Revelations from the Nematode Caenorhabditis elegans on the Complex Interplay of Metal Toxicological Mechanisms

Metals have been definitively linked to a number of disease states. Due to the widespread existence of metals in our environment from both natural and anthropogenic sources, understanding the mechanisms of their cellular detoxification is of upmost importance. Organisms have evolved cellular detoxification systems including glutathione, metallothioneins, pumps and transporters, and heat shock proteins to regulate intracellular metal levels. The model organism, Caenorhabditis elegans (C. elegans), contains these systems and provides several advantages for deciphering the mechanisms of metal detoxification. This review provides a brief summary of contemporary literature on the various mechanisms involved in the cellular detoxification of metals, specifically, antimony, arsenic, cadmium, copper, manganese, mercury, and depleted uranium using the C. elegans model system for investigation and analysis

The MST of symmetric disk graphs is light

AbstractSymmetric disk graphs are often used to model wireless communication networks. Given a set S of n points in Rd (representing n transceivers) and a transmission range assignment r:S→R, the symmetric disk graph of S (denoted SDG(S)) is the undirected graph over S whose set of edges is E={(u,v)|r(u)⩾|uv| and r(v)⩾|uv|}, where |uv| denotes the Euclidean distance between points u and v. We prove that the weight of the MST of any connected symmetric disk graph over a set S of n points in the plane, is only O(logn) times the weight of the MST of the complete Euclidean graph over S. We then show that this bound is tight, even for points on a line.Next, we prove that if the number of different ranges assigned to the points of S is only k, k≪n, then the weight of the MST of SDG(S) is at most 2k times the weight of the MST of the complete Euclidean graph. Moreover, in this case, the MST of SDG(S) can be computed efficiently in time O(knlogn).We also present two applications of our main theorem, including an alternative proof of the Gap Theorem, and a result concerning range assignment in wireless networks.Finally, we show that in the non-symmetric model (where E={(u,v)|r(u)⩾|uv|}), the weight of a minimum spanning subgraph might be as big as Ω(n) times the weight of the MST of the complete Euclidean graph

Revelations from the Nematode Caenorhabditis elegans on the Complex Interplay of Metal Toxicological Mechanisms

Metals have been definitively linked to a number of disease states. Due to the widespread existence of metals in our environment from both natural and anthropogenic sources, understanding the mechanisms of their cellular detoxification is of upmost importance. Organisms have evolved cellular detoxification systems including glutathione, metallothioneins, pumps and transporters, and heat shock proteins to regulate intracellular metal levels. The model organism, Caenorhabditis elegans (C. elegans), contains these systems and provides several advantages for deciphering the mechanisms of metal detoxification. This review provides a brief summary of contemporary literature on the various mechanisms involved in the cellular detoxification of metals, specifically, antimony, arsenic, cadmium, copper, manganese, mercury, and depleted uranium using the C. elegans model system for investigation and analysis

Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of Insulin Glargine and Lixisenatide, Compared with Basal-Bolus Regimen in Patients with Type 2 Diabetes: Propensity Score Matched Analysis

INTRODUCTION: Basal-bolus (BB) regimens are generally used to intensify basal insulin therapy in patients with type 2 diabetes (T2D) not meeting glycemic targets. However, drawbacks include multiple injection burden and risk of weight gain and hypoglycemia. A once-daily titratable fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi) may provide a simple, well-tolerated, and efficacious alternative. We compared these treatments in a post hoc propensity score matched analysis using randomized trial data. METHODS: From the LixiLan-L study, 195 patients who had been randomized to iGlarLixi were matched for age, sex, race, T2D duration, baseline body mass index, glycated hemoglobin (HbA1c), fasting plasma glucose, insulin dose, and metformin use to 195 patients who had been randomized to a BB regimen in the GetGoal Duo-2 trial. RESULTS: At study end, estimated treatment differences for reduction in HbA1c and weight change, and ratio of hypoglycemia events per patient-year (BB vs iGlarLixi) were − 0.28% (standard error 0.08, P = 0.0002), − 1.32 kg (standard error 0.30, P < 0.0001), and 2.85 (P < 0.0001), respectively, all favoring iGlarLixi over BB. Also, proportions of patients reaching individual and composite goals (HbA1c < 7% [< 53 mmol/mol], no weight gain, and no hypoglycemia) were higher in the iGlarLixi compared with the BB treatment group. Gastrointestinal side effects were more common with iGlarLixi. CONCLUSIONS: In patients with T2D inadequately controlled on basal insulin, iGlarLixi offers an effective alternative to BB regimen for reducing HbA1c, without increased risk of hypoglycemia and weight gain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02058160 (LixiLan-L trial); NCT01768559 (GetGoal Duo-2 trial)

