Evidence for a role of metformin in preventing olfactory dysfunction among older adults.

BACKGROUND: Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD. METHODS: Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use. RESULTS: Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3. CONCLUSIONS: Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.

A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.

Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem (ES) cells, which can be adapted to any ES cell derived cell type. We show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals terminating at signalling responsive transcription factors. Our work provides an important resource for studies of hematopoietic specification and highlights the mechanisms of how and where extrinsic signals program a cell type-specific chromatin landscape driving hematopoietic differentiation.

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO.

The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1.

RUNX1/ETO (RE), the t(8;21)-derived leukemic transcription factor associated with acute myeloid leukemia (AML) development, deregulates genes involved in differentiation, self-renewal and proliferation. In addition, these cells show differences in cellular adhesion behavior whose molecular basis is not well understood. Here, we demonstrate that RE epigenetically silences the gene encoding P-Selectin Glycoprotein Ligand-1 (PSGL-1) and downregulates PSGL-1 expression in human CD34+ and murine lin- hematopoietic progenitor cells. Levels of PSGL-1 inversely and dose-dependently correlate with RE oncogene levels. However, a DNA-binding defective mutant fails to downregulate PSGL-1. We show by ChIP experiments that the PSGL-1 promoter is a direct target of RE and binding is accompanied by high levels of the repressive chromatin mark histone H3K27me3. In t(8;21)+ Kasumi-1 cells, PSGL-1 expression is completely restored at both the mRNA and cell surface protein levels following RE downregulation with short hairpin RNA (shRNA) or RE inhibition with tetramerization-blocking peptides, and at the promoter H3K27me3 is replaced by the activating chromatin mark H3K9ac as well as by RNA polymerase II. Upregulation of PSGL-1 restores the binding of cells to P- and E-selectin and re-establishes myeloid-specific cellular adhesion while it fails to bind to lymphocyte-specific L-selectin. Overall, our data suggest that the RE oncoprotein epigenetically represses PSGL-1 via binding to its promoter region and thus affects the adhesive behavior of t(8;21)+ AML cells.

Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.

In vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, quinine, mefloquine and halofantrine in Abidjan (Côte d'Ivoire).

BACKGROUND: Malaria is the primary cause of hospitalization in Côte d'Ivoire. Early treatment is one of the strategies to control this illness. However, the spread of resistance of Plasmodium falciparum to antimalarial drugs can seriously compromise this strategy. OBJECTIVES: The aim of this study was to assess the in vitro susceptibility of P. falciparum to monodesethylamodiaquine and aminoalcohols in Abidjan (Côte d'Ivoire). METHODS: We assessed the in vitro susceptibility of isolates collected from patients with uncomplicated malaria by using the WHO optical microtest technique. RESULTS: The proportions of resistance to monodesethylamodiaquine, méfloquine and halofantrine were 12.5%, 15.6% and 25.9%, respectively. For quinine, none of isolates showed evidence of in vitro resistance. However, two isolates (6.1%) had IC(50) values above 300 nM. The IC(50) of each drug was positively and significantly correlated to that of the other three drugs, and the correlation was higher between halofantrine and mefloquine. CONCLUSIONS: Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore, it is necessary to implement a long-term monitoring system of antimalarial drug resistance.

In vitro susceptibility of Plasmodium falciparum to Monodesethylamodiaquine; Quinine; Mefloquine and Halofantrine in Abidjan (Cote d'Ivoire)

