A hypothesis-generating study to evaluate platelet activity in diabetics with chronic kidney disease

BACKGROUND: It is well described that diabetes mellitus is a hypercoagulable state. It is also known that patients with renal dysfunction have impaired platelet aggregation and function. It is not well described how renal dysfunction affects the hypercoagulability associated with diabetes. This post-hoc sub-group analysis compares platelet function, clot structure and thrombin generation time at baseline, and following enoxaparin exposure in three groups of subjects. METHODS: 30 total subjects were evaluated in the three groups: Group I: normal controls (n = 10), Group II: subjects with renal dysfunction but without diabetes (n = 13), and Group III: subjects with concomitant diabetes and renal dysfunction (n = 7). For each subject, platelet contractile force (PCF), clot elastic modulus (CEM) and thrombin generation time (TGT) were simultaneously measured in whole blood at baseline, and following increasing enoxaparin antifactor Xa activity exposure. The group means for each parameter were determined and compared using one-way analysis of variance, with post-hoc Tukey-Kramer test. RESULTS: At baseline, subjects in Group III (diabetics with concomitant renal dysfunction) display significantly enhanced platelet activity, as measured by PCF (p = 0.003) and CEM (p = 0.03), relative to the non-diabetic Groups I and II. Subjects in Group II (renal dysfunction without diabetes) had significantly prolonged TGT values relative to controls when the antifactor Xa activity concentration reached 0.5 (p = 0.007), 1.0 (p = 0.005) and 3.0 IU/mL (p < 0.0001), respectively. There were no differences between Group II and Group III with respect to TGT at these antifactor Xa activity concentrations. When the antifactor Xa activity concentration reached 3.0 IU/mL, Groups II and III formed significantly less rigid blood clots (CEM p = 0.003) and also trended toward reduced PCF (p = 0.06) relative to Group I. CONCLUSION: This hypothesis-generating sub-group analysis suggests that at baseline, patients with concomitant diabetes and renal dysfunction have significantly enhanced platelet activity (PCF), and form more rigid blood clots (CEM) compared to controls and subjects with renal dysfunction but no diabetes. This may suggest that the presence of renal dysfunction does not ameliorate the hypercoagulable state associated with diabetes. Secondly, it appears that subjects with renal dysfunction but without diabetes have an enhanced response to enoxaparin relative to controls

A hypothesis-generating study to evaluate platelet activity in diabetics with chronic kidney disease

Background It is well described that diabetes mellitus is a hypercoagulable state. It is also known that patients with renal dysfunction have impaired platelet aggregation and function. It is not well described how renal dysfunction affects the hypercoagulability associated with diabetes. This post-hoc sub-group analysis compares platelet function, clot structure and thrombin generation time at baseline, and following enoxaparin exposure in three groups of subjects. Methods 30 total subjects were evaluated in the three groups: Group I: normal controls (n = 10), Group II: subjects with renal dysfunction but without diabetes (n = 13), and Group III: subjects with concomitant diabetes and renal dysfunction (n = 7). For each subject, platelet contractile force (PCF), clot elastic modulus (CEM) and thrombin generation time (TGT) were simultaneously measured in whole blood at baseline, and following increasing enoxaparin antifactor Xa activity exposure. The group means for each parameter were determined and compared using one-way analysis of variance, with post-hoc Tukey-Kramer test. Results At baseline, subjects in Group III (diabetics with concomitant renal dysfunction) display significantly enhanced platelet activity, as measured by PCF (p = 0.003) and CEM (p = 0.03), relative to the non-diabetic Groups I and II. Subjects in Group II (renal dysfunction without diabetes) had significantly prolonged TGT values relative to controls when the antifactor Xa activity concentration reached 0.5 (p = 0.007), 1.0 (p = 0.005) and 3.0 IU/mL (p \u3c 0.0001), respectively. There were no differences between Group II and Group III with respect to TGT at these antifactor Xa activity concentrations. When the antifactor Xa activity concentration reached 3.0 IU/mL, Groups II and III formed significantly less rigid blood clots (CEM p = 0.003) and also trended toward reduced PCF (p = 0.06) relative to Group I. Conclusion This hypothesis-generating sub-group analysis suggests that at baseline, patients with concomitant diabetes and renal dysfunction have significantly enhanced platelet activity (PCF), and form more rigid blood clots (CEM) compared to controls and subjects with renal dysfunction but no diabetes. This may suggest that the presence of renal dysfunction does not ameliorate the hypercoagulable state associated with diabetes. Secondly, it appears that subjects with renal dysfunction but without diabetes have an enhanced response to enoxaparin relative to controls

