Inhibition of aldose reductase by dietary antioxidant curcumin: Mechanism of inhibition, specificity and significance

AbstractAccumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. In this study we show that curcumin inhibits ALR2 with an IC50 of 10μM in a non-competitive manner, but is a poor inhibitor of closely-related members of the aldo-keto reductase superfamily, particularly aldehyde reductase. Results from molecular docking studies are consistent with the pattern of inhibition of ALR2 by curcumin and its specificity. Moreover, curcumin is able to suppress sorbitol accumulation in human erythrocytes under high glucose conditions, demonstrating an in vivo potential of curcumin to prevent sorbitol accumulation. These results suggest that curcumin holds promise as an agent to prevent or treat diabetic complications

Tachyon: Reliable, Memory Speed Storage for Cluster Computing Frameworks

Tachyon is a distributed file system enabling reliable data sharing at memory speed across cluster computing frameworks. While caching today improves read workloads, writes are either network or disk bound, as replication is used for fault-tolerance. Tachyon eliminates this bottleneck by pushing lineage, a well-known technique, into the storage layer. The key challenge in making a long-running lineage-based storage system is timely data recovery in case of failures. Tachyon addresses this issue by introducing a checkpointing algorithm that guarantees bounded recovery cost and resource allocation strategies for recomputation under commonly used resource schedulers. Our evaluation shows that Tachyon outperforms in-memory HDFS by 110x for writes. It also improves the end-to-end latency of a realistic workflow by 4x. Tachyon is open source and is deployed at multiple companies.National Science Foundation (U.S.) (CISE Expeditions Award CCF-1139158)Lawrence Berkeley National Laboratory (Award 7076018)United States. Defense Advanced Research Projects Agency (XData Award FA8750-12-2-0331

Pitfalls of Single Measurement Screening for Diabetes and Hypertension in Community-Based Settings

Background: Cross-sectional screening programs are used to detect and refer individuals with non-communicable diseases to healthcare services. We evaluated the positive predictive value of cross-sectional measurements for Diabetes Mellitus (DM) and hypertension (HTN) as part of a community-based disease screening study, ‘Vukuzazi’ in rural South Africa. Methods: We conducted community-based screening for HTN and DM using the World Health Organization STEPS protocol and glycated haemoglobin A1c (HbA1c) testing, respectively. Nurses conducted follow-up home visits for confirmatory diagnostic testing among individuals with a screening BP above 140/90 mmHg and/or HbA1c above 6.5% at the initial screen, and without a prior diagnosis. We assessed the positive predictive value of the initial screening, compared to the follow up measure. We also sought to identify a screening threshold for HTN and DM with greater than 90% positive predictive value. Results: Of 18,027 participants enrolled, 10.2% (1,831) had a screening BP over 140/90 mmHg. Of those without a prior diagnosis, 871 (47.6%) received follow-up measurements. Only 51.2% (451) of those with completed follow-up measurements had a repeat BP>140/90 mmHg at the home visit and were referred to care. To achieve a 90% correct referral rate, a systolic BP threshold of 192 was needed at first screening. For DM screening, 1,615 (9.0%) individuals had an HbA1c > 6.5%, and of those without a prior diagnosis, 1,151 (71.2%) received a follow-up blood glucose. Of these, only 34.1% (395) met criteria for referral for DM. To ensure a 90% positive predictive value i.e. a screening HbA1c of >16.6% was needed. Conclusions: A second home-based screening visit to confirm a diagnosis of DM and HTN reduced health system referrals by 48% and 66%, respectively. Two-day screening programmes for DM and HTN screening might save individual and healthcare resources and should be evaluated carefully in future cost effectiveness evaluations

Taking up the cudgels against gay rights? Trends and trajectories in African Christian theologies on homosexuality

Against the background of the HIV epidemic and the intense public controversy on homosexuality in African societies, this article investigates the discourses of academic African Christian theologians on homosexuality. Distinguishing some major strands in African theology, that is, inculturation, liberation, women’s and reconstruction theology, the article examines how the central concepts of culture, liberation, justice, and human rights function in these discourses. On the basis of a qualitative analysis of a large number of publications, the article shows that stances of African theologians are varying from silence and rejection to acceptance. Although many African theologians have taken up the cudgels against gay rights, some “dissident voices” break the taboo and develop more inclusive concepts of African identity and African Christianity

