relapse mortality. This study shows that post-remission chemotherapy intensification is not associated with significantly better outcome as compared with standard-dose chemotherapy in elderly patients for whom, overall results remain disappointing.

[Feedback on clinical oncology pharmacy]. / Retour d'expérience en pharmacie clinique oncologique.

The rising of oral anticancer therapies let more and more patients to be cared at home and improve their quality of life. However the toxicities of these drugs and the distance with health professionals imply that the patient needs to be more autonomous with respect to his treatment. Patients through therapeutic education programs allows them to manage side effects, to be more observant and then to subsequently benefit from the treatment. We report here, oncology clinical pharmacists experiences in some health facilities in France, presented at the 1st day of clinical oncology pharmacy (December 2017, Marseille).

Switching to abacavir versus use of a nucleoside-sparing dual regimen for HIV-infected patients with tenofovir-associated renal toxicity.

OBJECTIVES: We investigated the reversibility of tenofovir disoproxil fumarate (TDF)-associated renal decline and tubular dysfunction using different antiretroviral strategies. METHODS: A successive evaluation of renal [estimated glomerular filtration rate (eGFR)] and tubular (phosphataemia, proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria and tubular proteinuria) parameters was performed in 231 patients, before and after switching from TDF to abacavir (n = 60), using dual therapy (n = 49), or continuing the same regimen including TDF (n = 122). RESULTS: In a successive evaluation after a median of 8.86 months, or less time if treatment was switched (4.8 months vs. 13.3 months to second evaluation; P < 0.01), a significant improvement in eGFR (median change +0.3 vs. -2.91 mL/min/1.73 m2 in patients who did not discontinue TDF; P = 0.04) and tubular dysfunction (median change -40% vs. +30%, respectively; P < 0.01) was observed. Lineal regression showed that age (ß = -0.14; P = 0.04), previous eGFR decline (ß = -0.42; P < 0.01), and time on TDF (ß = -0.19; P = 0.04) were associated with impaired eGFR recovery. There were no differences in eGFR slopes between patients using abacavir instead of TDF and those using a dual therapy, who showed similar improvement in proteinuria (-22% vs. -19%, respectively), phosphaturia (+10.1% vs. +9.4%, respectively), and urinary beta-2-microglobulin (-9% vs. -15%, respectively; P > 0.1 for all), although patients receiving the dual regimen were more heavily pretreated. A eGFR decrease (-6.17 mL/min/1.73 m2 ) was observed in patients taking dolutegravir or rilpivirine, but with similar improvement to that observed in the rest of switching patients in tubular abnormalities. CONCLUSIONS: Tenofovir disoproxil fumarate discontinuation was associated with a rapid and significant improvement in eGFR and tubular abnormalities, regardless of whether abacavir or dual therapy was chosen. Switching to a regimen that included dolutegravir and/or rilpivirine was associated with a eGFR decrease without differences in the rate of tubular dysfunction improvement in comparison with the rest of patients who discontinued tenofovir.

Thermodynamic Description of Synergy in Solvent Extraction: II Thermodynamic Balance of Driving Forces Implied in Synergistic Extraction.

In the second part of this study, we analyze the free energy of transfer in the case of synergistic solvent extraction. This free energy of the transfer of an ion in dynamic equilibrium between two coexisting phases is decomposed into four driving forces combining long-range interactions with the classical complexation free energy associated with the nearest neighbors. We demonstrate how the organometallic complexation is counterbalanced by the cost in free energy related to structural change on the colloidal scale in the solvent phase. These molecular forces of synergistic extraction are driven not only by the entropic term associated with the tight packing of electrolytes in the solvent and by the free energy cost of coextracting water toward the hydrophilic core of the reverse aggregates present but also by the entropic costs in the formation of the reverse aggregate and by the interfacial bending energy of the extractant molecules packed around the extracted species. Considering the sum of the terms, we can rationalize the synergy observed, which cannot be explained by classical extraction modeling. We show an industrial synergistic mixture combining an amide and a phosphate complexing site, where the most efficient/selective mixture is observed for a minimal bending energy and maximal complexation energy.

Thermodynamic Description of Synergy in Solvent Extraction: I. Enthalpy of Mixing at the Origin of Synergistic Aggregation.

