Coulombic Surface-Ion Interactions Induce Nonlinear and Chemistry-Specific Charging Kinetics.

While important for many industrial applications, chemical reactions responsible for the charging of solids in water are often poorly understood. We theoretically investigate the charging kinetics of solid-liquid interfaces and find that the time-dependent equilibration of surface charge contains key information not only on the reaction mechanism, but also on the valency of the reacting ions. We construct a nonlinear differential equation describing surface charging by combining chemical Langmuir kinetics and electrostatic Poisson-Boltzmann theory. Our results reveal a clear distinction between late-time (near-equilibrium) and short-time (far-from-equilibrium) relaxation rates, the ratio of which contains information on the charge valency and ad- or desorption mechanism of the charging process. Similarly, we find that single-ion reactions can be distinguished from two-ion reactions, as the latter show an inflection point during equilibration. Interestingly, such inflection points are characteristic of autocatalytic reactions, and we conclude that the Coulombic ion-surface interaction is an autocatalytic feedback mechanism.

Iontronic Neuromorphic Signaling with Conical Microfluidic Memristors.

Experiments have shown that the conductance of conical channels, filled with an aqueous electrolyte, can strongly depend on the history of the applied voltage. These channels hence have a memory and are promising elements in brain-inspired (iontronic) circuits. We show here that the memory of such channels stems from transient concentration polarization over the ionic diffusion time. We derive an analytic approximation for these dynamics which shows good agreement with full finite-element calculations. Using our analytic approximation, we propose an experimentally realizable Hodgkin-Huxley iontronic circuit where micrometer cones take on the role of sodium and potassium channels. Our proposed circuit exhibits key features of neuronal communication such as all-or-none action potentials upon a pulse stimulus and a spike train upon a sustained stimulus.

Unveiling the capabilities of bipolar conical channels in neuromorphic iontronics.

Conical channels filled with an aqueous electrolyte have been proposed as promising candidates for iontronic neuromorphic circuits. This is facilitated by a novel analytical model for the internal channel dynamics [T. M. Kamsma, W. Q. Boon, T. ter Rele, C. Spitoni and R. van Roij, Phys. Rev. Lett., 2023, 130(26), 268401], the relative ease of fabrication of conical channels, and the wide range of achievable memory retention times by varying the channel lengths. In this work, we demonstrate that the analytical model for conical channels can be generalized to channels with an inhomogeneous surface charge distribution, which we predict to exhibit significantly stronger current rectification and more pronounced memristive properties in the case of bipolar channels, i.e. channels where the tip and base carry a surface charge of opposite sign. Additionally, we show that the use of bipolar conical channels in a previously proposed iontronic circuit features hallmarks of neuronal communication, such as all-or-none action potentials and spike train generation. Bipolar channels allow, however, for circuit parameters in the range of their biological analogues, and exhibit membrane potentials that match well with biological mammalian action potentials, further supporting their potential biocompatibility.

Going to war on COVID-19: Mobilizing an academic nephrology group practice.

AIM: The COVID-19 pandemic poses unprecedented operational challenges to nephrology divisions in every country as they cope with COVID-19-related kidney disease in addition to regular patient care. Although general approaches have been proposed, there is a lack of practical guidance for nephrology division response in a hospital facing a surge of cases. Here, we describe the specific measures that our division has taken in the hope that our experience in Singapore may be helpful to others. METHODS: Descriptive narrative. RESULTS: A compilation of operational responses to the COVID-19 pandemic taken by a nephrology division at a Singapore university hospital. CONCLUSION: Nephrology operational readiness for COVID-19 requires a clinical mindset shift from usual standard of care to a crisis exigency model that targets best outcomes for available resources. Rapid multi-disciplinary efforts that evolve flexibly with the local dynamics of the outbreak are required.

Mental health problems and hypertension in the elderly: Review from the HOPE Asia Network.

The "triple burden" of aging population, hypertension, and mental health problems making elderly in Asia is more vulnerable. There is evidence of a bidirectional relationship between mental health and hypertension, which results in lower quality of life, lower rate of treatment adherence, and higher mortality among elderly individuals. It is essential to overcome known barriers and care for the elderly with high-risk factors in order to address these burdens. This review revealed that elderly with hypertension were more likely to suffer from depression and anxiety. Therefore, debunking myths, creating awareness regarding mental health, and increasing access to mental health resources through holistic community-based programs would greatly reduce such problems and optimize the chances of success in controlling hypertension-related problems.