Protective behaviours and secondary harms from non-pharmaceutical interventions during the COVID-19 epidemic in South Africa: a multisite prospective longitudinal study

BACKGROUND: In March 2020 South Africa implemented strict non-pharmaceutical interventions (NPIs) to contain Covid-19. Over the subsequent five months NPIs were eased in stages according to national strategy. Covid-19 spread throughout the country heterogeneously, reaching rural areas by July and peaking in July-August. Data on the impact of NPI policies on social and economic wellbeing and access to healthcare is limited. We therefore analysed how rural residents of three South African provinces changed their behaviour during the first epidemic wave. METHODS: The South African Population Research Infrastructure Network (SAPRIN) nodes in Mpumalanga (Agincourt), KwaZulu-Natal (AHRI) and Limpopo (DIMAMO) provinces conducted longitudinal telephone surveys among randomly sampled households from rural and peri-urban surveillance populations every 2-3 weeks. Interviews included questions on: Covid-19 knowledge and behaviours; health and economic impact of NPIs; and mental health. RESULTS: 2262 households completed 10,966 interviews between April and August 2020. By August, self-reported satisfaction with Covid-19 knowledge had risen from 48% to 85% and facemask use to over 95%. As selected NPIs were eased mobility increased, and economic losses and anxiety and depression symptoms fell. When Covid-19 cases spiked at one node in July, movement dropped rapidly, and missed daily medication rates doubled. Economic concerns and mental health symptoms were lower in households receiving a greater number of government-funded old-age pensions. CONCLUSIONS: South Africans reported complying with stringent Covid-19 NPIs despite the threat of substantial social, economic and health repercussions. Government-supported social welfare programmes appeared to buffer interruptions in income and healthcare access during local outbreaks. Epidemic control policies must be balanced against impacts on wellbeing in resource-limited settings and designed with parallel support systems where they threaten income and basic service access

Prevalence of Mycobacterium tuberculosis in sputum and reported symptoms among clinic attendees compared to a community survey in rural South Africa

BACKGROUND: Tuberculosis (TB) case finding efforts typically target symptomatic people attending health facilities. We compared the prevalence of Mycobacterium tuberculosis (Mtb) sputum culture-positivity among adult clinic attendees in rural South Africa with a concurrent, community-based estimate from the surrounding demographic surveillance area (DSA). METHODS: Clinic: Randomly-selected adults (≥18 years) attending two primary healthcare clinics were interviewed and requested to give sputum for mycobacterial culture. HIV and antiretroviral therapy (ART) status were based on self-report and record review. Community: All adult (≥15 years) DSA residents were invited to a mobile clinic for health screening, including serological HIV testing; those with ≥1 TB symptom (cough, weight loss, night sweats, fever) or abnormal chest radiograph were asked for sputum. RESULTS: Clinic: 2,055 patients were enrolled (76.9% female, median age 36 years); 1,479 (72.0%) were classified HIV-positive (98.9% on ART) and 131 (6.4%) reported ≥1 TB symptom. Of 20/2,055 (1.0% [95% CI 0.6-1.5]) with Mtb culture-positive sputum, 14 (70%) reported no symptoms. Community: 10,320 residents were enrolled (68.3% female, median age 38 years); 3,105 (30.3%) tested HIV-positive (87.4% on ART) and 1,091 (10.6%) reported ≥1 TB symptom. Of 58/10,320 (0.6% [95% CI 0.4-0.7]) with Mtb culture-positive sputum, 45 (77.6%) reported no symptoms.In both surveys, sputum culture positivity was associated with male sex and reporting >1 TB symptom. CONCLUSIONS: In both clinic and community settings, most participants with Mtb culture-positive sputum were asymptomatic. TB screening based only on symptoms will miss many people with active disease in both settings

The impact of whole human blood on the kinetic inertness of platinum(IV) prodrugs - an HPLC-ICP-MS study