Registry of people with diabetes in three Latin American countries : a suitable approach to evaluate the quality of health care provided to people with type 2 diabetes

Q2Q2Aims: To implement a patient registry and collect data related to the care providedto people with type 2 diabetes in six specialized centers of three Latin Americancountries, measure the quality of such care using a standardized form (QUALIDIAB)that collects information on different quality of care indicators, and analyze thepotential of collecting this information for improving quality of care and conductingclinical research. Methods: We collected data on clinical, metabolic and therapeu-tic indicators, micro- and macrovascular complications, rate of use of diagnosticand therapeutic elements and hospitalization of patients with type 2 diabetes in sixdiabetes centers, four in Argentina and one each in Colombia and Peru. Results:We analyzed 1157 records from patients with type 2 diabetes (Argentina, 668;Colombia, 220; Peru, 269); 39 records were discarded because of data entry errorsor inconsistencies. The data demonstrated frequency performance deficiencies inseveral procedures, including foot and ocular fundus examination and variouscardiovascular screening tests. In contrast, HbA1cand cardiovascular risk factorassessments were performed with a greater frequency than recommended by inter-national guidelines. Management of insulin therapy was sub-optimal, and deficien-cies were also noted among diabetes education indicators. Conclusions: Patientregistry was successfully implemented in these clinics following an interactiveeducational program. The data obtained provide useful information as to deficien-cies in care and may be used to guide quality of care improvement efforts.https://orcid.org/0000-0002-6860-3620N/

Stressed-Induced TMEM135 Protein Is Part of a Conserved Genetic Network Involved in Fat Storage and Longevity Regulation in Caenorhabditis elegans

Disorders of mitochondrial fat metabolism lead to sudden death in infants and children. Although survival is possible, the underlying molecular mechanisms which enable this outcome have not yet been clearly identified. Here we describe a conserved genetic network linking disorders of mitochondrial fat metabolism in mice to mechanisms of fat storage and survival in Caenorhabditis elegans (C. elegans). We have previously documented a mouse model of mitochondrial very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency.[1] We originally reported that the mice survived birth, but, upon exposure to cold and fasting stresses, these mice developed cardiac dysfunction, which greatly reduced survival. We used cDNA microarrays[2], [3], [4] to outline the induction of several markers of lipid metabolism in the heart at birth in surviving mice. We hypothesized that the induction of fat metabolism genes in the heart at birth is part of a regulatory feedback circuit that plays a critical role in survival.[1] The present study uses a dual approach employing both C57BL/6 mice and the nematode, C. elegans, to focus on TMEM135, a conserved protein which we have found to be upregulated 4.3 (±0.14)-fold in VLCAD-deficient mice at birth. Our studies have demonstrated that TMEM135 is highly expressed in mitochondria and in fat-loaded tissues in the mouse. Further, when fasting and cold stresses were introduced to mice, we observed 3.25 (±0.03)- and 8.2 (±0.31)- fold increases in TMEM135 expression in the heart, respectively. Additionally, we found that deletion of the tmem135 orthologue in C. elegans caused a 41.8% (±2.8%) reduction in fat stores, a reduction in mitochondrial action potential and decreased longevity of the worm. In stark contrast, C. elegans transgenic animals overexpressing TMEM-135 exhibited increased longevity upon exposure to cold stress. Based on these results, we propose that TMEM135 integrates biological processes involving fat metabolism and energy expenditure in both the worm (invertebrates) and in mammalian organisms. The data obtained from our experiments suggest that TMEM135 is part of a regulatory circuit that plays a critical role in the survival of VLCAD-deficient mice and perhaps in other mitochondrial genetic defects of fat metabolism as well

Estudio IDEA (International Day for Evaluation of Abdominal Obesity): prevalencia de obesidad abdominal y factores de riesgo asociados en atención primaria en Colombia