Revisiting aggregation of extractant molecules into water-poor mixed reverse micelles, we propose in this paper to identify the thermodynamic origins of synergy in solvent extraction. Considering that synergistic extraction properties of a mixture of extractants is related to synergistic aggregation of this mixture, we identify here the elements at the origin of synergy by independently investigating the effect of water, acid, and extracted cations. Thermodynamic equations are proposed to describe synergistic aggregation in the peculiar case of synergistic solvent extraction by evaluating critical aggregation concentration (CAC) as well as specific interactions between extractants due to the presence of water, acid and cations. Distribution of two extractant molecules in the free extractants and in reverse micelles was assessed, leading to an estimation of the in-plane interaction parameter between extractants in the aggregates as introduced by Bergström and Eriksson ( Bergström, M.; Eriksson, J. C. A Theoretical Analysis of Synergistic Effects in Mixed Surfactant Systems . Langmuir 2000 , 16 , 7173 - 7181 ). Based on this model, we study the N,N'-dimethyl-N,N'-dioctylhexylethoxymalonamide (DMDOHEMA) and di(2-ethylexyl) phosphoric acid (HDEHP) mixture and show that adding nitric acid enhances synergistic aggregation at the equimolar ratio of the two extractants and that this configuration can be related to a favored enthalpy of mixing.

High-definition endoscopy with iScan and Lugol's solution for the detection of inflammation in patients with nonerosive reflux disease: histologic evaluation in comparison with a control group.

Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients.

Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN).

A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.

Efficient infection of a human B cell line with cell-free Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is causatively linked to two B cell lymphoproliferative disorders, multicentric Castleman's disease and primary effusion lymphoma. Latently infected B cells are a major KSHV reservoir, and virus activation from tonsillar B cells can result in salivary shedding and virus transmission. Paradoxically, human B cells (primary and continuous) are notoriously refractory to infection, thus posing a major obstacle to the study of KSHV in this cell type. By performing a strategic search of human B cell lymphoma lines, we found that MC116 cells were efficiently infected by cell-free KSHV. Upon exposure to recombinant KSHV.219, enhanced green fluorescent protein reporter expression was detected in 17 to 20% of MC116 cells. Latent-phase transcription and protein synthesis were detected by reverse transcription-PCR and detection of latency-associated nuclear antigen expression, respectively, in cell lysates and individual cells. Selection based on the puromycin resistance gene in KSHV.219 yielded cultures with all cells infected. After repeated passaging of the selected KSHV-infected cells without puromycin, latent KSHV was maintained in a small fraction of cells. Infected MC116 cells could be induced into lytic phase with histone deacetylase inhibitors, as is known for latently infected non-B cell lines, and also selectively by the B cell-specific pathway involving B cell receptor cross-linking. Lytic-phase transition was documented by red fluorescent protein reporter expression, late structural glycoprotein (K8.1A, gH) detection, and infectious KSHV production. MC116 cells were CD27(-)/CD10(+), characteristic of transitional B cells. These findings represent an important step in the establishment of an efficient continuous B cell line model to study the biologically relevant steps of KSHV infection. Kaposi's sarcoma-associated herpesvirus (KSHV) causes two serious pathologies of B cells, the antibody-producing cells of the immune system. B cells are a major reservoir for KSHV persistence in the body. Paradoxically, in the laboratory, B cells are extremely difficult to infect with KSHV; this problem greatly hinders scientific analysis of B cell infection. We describe our search for and successful identification of a stable human B cell line that can be efficiently infected by KSHV. Upon infection of these cells, the virus goes into a quiet latent phase, a characteristic feature of many herpesvirus infections. The virus can be triggered to enter an active lytic phase by treatments known to stimulate normal B cell functions. These findings suggest that the new B cell line will be a valuable model in which to study KSHV infection of this major target cell type.

Synergy in Extraction System Chemistry: Combining Configurational Entropy, Film Bending, and Perturbation of Complexation.

Iron-uranium selectivity in liquid-liquid extraction depends not only on the mole fraction of extractants, but also on the nature of the diluent used, even if the diluent has no complexation interaction with the extracted ions. Modeling strong nonlinearity is difficult to parametrize without a large number of parameters, interpreted as "apparent constants". We determine in this paper the synergy curve versus mole fraction of HDEHP-TOPO (di(2-ethylexyl) phosphoric acid/tri-n-octyl phosphine oxide) and compare the free energy of aggregation to the free energy of extraction in various diluents. There is always a concomitant maximum of the two quantities, but with a gradual influence on intensity. The diluent is wetting the chains of the reverse aggregates responsible of the extraction. We show here that the intensity of the unexplained synergy peak is strongly dependent on the "penetrating" or "nonpenetrating" nature of the diluent. This experimental determination allows us to attribute the synergy to a combination of entropic effects favoring extraction, opposed to perturbation of the first coordination sphere by penetration as well as surfactant film bending energy.

[Catch me if you can: endoscopic remove of a needle from the jejunum]. / Catch me if you can: Endoskopische Bergung einer Sicherheitsnadel aus dem tiefen Dünndarm.