Background: Malaria is the primary cause of hospitalization in Ctte d'Ivoire. Early treatment is one of the strategies to control this illness. However; the spread of resistance of Plasmodium falciparum to antimalarial drugs can seriously compromise this strategy. Objectives: The aim of this study was to assess the in vitro susceptibility of P. falciparum to monodesethylamodiaquine and aminoalcohols in Abidjan (Ctte d'Ivoire). Methods: We assessed the in vitro susceptibility of isolates collected from patients with uncomplicated malaria by using the WHO optical microtest technique. Results: The proportions of resistance to monodesethylamodiaquine; m?floquine and halofantrine were 12.5; 15.6and 25.9; respectively. For quinine; none of isolates showed evidence of in vitro resistance. However; two isolates (6.1) had IC 50 values above 300 nM. The IC 50 of each drug was positively and significantly correlated to that of the other three drugs; and the correlation was higher between halofantrine and mefloquine. Conclusions: Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore; it is necessary to implement a long-term monitoring system of antimalarial drug resistance. 15.6and 25.9; respectively. For quinine; none of isolates showed evidence of in vitro resistance. However; two isolates (6.1) had IC 50 values above 300 nM. The IC 50 of each drug was positively and significantly correlated to that of the other three drugs; and the correlation was higher between halofantrine and mefloquine. Conclusions: Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore; it is necessary to implement a long-term monitoring system of antimalarial drug resistance

[Popular nosology of infantile diseases in West Côte-d'Ivoire and consequences for malaria care management]. / Nosologie populaire des maladies infantiles dans l'Ouest de la Côte-d'Ivoire. Implications pour le paludisme.

In a rural area of intense and permanent malaria transmission in Southwest Côte-d'lvoire, traditional midwifes of the Yacouba ethnic group, with also an important function for the children health and care, were interviewed in 2002 about their knowledge of the infantile pathologies. Their nosology is greatly based on symptoms and etiologic explanations of the disorder of secretions. The accumulation of a viscous liquid in different parts of the body, especially in the chest, the throat or the head, explains numerous febrile or afebrile diseases, including malnutrition. Some pathologies, particularly convulsions, are described by analogy with animals behaviour Relations between these entities and the biomedical ones are difficult to establish. The traditional care and treatments result from these concepts. A vomiting child or a child suffering from diarrhoea is subject to devices to evacuate his excess of liquid. Yellow brews are used against jaundice. Furthermore, an important mistrust remains towards medical treatments particularly for all parenteral therapies. Health facilities are only used as a the last resort. Their bad reputation is confirmed by the high rate of mortality of patients coming often too late. To improve malaria care management, health-care workers have to take into consideration these concepts and also prove their abilities to ensure good medical practices.

[Clinical study of orientation and reference planes in cephalometry]. / Etude critique des plans d'orientation et de référence en céphalométrie.

A critical study of orientation and reference planes used in cephalometrics is undergone. The data consists of cephalometric measurements evaluated in a sample of 90 young lebanese adults, divided into 43 girls and 47 boys, whose lateral cephalograms were registered according to the natural head position. This study shows the importance of the true horizontal as orientation and reference planes, due to the high reproducibility of the natural head position, and the high variability of the intra-cranial reference planes as compared to the true vertical, as well as the low correlation among measurements based on the true horizontal as a reference plane (AB-horizontal), and the measurements based on the intra-cranial planes and points (ANB) as reference. This study also evaluated the variations of some angular and sagittal measurements (SNA, SNB, SNPog) registered according to two orientations: Frankfort plane and the natural head position.

[Therapeutic efficiency of chloroquine in the savannah region in the north of Côte d'Ivoire (1997)]. / Efficacité thérapeutique de la chloroquine en région de savane du nord de la Côte d'Ivoire en 1997.

We evaluated from August to December 1997 the therapeutic effect of chloroquine (CQ) in treatment of mild malaria. Five villages of the savannah area of Côte d'Ivoire were selected for this study In this area and season, the transmission of malaria is of hyper-endemic type. The 14-day protocol of WHO was used and all the patients were treated with CQ 25 mg/kg over three days. 360 febrile children between 6 and 83 months old out of 545 were selected, and 286 were fully followed. At the beginning of the study axillary temperatures and parasitemia showed no difference in the 5 villages. The average therapy failure rate was 11.5% (IC to 95%; 7.8-15.2) with a maximum of 18.5%. The failure rates estimated in the various villages showed a hardly significant difference (p = 0.05). In the North of Côte d'Ivoire, the good efficiency of CQ can be explained by the low drugs pressure related to the behaviour of populations who use traditional phytotherapy in first resort to treat the fevers.

Inland valley rice production systems and malaria infection and disease in the savannah of Côte d'Ivoire.