Utilization Patterns of IV Iron and Erythropoiesis Stimulating Agents in Anemic Chronic Kidney Disease Patients: A Multihospital Study

Intravenous (IV) iron and Erythropoiesis Stimulating Agents (ESAs) are recommended for anemia management in chronic kidney disease (CKD). This retrospective cohort study analyzed utilization patterns of IV iron and ESA in patients over 18 years of age admitted to University Health System Hospitals with a primary or secondary diagnosis of CKD between January 1, 2006 to December 31, 2008. A clustered binomial logistic regression using the GEE methodology was used to identify predictors of IV iron utilization. Only 8% (n = 6678) of CKD patients on ESA therapy received IV iron supplementation in university hospitals. Those receiving iron used significantly less amounts of ESAs. Patient demographics (age, race, primary payer), patient clinical conditions (admission status, severity of illness, dialysis status), and physician specialty were identified as predictors of IV iron use in CKD patients. Use of IV iron with ESAs was low despite recommendations from consensus guidelines. The low treatment rate of IV iron represents a gap in treatment practices and signals an opportunity for healthcare improvement in CKD anemic patients

Activation of inflammasomes in podocyte injury of mice on the high fat diet: Effects of ASC gene deletion and silencing

AbstractInflammasome, an intracellular inflammatory machinery, has been reported to be involved in a variety of chronic degenerative diseases such as atherosclerosis, autoinflammatory diseases and Alzheimer's disease. The present study hypothesized that the formation and activation of inflammasomes associated with apoptosis associated speck-like protein (ASC) are an important initiating mechanism resulting in obesity-associated podocyte injury and consequent glomerular sclerosis. To test this hypothesis, Asc gene knockout (Asc−/−), wild type (Asc+/+) and intrarenal Asc shRNA-transfected wild type (Asc shRNA) mice were fed a high fat diet (HFD) or normal diet (ND) for 12weeks to produce obesity and associated glomerular injury. Western blot and RT-PCR analyses demonstrated that renal tissue Asc expression was lacking in Asc−/− mice or substantially reduced in Asc shRNA transfected mice compared to Asc+/+ mice. Confocal microscopic and co-immunoprecipitation analysis showed that the HFD enhanced the formation of inflammasome associated with Asc in podocytes as shown by colocalization of Asc with Nod-like receptor protein 3 (Nalp3). This inflammasome complex aggregation was not observed in Asc−/− and local Asc shRNA-transfected mice. The caspase-1 activity, IL-1β production and glomerular damage index (GDI) were also significantly attenuated in Asc−/− and Asc shRNA-transfected mice fed the HFD. This decreased GDI in Asc−/− and Asc shRNA transfected mice on the HFD was accompanied by attenuated proteinuria, albuminuria, foot process effacement of podocytes and loss of podocyte slit diaphragm molecules. In conclusion, activation and formation of inflammasomes in podocytes are importantly implicated in the development of obesity-associated glomerular injury