Prostate cancer in multi-ethnic Asian men: Real-world experience in the Malaysia Prostate Cancer (M-CaP) Study.

Prostate cancer is the third most common cancer in Malaysia with the lifetime risk of 1 in 117 men. Here, we initiated a longitudinal Malaysia Prostate Cancer (M-CaP) Study to investigate the clinical and tumour characteristics, treatment patterns as well as disease outcomes of multi-ethnic Asian men at real-world setting. The M-CaP database consisted of 1839 new patients with prostate cancer diagnosed between 2016 and 2018 from nine public urology referral centres across Malaysia. Basic demographic and clinical parameters, tumour characteristics, primary treatment, follow-up and vital status data were retrieved prospectively from the hospital-based patients' case notes or electronic medical records. Primary endpoints were overall survival (OS) and biochemical progression-free survival (bPFS). The median age at diagnosis of M-CaP patients was 70 years (interquartile range, IQR 65-75). Majority of patients were Chinese (831, 45.2%), followed by Malays (704, 38.3%), Indians (124, 6.7%) and other races (181, 9.8%). The median follow-up for all patients was 23.5 months (IQR 15.9-33.6). Although 58.1% presented with late-stage cancer, we observed ethnic and geographic disparities in late-stage prostate cancer diagnosis. Curative radiotherapy and primary androgen deprivation therapy were the most common treatment for stage III and stage IV diseases, respectively. The median OS and bPFS of stage IV patients were 40.1 months and 19.2 months (95% CI 17.6-20.8), respectively. Late stage at presentation remains a challenge in multi-ethnic Asian men. Early detection is imperative to improve treatment outcome and survival of patients with prostate cancer.

Comparison of guidelines for the management of hypertension: Similarities and differences between international and Asian countries; perspectives from HOPE-Asia Network.

Guidelines on the management of hypertension have been developed by various professional bodies and institutions to primarily address the issues of diagnosis, treatment, and control in order to rationalize and improve the management of hypertension. Hypertension guidelines across the world have recently been updated following the new and controversial lower blood pressure threshold of ≥130/80 mmHg for the diagnosis of hypertension adopted by the Americans. While there are differences between the major as well as between the Asian national guidelines, there were also many similarities. This paper discusses and highlights the differences and similarities between the major international guidelines of the American College of Cardiology/American Heart Association, of the European Society of Cardiology/European Society of Hypertension, and of the International Society of Hypertension and also compares them with the Asian guidelines.

The choice of estimating equations for glomerular filtration rate significantly affects the prevalence of chronic kidney disease in a multi-ethnic population during health screening.

BACKGROUND: Patients present to the National University Hospital of Singapore and select one of several health screening packages after counselling. The prevalence of chronic kidney disease (CKD) in this population when different glomerular filtration rate (GFR) estimating equations are used has not been examined. METHODS: Demographic data and urinalyses of patients from 2000 to 2005 were extracted from laboratory computer databases and analysed. CKD was classified into stages according to the US National Kidney Foundation guidelines by eGFR (mL/min per 1.73 m(2)) using the four-variable Modification of Diet in Renal Disease equation. GFR of ethnic Chinese was also estimated using Ma's equation 8 (cGFR). Stage 1 and normal (eGFR or cGFR > 90) was discriminated by urinary microscopy or dipstick for proteinuria, albuminuria, hematuria or leukocyturia. RESULTS: There were 3979 screenings (55.9% males, 61.9% Chinese). Means: age = 47.0 +/- 12.3 years, creatinine = 80.1 +/- 26.5 micromol/L, eGFR = 89.6 +/- 19.7, cGFR = 110.8 +/- 23.8 and (eGFR + cGFR) = 102.5 +/- 24.9. By eGFR in all patients, the prevalence of CKD was 45.7%, 50.6%, 3.3%, 0.3% and 0.08% for stages normal or 1, 2, 3, 4 and 5, respectively. For Chinese patients only, eGFR and cGFR resulted in a different distribution (eGFR%/cGFR%): 24.9/50.5, 15.2/29.3, 56.8/19.7, 3/0.8, 0.2/0.2, 0/0 for stages 'Normal', 1, 2, 3, 4 and 5, respectively (P < 0.001). CONCLUSION: The prevalence of moderate to severe CKD (stage 3 to 5) in patients presenting for health screening in Singapore was 3.7%. Notably, the prevalence of mild to moderate CKD (stages 1, 2 and 3) in Chinese patients was affected significantly by the choice of GFR estimating equation.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.