Introduction. Obesity is frequently associated with risk factors for cardiovascular and metabolic diseases. Central obesity is a marker of increased intra-abdominal adiposity and a known risk factor for atherosclerosis and diabetes; it is also a good predictor of risk for coronary events, cardiovascular mortality, diabetes and metabolic syndrome. A less predictive alternate measurement is known as the body mass index (BMI).Objective. Obesity prevalence was estimated first by BMI and then by abdominal obesity (measuredby waist circumference, WC) in primary care patients.Materials and methods. As part of an international study, primary care physicians recruited consecutive patients aged 18 to 80 years who consulted for any reason on two pre-specified half-days. Age, gender, smoking status and history of cardiovascular disease or diabetes were recorded. Height, weight and WC were measured using standard methods. Pregnant women and subjects unwilling to participate were excluded.Results. A total of 3,795 patients from 105 primary care centers located throughout Colombia were evaluated. The mean age was 45 years (69% females). Of these, 60.7% of males and 53.9% of females were overweight or obese according to their BMI; 24.6% of males and 44.6% of females had abdominal obesity when National Cholesterol Education Program guidelines were used, but numbers changed to62.5% and 67.0% when the International Diabetes Federation guidelines were used. Obesity, either determined by BMI or by WC, was associated with higher prevalence of diabetes, hypertension and dyslipidemia.Conclusions. Increased waist circumference is a practical and useful marker for cardiovascular and metabolic conditions. The prevalence of abdominal obesity in Colombian primary care patients is highand more frequent in females. doi: http://dx.doi.org/10.7705/biomedica.v32i4.799Introducción. La obesidad está asociada con factores de riesgo para enfermedades cardiovasculares y metabólicas. La obesidad central, marcador de adiposidad intraabdominal aumentada, es mejor factor de riesgo para aterosclerosis y diabetes que el índice de masa corporal (IMC), y buen predictor de riesgo de morbimortalidad cardiovascular, síndrome metabólico y diabetes.Objetivo. Estimar prevalencias de obesidad por IMC y de obesidad abdominal por circunferencia abdominal en pacientes de atención primaria en Colombia.Materiales y métodos. Como parte de un estudio internacional, 105 médicos de atención primaria elegidos al azar reclutaron consecutivamente a pacientes de 18 a 80 años, que consultaran por cualquier razón, en dos medios días especificados previamente. Se registraron edad, sexo, tabaquismo, antecedentes cardiovasculares, diabetes, altura, peso y circunferencia abdominal mediante métodos estandarizados. Se excluyeron mujeres embarazadas y quienes no quisieran participar.Resultados. Se evaluaron 3.795 pacientes, con edad promedio de 45 años (69 % mujeres). El 60,7% de los hombres y el 53,9 % de las mujeres tenían sobrepeso u obesidad según el IMC. El 24,6 % de los hombres y el 44,6 % de las mujeres tenían obesidad abdominal (según las guías del National Cholesterol Education Program), pero las cifras cambiaban a 62,5 % y 67,0 %, respectivamente, si se consideraban las guías de la International Diabetes Federation. La obesidad, determinada por el IMC o por la circunferencia abdominal, se asoció con mayor prevalencia de diabetes, hipertensión y dislipidemia.Conclusiones. El aumento de la circunferencia abdominal es un marcador práctico y útil para enfermedades cardiovasculares y metabólicas. La prevalencia de obesidad abdominal en pacientes de atención primaria en Colombia fue alta, y más frecuente en mujeres. doi: http://dx.doi.org/10.7705/biomedica.v32i4.799

The role for saxagliptin within the management of type 2 diabetes mellitus: an update from the 2010 European Association for the Study of Diabetes (EASD) 46th annual meeting and the American Diabetes Association (ADA) 70th scientific session

Saxagliptin is a potent, selective DPP4 inhibitor. Highlights from abstracts presented at the 2010 meetings of the European Association for the Study of Diabetes and the American Diabetes Association include studies and analyses that shed light on the promising role for saxagliptin within the management of type 2 diabetes mellitus. Data show that saxagliptin combination therapy improves HbA1c levels compared with placebo, particularly in patients with high HbA1c at baseline, long duration of disease, low baseline creatinine clearance, and low homeostasis model assessment 2 β-cell function at baseline. These efficacy benefits are achieved without any increase in hypoglycemia or other adverse events. The study results also show that the saxagliptin plus metformin combination is a good candidate for initial therapy in drug-naïve patients treated for as long as 72 weeks. Survey data presented confirm that hypoglycemia (and fear of hypoglycemia) is a barrier to patients' acceptance of diabetes treatment, limiting its efficacy. Therefore, therapies such as saxagliptin that have a low risk of hypoglycemia may be more acceptable to patients in helping them to achieve glycemic control and to optimize their quality of life. In patients with renal impairment, for whom metformin is contraindicated, saxagliptin monotherapy is a promising option for antidiabetic management as, when given at a reduced dose, it is well-tolerated with a safety profile similar to that of placebo