Moving in the anthropocene: global reductions in terrestrial mammalian movements

Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

DATA AND MATERIALS AVAILABILITY : The full dataset used in the final analyses (33) and associated code (34) are available at Dryad. A subset of the spatial coordinate datasets is available at Zenodo (35). Certain datasets of spatial coordinates will be available only through requests made to the authors due to conservation and Indigenous sovereignty concerns (see table S1 for more information on data use restrictions and contact information for data requests). These sensitive data will be made available upon request to qualified researchers for research purposes, provided that the data use will not threaten the study populations, such as by distribution or publication of the coordinates or detailed maps. Some datasets, such as those overseen by government agencies, have additional legal restrictions on data sharing, and researchers may need to formally apply for data access. Collaborations with data holders are generally encouraged, and in cases where data are held by Indigenous groups or institutions from regions that are under-represented in the global science community, collaboration may be required to ensure inclusion.COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals’ 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.The Radboud Excellence Initiative, the German Federal Ministry of Education and Research, the National Science Foundation, Serbian Ministry of Education, Science and Technological Development, Dutch Research Council NWO program “Advanced Instrumentation for Wildlife Protection”, Fondation Segré, RZSS, IPE, Greensboro Science Center, Houston Zoo, Jacksonville Zoo and Gardens, Nashville Zoo, Naples Zoo, Reid Park Zoo, Miller Park, WWF, ZCOG, Zoo Miami, Zoo Miami Foundation, Beauval Nature, Greenville Zoo, Riverbanks zoo and garden, SAC Zoo, La Passarelle Conservation, Parc Animalier d’Auvergne, Disney Conservation Fund, Fresno Chaffee zoo, Play for nature, North Florida Wildlife Center, Abilene Zoo, a Liber Ero Fellowship, the Fish and Wildlife Compensation Program, Habitat Conservation Trust Foundation, Teck Coal, and the Grand Teton Association. The collection of Norwegian moose data was funded by the Norwegian Environment Agency, the German Ministry of Education and Research via the SPACES II project ORYCS, the Wyoming Game and Fish Department, Wyoming Game and Fish Commission, Bureau of Land Management, Muley Fanatic Foundation (including Southwest, Kemmerer, Upper Green, and Blue Ridge Chapters), Boone and Crockett Club, Wyoming Wildlife and Natural Resources Trust, Knobloch Family Foundation, Wyoming Animal Damage Management Board, Wyoming Governor’s Big Game License Coalition, Bowhunters of Wyoming, Wyoming Outfitters and Guides Association, Pope and Young Club, US Forest Service, US Fish and Wildlife Service, the Rocky Mountain Elk Foundation, Wyoming Wild Sheep Foundation, Wild Sheep Foundation, Wyoming Wildlife/Livestock Disease Research Partnership, the US National Science Foundation [IOS-1656642 and IOS-1656527, the Spanish Ministry of Economy, Industry and Competitiveness, and by a GRUPIN research grant from the Regional Government of Asturias, Sigrid Rausing Trust, Batubay Özkan, Barbara Watkins, NSERC Discovery Grant, the Federal Aid in Wildlife Restoration act under Pittman-Robertson project, the State University of New York, College of Environmental Science and Forestry, the Ministry of Education, Youth and Sport of the Czech Republic, the Ministry of Agriculture of the Czech Republic, Rufford Foundation, an American Society of Mammalogists African Graduate Student Research Fund, the German Science Foundation, the Israeli Science Foundation, the BSF-NSF, the Ministry of Agriculture, Forestry and Food and Slovenian Research Agency (CRP V1-1626), the Aage V. Jensen Naturfond (project: Kronvildt - viden, værdier og værktøjer), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy, National Centre for Research and Development in Poland, the Slovenian Research Agency, the David Shepherd Wildlife Foundation, Disney Conservation Fund, Whitley Fund for Nature, Acton Family Giving, Zoo Basel, Columbus, Bioparc de Doué-la-Fontaine, Zoo Dresden, Zoo Idaho, Kolmården Zoo, Korkeasaari Zoo, La Passarelle, Zoo New England, Tierpark Berlin, Tulsa Zoo, the Ministry of Environment and Tourism, Government of Mongolia, the Mongolian Academy of Sciences, the Federal Aid in Wildlife Restoration act and the Illinois Department of Natural Resources, the National Science Foundation, Parks Canada, Natural Sciences and Engineering Research Council, Alberta Environment and Parks, Rocky Mountain Elk Foundation, Safari Club International and Alberta Conservation Association, the Consejo Nacional de Ciencias y Tecnología (CONACYT) of Paraguay, the Norwegian Environment Agency and the Swedish Environmental Protection Agency, EU funded Interreg SI-HR 410 Carnivora Dinarica project, Paklenica and Plitvice Lakes National Parks, UK Wolf Conservation Trust, EURONATUR and Bernd Thies Foundation, the Messerli Foundation in Switzerland and WWF Germany, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions, NASA Ecological Forecasting Program, the Ecotone Telemetry company, the French National Research Agency, LANDTHIRST, grant REPOS awarded by the i-Site MUSE thanks to the “Investissements d’avenir” program, the ANR Mov-It project, the USDA Hatch Act Formula Funding, the Fondation Segre and North American and European Zoos listed at http://www.giantanteater.org/, the Utah Division of Wildlife Resources, the Yellowstone Forever and the National Park Service, Missouri Department of Conservation, Federal Aid in Wildlife Restoration Grant, and State University of New York, various donors to the Botswana Predator Conservation Program, data from collared caribou in the Northwest Territories were made available through funds from the Department of Environment and Natural Resources, Government of the Northwest Territories. The European Research Council Horizon2020, the British Ecological Society, the Paul Jones Family Trust, and the Lord Kelvin Adam Smith fund, the Tanzania Wildlife Research Institute and Tanzania National Parks. The Eastern Shoshone and Northern Arapahoe Fish and Game Department and the Wyoming State Veterinary Laboratory, the Alaska Department of Fish and Game, Kodiak Brown Bear Trust, Rocky Mountain Elk Foundation, Koniag Native Corporation, Old Harbor Native Corporation, Afognak Native Corporation, Ouzinkie Native Corporation, Natives of Kodiak Native Corporation and the State University of New York, College of Environmental Science and Forestry, and the Slovenia Hunters Association and Slovenia Forest Service. F.C. was partly supported by the Resident Visiting Researcher Fellowship, IMéRA/Aix-Marseille Université, Marseille. This work was partially funded by the Center of Advanced Systems Understanding (CASUS), which is financed by Germany’s Federal Ministry of Education and Research (BMBF) and by the Saxon Ministry for Science, Culture and Tourism (SMWK) with tax funds on the basis of the budget approved by the Saxon State Parliament. This article is a contribution of the COVID-19 Bio-Logging Initiative, which is funded in part by the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society.https://www.science.org/journal/sciencehj2023Mammal Research InstituteZoology and Entomolog