Estrogen and adiposity--utilizing models of aromatase deficiency to explore the relationship.

Estrogen has an important role to play in energy homeostasis in both men and mice. Lack of estrogen results in the development of a metabolic syndrome in humans and rodents, including excess adiposity, hepatic steatosis (in male but not female aromatase knockout (ArKO) mice) and insulin resistance. Estrogen replacement results in a prompt reversal of the energy imbalance symptoms associated with estrogen deficiency. A corollary to the perturbed energy balance observed in the ArKO mouse is the death by apoptosis of dopaminergic neurons in the hypothalamic arcuate nucleus of male ArKO mice, an area of the brain pivotal to the regulation of energy uptake, storage, and mobilisation. An extension of our work exploring the relationship between estrogen and adiposity has been to examine the role played by androgens in energy balance. We have demonstrated that an increased androgen to estrogen ratio can promote visceral fat accumulation in the rodent by inhibiting AMPK activation and stimulating lipogenesis. Therefore, understanding the regulation of energy homeostasis is becoming an increasingly fascinating challenge, as the number of contributors, their communications, and the complexity of their interactions, involved in the preservation of this equilibrium continues to increase. Models of aromatase deficiency, both naturally occurring and engineered, will continue to provide valuable insights into energy homeostasis.

Identification of genes potentially involved in rupture of human atherosclerotic plaques.

Although rupture of an atherosclerotic plaque is the major cause of acute vascular occlusion, the exact molecular mechanisms underlying this process are still poorly understood. In this study, we used suppression subtractive hybridization to make an inventory of genes that are differentially expressed in whole-mount human stable and ruptured plaques. Two libraries were generated, one containing 3000 clones upregulated and one containing 2000 clones downregulated in ruptured plaques. Macroarray analysis of 500 randomly chosen clones showed differential expression of 45 clones. Among the 25 clones that showed at least a 2-fold difference in expression was the gene of perilipin, upregulated in ruptured plaques, and the genes coding for fibronectin and immunoglobulin lambda chain, which were downregulated in ruptured plaques. Reverse transcriptase-polymerase chain reaction analysis on 10 individual ruptured and 10 individual stable plaques showed a striking consistency of expression for the clones SSH6, present in 8 ruptured and 2 stable plaques, and perilipin, expressed in 8 ruptured plaques and completely absent in stable plaques. Localization studies of both perilipin mRNA and protein revealed expression in cells surrounding the cholesterol clefts and in foam cells of ruptured atherosclerotic plaques. No expression was observed in nondiseased artery, and only a few cells in the shoulder region of stable plaques tested positive for perilipin. In conclusion, this study shows that it is possible to identify genes that are differentially expressed in whole-mount stable or ruptured atherosclerotic plaques. This approach may yield several potential regulators of plaque destabilization.

A multi-agent cell-based model for wound contraction.

A mathematical model for wound contraction is presented. The model is based on a cell-based formalism where fibroblasts, myofibroblasts and the immune reaction are taken into account. The model is used to simulate contraction of a wound using point forces on the cell boundary and it also determines the orientation of collagen after restoration of the damage. The paper presents the mathematical model in terms of the equations and assumptions, as well as some implications of the modelling. The present model predicts that the amount of final contraction is larger if the migration velocity of the leukocytes is larger and hence it is important that the immune system functions well to prevent contractures. Further, the present model is the first cell-based model that combines the immune system to final contractions.

Restoration of the Dopamine Transporter through Cell Therapy Improves Dyskinesia in a Rat Model of Parkinson's Disease.

The dyskinesia of Parkinson's Disease is most likely due to excess levels of dopamine in the striatum. The mechanism may be due to aberrant synthesis but also, a deficiency or absence of the Dopamine Transporter. In this study we have examined the proposition that reinstating Dopamine Transporter expression in the striatum would reduce dyskinesia. We transplanted c17.2 cells that stably expressed the Dopamine Transporter into dyskinetic rats. There was a reduction in dyskinesia in rats that received grafts expressing the Dopamine Transporter. Strategies designed to increase Dopamine Transporter in the striatum may be useful in treating the dyskinesia associated with human Parkinson's Disease.

Cloning and expression analysis of a cytochrome P-450(11 beta) cDNA in sheep.