In sub-Saharan Africa, lowlands developed for rice cultivation favour the development of Anopheles gambiae s. l. populations. However, the epidemiological impact is not clearly determined. The importance of malaria was compared in terms of prevalence and parasite density of infections as well as in terms of disease incidence between three agroecosystems: (i) uncultivated lowlands, 'R0', (ii) lowlands with one annual rice cultivation in the rainy season, 'R1' and (iii) developed lowlands with two annual rice cultivation cycles, 'R2'. We clinically monitored 2000 people of all age groups, selected randomly in each agroecosystem, for 40 days (in eight periods of five consecutive days scheduled every 6 weeks for 1 year). During each survey, a systematic blood sample was taken from every sick and asymptomatic person. The three agroecosystems presented a high endemic situation with a malaria transmission rate of 139-158 infective bites per person per year. The age-standardized annual malaria incidence reached 0.9 malaria episodes per person in R0, 0.6 in R1 and 0.8 in R2. Children from 0 to 9-year-old in R0 and R2 had two malarial attacks annually, but this was less in R1 (1.4 malaria episodes per child per year). Malaria incidence varied with season and agroecosystem. In parallel with transmission, a high malaria risk occurs temporarily at the beginning of the dry season in R2, but not in R0 and R1. Development of areas for rice cultivation does not modify the annual incidence of malarial attacks despite their seasonal influence on malaria risk. However, the lower malaria morbidity rate in R1 could be explained by socio-economic and cultural factors.

Hepatic encephalopathy. Metabolic consequence of cirrhosis often is reversible.

Hepatic encephalopathy is a well-recognized clinical complication of chronic liver disease. About 30% of patients with cirrhosis die in hepatic coma. Hepatic encephalopathy can occur in patients with fulminant liver disease without evidence of portal-systemic shunting. These patients have increased intracranial pressure and brain edema with a deleterious clinical course and poor prognosis unless liver transplantation is available. The pathogenesis of portal-systemic hepatic encephalopathy probably is multifactorial, although the predominant causative agent appears to be ammonia. The molecular basis of neurotoxicity of ammonia or other agents implicated in the condition is poorly understood. Therapy includes timely recognition and correction of precipitating factors. Once the condition is manifested, standard therapy is acute administration of lactulose, a disaccharide that is undigested in the small intestine. Its beneficial action is not fully understood. The use of oral antibiotics and BCAAs is of some benefit in patients who do not respond to lactulose. Limitation of protein in the diet may be useful for short periods but is not recommended for long-term use because of potential worsening of already poor nutrition. Several experimental therapies based on potential pathogenetic mechanisms have not resulted in improved outcomes over standard therapy with lactulose. However, future research will likely focus on the correction of alterations in neurotransmission. It is hoped that newer therapies will provide protection from the putative neurotoxins that cause secondary defects in neurotransmission.

Nutrition in acute pancreatitis.

The majority of patients (80%) admitted with acute pancreatitis recovers after a few days of bowel rest and intravenous fluids. However, some cases progress to a fulminant disease complicated by a severe systemic inflammatory response and multiple organ failure, a condition in which mortality is related to the degree of negative nitrogen balance. The goal of nutrition support in this situation is to cover the increased metabolic demands without stimulating pancreatic secretion and exacerbating the "autodigestion" that characterizes the condition. Although human and animal studies have shown conflicting results regarding the effect of composition and location of feeding on pancreatic enzyme secretion, there is consensus that total parenteral nutrition (TPN), given at moderate infusion rates, does not significantly stimulate secretion in humans and that enteral diets stimulate enzyme secretion unless delivered below the jejunum. Consequently, until recently TPN has been the standard of therapy. The fact that the cost and complications of TPN can often outweigh its benefits (catheter sepsis, hyperglycemia) has led to a series of recent controlled clinical trials of modified enteral diets in which the diet is delivered by nasojejunal tube. Results have demonstrated that enteral nutrition, with either elemental or polymeric formulas, was cheaper, safer, and at the same time more effective in reducing the systemic inflammatory response. The pathophysiologic explanation for these observations needs further investigation.