Use of Diuretics in the Treatment of Heart Failure in Older Adults

Diuretics are the most commonly prescribed class of drugs in patients with heart failure, and in the short term they remain the most effective treatment for relief from fluid congestion. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow and sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly. In addition, the article reviews the common side effects related to diuretics

Curcumin and Chronic Kidney Disease (CKD): Major Mode of Action through Stimulating Endogenous Intestinal Alkaline Phosphatase

Curcumin, an active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa), has significant anti-inflammatory properties. Chronic kidney disease (CKD), an inflammatory disease, can lead to end stage renal disease resulting in dialysis and transplant. Furthermore, it is frequently associated with other inflammatory disease such as diabetes and cardiovascular disorders. This review will focus on the clinically relevant inflammatory molecules that play a role in CKD and associated diseases. Various enzymes, transcription factors, growth factors modulate production and action of inflammatory molecules; curcumin can blunt the generation and action of these inflammatory molecules and ameliorate CKD as well as associated inflammatory disorders. Recent studies have shown that increased intestinal permeability results in the leakage of pro-inflammatory molecules (cytokines and lipopolysaccharides) from gut into the circulation in diseases such as CKD, diabetes and atherosclerosis. This change in intestinal permeability is due to decreased expression of tight junction proteins and intestinal alkaline phosphatase (IAP). Curcumin increases the expression of IAP and tight junction proteins and corrects gut permeability. This action reduces the levels of circulatory inflammatory biomolecules. This effect of curcumin on intestine can explain why, despite poor bioavailability, curcumin has potential anti-inflammatory effects in vivo and beneficial effects on CKD