A full length ovine steroid 11 beta-hydroxylase (cytochrome P-450(11 beta)) cDNA clone from a sheep adrenal cortex cDNA library was isolated. Sequence analysis indicates that this cDNA clone resembles bovine P-450(11 beta) cDNA (95% nucleotide sequence homology) more closely than rat P-450(11 beta) cDNA (69% nucleotide sequence homology). Although the levels of nucleotide sequence homology of this cDNA clone to the rat P-450(11 beta) cDNA and the rat P-450aldo cDNA are similar, the putative amino acid sequence shows a closer resemblance to rat P-450aldo protein. Northern blot analysis shows that there are three sizes of transcript and they are expressed throughout the adrenal cortex.

Aldosterone secretion: a molecular perspective.

The major mineralocorticoid hormone aldosterone is secreted from the zona glomerulosa of the adrenal cortex. Aldosterone is synthesized from cholesterol via a series of hydroxylations and oxidations. The enzymes involved in these reactions are mostly members of the cytochrome P450 superfamily. The final steps of this pathway, the conversion of 11-deoxycorticosterone (DOC) to aldosterone, require conversion via the intermediates 18-hydroxy-DOC or corticosterone and 18-hydroxycorticosterone. There are significant differences between species in the number of genes that encode the P450(11beta)-related enzymes (CYP11B) involved in these steps and the zonal distribution of their expression. One enzyme is capable of 11-hydroxylation, 18-hydroxylation, and 18-oxidation of DOC to aldosterone. The genetic basis of four diseases-congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency, glucocorticoid-remediable aldosteronism, aldosterone synthase deficiency type I and type II-is explicable by mutations in these cytochrome P450(11beta)-related genes.

Use of the conditional marketing authorization pathway for oncology medicines in Europe.

Conditional marketing authorization (CMA) in the European Union (EU) is an early access pathway for medicines that show promising therapeutic effects, but for which comprehensive data are not available. Using a mixed quantitative-qualitative research design, we evaluated how CMA has been used in marketing authorization of oncology medicines in the period 2006 to 2013. We show that compared to full marketing authorization, CMA is granted based on less comprehensive data. However, this is accompanied by significantly longer assessment times and less consensus among regulators about marketing authorization. Moreover, development time from first-in-human testing to marketing authorization did not differ between full marketing authorization and CMA, but was significantly longer for CMA compared to accelerated approved products in the United States (US). Results indicate that CMA is not used by companies as a prospectively planned pathway to obtain early access, but as a "rescue option" when submitted data are not strong enough to justify full marketing authorization.

Aldosterone secretion by the mid-gestation ovine fetus: role of the AT2 receptor.

This study shows a short-term (3 h) infusion of ACTH but not angiotensin II (Ang II) stimulates aldosterone production in the mid-gestation fetus. No synergistic effect between ACTH and Ang II was observed. The fetal response was significantly less than observed in the adult animal when infused in a similar manner. Interestingly, plasma aldosterone could be stimulated by Ang II in the presence of a specific AT2 receptor blocker. This suggests that the inability of Ang II to stimulate aldosterone may be due in part to Ang II binding to the AT2 receptor and limiting the amount of available Ang II and/or antagonising the effects of Ang II on the AT1 receptor.

Lack of influence of co-trimoxazole on theophylline pharmacokinetics.

In an open cross-over experiment, the influence of the antimicrobial agent co-trimoxazole on the single-dose pharmacokinetics of theophylline was studied in six healthy adults by comparing the pharmacokinetic parameters found after intravenous administration of theophylline without and with co-medication of co-trimoxazole for the previous 8 d. Theophylline concentrations in plasma were measured by high-performance liquid chromatography (HPLC) analysis. During each treatment, a concentration-time curve was evaluated. No influence of co-trimoxazole on the rate of elimination and volume of distribution of theophylline could be found, as a result of which theophylline concentrations in plasma were not significantly different in both periods of drug administration. A similar lack of influence of co-trimoxazole may apply to the steady-state pharmacokinetics of theophylline. The present study suggests that both drugs can be given concomitantly without the need for dosage adjustment of theophylline.

Prototyping with AIDA for a hospital pharmacy system.

The CENTRASYS system for the Hospital Pharmacy, developed as part of a research project of the Department of Medical Informatics is described. The role of AIDA, a fourth-generation software package, as a prototyping tool is discussed. It is concluded that AIDA facilitates prototyping and is also very suitable as a vehicle for systems in operation. It is further concluded that prototyping is of great help in the developmental phase of a project, but that great care has to be taken during evaluation of the prototypes: minimize the number of test sites and try to avoid that users become dependent on the system, because every prototype needs further tuning before it really becomes an operational system.