INTRODUCTION: The ingestion of foreign bodies is a frequently observed problem in daily clinical practice. In order to avoid complications such as perforation, endoscopic removal of potentially penetrating foreign bodies should be attempted quickly. The use of various endoscopic techniques has been reported for this purpose. However, extraction of foreign bodies from the mid gastrointestinal tract has rarely been reported. CASE REPORT: We present the case of a patient who had swallowed a safety needle which could safely be removed from the jejunum by means of double-balloon enteroscopy (DBE). The combination of a thin p-type enteroscope with a thick t-type overtube was used in order to improve the manoeuvrability of the endoscope. The needle was pulled into the overtube which served as a protective shield during the retrieval of the endoscope. CONCLUSION: Our case report describes the potential of removing foreign bodies from the deep small bowel by pulling them into the overtube of a double-balloon enteroscope. If the suspicion of foreign body impaction in the small bowel is made, it may be advisable to primarily choose a balloon enteroscopy system. Through this, quick and deep insertion can be combined with a safe removal of the foreign body.

Prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil.

Chemokines are low-molecular weight proteins that play a key role in inflammatory processes. Genomic variations in chemokine receptors are associated with the susceptibility to various diseases. Polymorphisms in chemokine receptor type 5 (CCR5)-Δ32 and CCR2-V64I are related to human immunodeficiency virus infection resistance, which has led to genetic association studies for several other diseases. Given the heterogeneous distribution of these polymorphisms in different global populations and within Brazilian populations, we analyzed the prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil. The study included 223 individuals from the general population of the city of Parnaíba, Piauí, who had a mean age of 73 years. Of these individuals, 37.2% were men and 62.8% were women. Polymorphisms were analyzed using DNA extracted from peripheral blood leukocytes by using polymerase chain reaction alone (CCR5-Δ32) or accompanied by restriction endonuclease digestion (CCR2-V64I). In both cases, the genotypes were determined using 8% polyacrylamide gel electrophoresis and silver nitrate staining. The population conformed to Hardy-Weinberg equilibrium for both the loci studied. No individuals were homozygous for allele-Δ32, which was present in 1.8% of the population, whereas allele-64I was present in 13.9% of the participants studied; 74.9% were homozygous for the wild-type allele, while 22.4 and 2.7% were heterozygous and homozygous for the mutant allele, respectively. Additional studies are needed to investigate the relationship between these polymorphisms and disease etiopathogenesis in reference populations.

[Patients' satisfaction and waiting time in oncology day care centers in Champagne-Ardenne]. / Programme d'évaluation de l'administration des chimiothérapies en hôpital de jour en Champagne-Ardenne (PEACH) : satisfaction et délais d'attente des patients.

AIM: Quality of life of patients suffering from cancer may be influenced by the way healthcare is organized and by patient experiences. Nowadays, chemotherapy is often provided in day care centers. This study aimed to assess patient waiting time and satisfaction in oncology day care centers in Champagne-Ardenne, France. METHODS: This cross-sectional survey involved all patients receiving ambulatory chemotherapy during a one-week period in day care centers of Champagne-Ardenne public and private healthcare institutions participating in the study. Sociodemographic, medical and outpatient data were collected. Patient satisfaction was measured using the Out-Patsat35 questionnaire. RESULTS: Eleven (out of 16) oncology day care centers and 441 patients participated in the study. Most of the patients were women (n=252, 57.1%) and the mean age was 61±12 years. The mean satisfaction score was 82±14 (out of 100) and the mean waiting time between the assigned appointment time and administration of chemotherapy was 97±60 min. CONCLUSION: This study has shown that waiting times are important. However, patients are satisfied with the healthcare organization, especially regarding nursing support. Early preparation of chemotherapy could improve these parameters.

Contrasting energy allocation strategies of two sympatric Merluccius species in an upwelling system.

This study investigated the somatic growth and energy allocation strategy of two sympatric hake species (Merluccius polli and Merluccius senegalensis), coexisting under the strong influence of the Mauritanian upwelling. The results revealed that ontogeny, bathymetry, geography and reproduction shaped the differences found between the condition dynamics of the two species. Aside from species-specific differences, individuals were observed in better condition in the northernmost area (more influenced by the permanent upwelling) and in the deepest waters, probably the most favourable habitat for Merluccius spp. Both species also displayed contrasting trade-offs in energy allocation probably due to the dissimilarity of their habitats, which favours the existence of divergent adaptive strategies in response to different ontogenic requirements. It was hypothesized that M. polli invests in mass and energy reserves while sacrificing growth, as larger sizes may not provide an ecological advantage in a deeper and more stable environment. Moreover, M. senegalensis capitalizes on a steady growth without major disruptions, enabling earlier spawning at the expense of a lower somatic mass, which is fitting to a less stable shallower environment. This study sheds new light on differences in the biological traits and life strategies of Merluccius spp., which permit their overlap in a complex upwelling system and may contribute to the long-lasting scientific-based management of these species.

Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells.

NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.