20 research outputs found
Evidence for Mechanistic Alterations of Ca2+ Homeostasis in Type 2 Diabetes Mellitus
Altered cytosolic Ca2+ is implicated in the aetiology
of many diseases including diabetes but there are
few studies on the mechanism(s) of the altered Ca2+
regulation. Using human lymphocytes, we studied
cytosolic calcium (Cai) and various Ca2+ transport
mechanisms in subjects with Type 2 diabetes
mellitus and control subjects. Ca2+-specific fluorescent
probes (Fura-2 and Fluo-3) were used to
monitor the Ca2+ signals. Thapsigargin, a potent and
specific inhibitor of the sarco(endo)plasmic reticulum
Ca2+-ATPase (SERCA), was used to study Ca2+-
store dependent Ca2+ fluxes. Significant (P < 0.05)
elevation of basal Cai levels was observed in
lymphocytes from diabetic subjects. Cai levels were
positively correlated with fasting, plasma glucose
and HbAlc. There was also a significant (P < 0.05)
reduction in plasma membrane calcium (PMCA)
ATPase activity in diabetic subjects compared to
controls. Cells from Type 2 diabetics exhibited an
increased Ca2+ influx (as measured both by Fluo-3
fliorescence and C45a assays) as a consequence of
of thapsigargin-mediated Ca2+ store depletion. Upon
addition of Mn2+ (a surrogate of Ca2+), the fura-2
fluorescence decayed in an exponential fashion and
the rate and extent of this decline was steeper and
greater in cells from type 2 diabetic patients. There
was also a significant (P < 0.05) difference in the
Na+/Ca2+ exchange activity in Type 2 diabetic
patients, both under resting conditions and after challenging the cells with thapsigargin, when the
internal store Ca2+ sequestration was circumvented.
Pharmacological activation of protein kinase C
(PKC) in cells from patients resulted in only partial
inhibition of Ca2+ entry. We conclude that cellular
Ca2+ accumulation in cells from Type 2 diabetes
results from (a) reduction in PMCA ATPase activity,
(b) modulation of Na+/Ca2+ exchange and (3)
increased Ca2+ influx across the plasma membrane
Weak signal detection: A discrete window of opportunity for achieving âVision 90:90:90â?
INTRODUCTION: UNAIDSâ Vision 90:90:90 is a call to âend AIDSâ. Developing predictive foresight of the unpredictable changes that
this journey will entail could contribute to the ambition of âending AIDSâ. There are few opportunities for managing
unpredictable changes. We introduce âweak signal detectionâ as a potential opportunity to fill this void. METHOD: Combining
futures and complexity theory, we reflect on two pilot case studies that involved the Archetype Extraction technique and the
SenseMakerw CollectorTM tool. RESULTS: Both the piloted techniques have the potentials to surface weak signals but there is
room for improvement. DISCUSSION: A management response to a complex weak signal requires pattern management, rather
than an exclusive focus on behaviour management. CONCLUSION: Weak signal detection is a window of opportunity to improve
resilience to unpredictable changes in the HIV/AIDS landscape that can both reduce the risk that emerges from the changes and
increase the visibility of opportunities to exploit the unpredictable changes that could contribute to âending AIDSâ.IS
Evidence for mechanistic alterations of Ca<SUP>2+</SUP> homeostasis in Type 2 diabetes mellitus
Altered cytosolic Ca2+ is implicated in the aetiology of many diseases including diabetes but there are few studies on the mechanism(s) of the altered Ca2+ regulation. Using human lymphocytes, we studied cytosolic calcium (Cai) and various Ca2+ transport mechanisms in subjects with Type 2 diabetes mellitus and control subjects. Ca2+-specific fluorescent probes (Fura-2 and Fluo-3) were used to monitor the Ca2+ signals. Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was used to study Ca2+-store dependent Ca2+ fluxes. Significant (P<0.05) elevation of basal Ca, levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting plasma glucose and HbA1c. There was also a significant (P<0.05) reduction in plasma membrane calcium (PMCA) ATPase activity in diabetic subjects compared to controls. Cells from Type 2 diabetics exhibited an increased Ca2+ influx (as measured both by Fluo-3 fluorescence and 45Ca assays) as a consequence of thapsigargin-mediated Ca2+ store depletion. Upon addition of Mn2+ (a surrogate of Ca2+), the fura-2 fluorescence decayed in an exponential fashion and the rate and extent of this decline was steeper and greater in cells from type 2 diabetic patients. There was also a significant (P<0.05) difference in the Na+/Ca2+ exchange activity in Type 2 diabetic patients, both under resting conditions and after challenging the cells with thapsigargin, when the internal store Ca2+ sequestration was circumvented. Pharmacological activation of protein kinase C (PKC) in cells from patients resulted in only partial inhibition of Ca2+ entry. We conclude that cellular Ca2+ accumulation in cells from Type 2 diabetes results from (a) reduction in PMCA ATPase activity, (b) modulation of Na+/Ca2+ exchange and (3) increased Ca2+ influx across the plasma membrane
Erratum for:Echocardiography versus Cardiac MRI for Measurement of Left Ventricular Ejection Fraction in Individuals with Cancer and Suspected Cardiotoxicity (Radiology: Cardiothoracic Imaging 2024;6(1))
Royal Brompton Cardio-Oncology Centre of Excellence supported by the The Big Heart Foundation was moved from the disclosures of conflicts of interest section to the funding section. In the Study Participants section, at Guyâs and St Thomasâ Hospital was added to the sentence âThe study was approved by the institutional review boards at Guyâs and St Thomasâ Hospital and the Health Research Authority.â</p
SYNTHESIS OF SPIRO-1-PYRAZOLINES BY THE REACTION OF Z-3-ARYLIDENE-1-THIOFLAVANONES WITH DIAZOMETHANE
Echocardiography versus Cardiac MRI for Measurement of Left Ventricular Ejection Fraction in Individuals with Cancer and Suspected Cardiotoxicity
Two-dimensional echocardiography showed large variations compared with reference standard cardiac MRI for left ventricular ejection fraction measurement, which may lead to downstream impact on clinical decision-making for cardio-oncology patients.Purpose:To compare left ventricular ejection fraction (LVEF) measured with echocardiography and cardiac MRI in individuals with cancer and suspected cardiotoxicity and assess the potential effect on downstream clinical decision-making.Materials and Methods:In this prospective, single-center observational cohort study, participants underwent same-day two-dimensional (2D) echocardiography and cardiac MRI between 2011 and 2021. Participants with suboptimal image quality were excluded. A subset of 74 participants also underwent three-dimensional (3D) echocardiography. The agreement of LVEF derived from each modality was assessed using Bland-Altman analysis and at relevant thresholds for cardiotoxicity.Results:A total of 745 participants (mean age, 60 years ± 5 [SD]; 460 [61.7%] female participants) underwent same-day echocardiography and cardiac MRI. According to Bland-Altman analysis, the mean bias was â3.7% ± 7.6 (95% limits of agreement [LOA]: â18.5% to 11.1%) for 2D echocardiography versus cardiac MRI. In 74 participants who underwent cardiac MRI, 3D echocardiography, and 2D echocardiography, the mean LVEFs were 60.0% ± 10.4, 58.4% ± 9.4, and 57.2% ± 8.9, respectively (P < .001). At the 50% LVEF threshold for detection of cardiotoxicity, there was disagreement for 9.3% of participants with 2D echocardiography and cardiac MRI. Agreement was better with 3D echocardiography and cardiac MRI (mean bias, â1.6% ± 6.3 [95% LOA: â13.9% to 10.7%]) compared with 2D echocardiography and cardiac MRI (mean bias, â2.8% ± 6.3 [95% LOA: â15.2% to 9.6%]; P = .016).Conclusion: Two-dimensional echocardiography had variations of ±15% for LVEF measurement compared with cardiac MRI in participants with cancer and led to misclassification of approximately 10% of participants for cardiotoxicity detection. Three-dimensional echocardiography had better agreement with cardiac MRI and should be used as first-line imaging