The potential advantage of platinum(IV) complexes as alternative to classical platinum(II)-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow was developed to investigate the reductive biotransformation and kinetic inertness of platinum(IV) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of the platinum(IV) complexes in blood pellet and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. An analytical approach based on reversed-phase (RP)-ICP-MS was used to monitor the parent compound and the formation of metabolites using two different extraction procedures. The ligand coordination sphere of the platinum(IV) complexes had significant impact on their accumulation in red blood cells and on their degree of kinetic inertness in whole human blood. The most lipophilic platinum(IV) compound featuring equatorial chlorido ligands showed a pronounced penetration into blood cells and a rapid reductive biotransformation. In contrast, the more hydrophilic platinum(IV) complexes with a carboplatin- and oxaliplatin-core exerted kinetic inertness on a pharmacologically relevant time scale with notable amounts of the compound accumulated in the plasma fraction

Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC

Investigation of tumor hypoxia using a two-enzyme system for in vitro generation of oxygen deficiency

<p>Abstract</p> <p>Background</p> <p>Oxygen deficiency in tumor tissue is associated with a malign phenotype, characterized by high invasiveness, increased metastatic potential and poor prognosis. Hypoxia chambers are the established standard model for <it>in vitro </it>studies on tumor hypoxia. An enzymatic hypoxia system (GOX/CAT) based on the use of glucose oxidase (GOX) and catalase (CAT) that allows induction of stable hypoxia for <it>in vitro </it>approaches more rapidly and with less operating expense has been introduced recently. Aim of this work is to compare the enzymatic system with the established technique of hypoxia chamber in respect of gene expression, glucose metabolism and radioresistance, prior to its application for <it>in vitro </it>investigation of oxygen deficiency.</p> <p>Methods</p> <p>Human head and neck squamous cell carcinoma HNO97 cells were incubated under normoxic and hypoxic conditions using both hypoxia chamber and the enzymatic model. Gene expression was investigated using Agilent microarray chips and real time PCR analysis. ¹⁴C-fluoro-deoxy-glucose uptake experiments were performed in order to evaluate cellular metabolism. Cell proliferation after photon irradiation was investigated for evaluation of radioresistance under normoxia and hypoxia using both a hypoxia chamber and the enzymatic system.</p> <p>Results</p> <p>The microarray analysis revealed a similar trend in the expression of known HIF-1 target genes between the two hypoxia systems for HNO97 cells. Quantitative RT-PCR demonstrated different kinetic patterns in the expression of carbonic anhydrase IX and lysyl oxidase, which might be due to the faster induction of hypoxia by the enzymatic system. ¹⁴C-fluoro-deoxy-glucose uptake assays showed a higher glucose metabolism under hypoxic conditions, especially for the enzymatic system. Proliferation experiments after photon irradiation revealed increased survival rates for the enzymatic model compared to hypoxia chamber and normoxia, indicating enhanced resistance to irradiation. While the GOX/CAT system allows independent investigation of hypoxia and oxidative stress, care must be taken to prevent acidification during longer incubation.</p> <p>Conclusion</p> <p>The results of our study indicate that the enzymatic model can find application for <it>in vitro </it>investigation of tumor hypoxia, despite limitations that need to be considered in the experimental design.</p

Application of Diffusion Tensor Imaging Parameters to Detect Change in Longitudinal Studies in Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is the major cause of vascular cognitive impairment, resulting in significant disability and reduced quality of life. Cognitive tests have been shown to be insensitive to change in longitudinal studies and, therefore, sensitive surrogate markers are needed to monitor disease progression and assess treatment effects in clinical trials. Diffusion tensor imaging (DTI) is thought to offer great potential in this regard. Sensitivity of the various parameters that can be derived from DTI is however unknown. We aimed to evaluate the differential sensitivity of DTI markers to detect SVD progression, and to estimate sample sizes required to assess therapeutic interventions aimed at halting decline based on DTI data. We investigated 99 patients with symptomatic SVD, defined as clinical lacunar syndrome with MRI confirmation of a corresponding infarct as well as confluent white matter hyperintensities over a 3 year follow-up period. We evaluated change in DTI histogram parameters using linear mixed effect models and calculated sample size estimates. Over a three-year follow-up period we observed a decline in fractional anisotropy and increase in diffusivity in white matter tissue and most parameters changed significantly. Mean diffusivity peak height was the most sensitive marker for SVD progression as it had the smallest sample size estimate. This suggests disease progression can be monitored sensitively using DTI histogram analysis and confirms DTI's potential as surrogate marker for SVD