Endothelial TRPV4 Dysfunction in a Streptozotocin-Diabetic Rat Model

Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia due to compromised insulin synthesis and secretion, or decreased tissue sensitivity to insulin, if not all three conditions. Endothelial dysfunction is a common complication in diabetes in which endothelium-dependent vasodilation is impaired. The aim of this study was to examine the involvement of TRPV4 in diabetes endothelial dysfunction. Male Charles River Wistar rats (350–450 g) were injected with 65mg/kg streptozotocin (STZ) intraperitoneally. STZ-injected rats were compared with naïve rats (not injected with STZ) or control rats (injected with 10ml/kg of 20mM citrate buffer, pH 4.0–4.5), if not both. Rats with blood glucose concentrations greater than 16mmol/L were considered to be diabetic. As the results revealed, STZ-diabetic rats showed significant endothelial dysfunction characterised by impaired muscarinic-induced vasodilation, as well as significant impairment in TRPV4-induced vasodilation in aortic rings and mesenteric arteries. Furthermore, STZ-diabetic primary aortic endothelial cells (ECs) showed a significant reduction in TRPV4-induced intracellular calcium ([Ca2+]i) elevation. TRPV4, endothelial nitric oxide synthase (eNOS), and caveolin-1 (CAV-1) were also significantly downregulated in STZ-diabetic primary aortic ECs and were later significantly restored by in vitro insulin treatment. Methylglyoxal (MGO) was significantly elevated in STZ-diabetic rat serum, and nondiabetic aortic rings incubated with MGO (100μM) for 12 hours showed significant endothelial dysfunction. Moreover, nondiabetic primary aortic ECs treated with MGO (100μM) for 5 days showed significant TRPV4 downregulation and significant suppression of 4-α-PDD-induced [Ca2+]i elevation, which was later restored by L-arginine (100μM) co-incubation. Incubating nondiabetic aortic rings with MGO (100μM) for 2 hours induced a spontaneous loss of noradrenaline-induced contractility persistence. Moreover, MGO induced significant [Ca2+]i elevation in Chinese hamster ovary cells expressing rat TRPM8 channels (rTRPM8), which was significantly inhibited by AMTB (1–5μM). Taken together, TRPV4, CAV-1, and eNOS can form a functional complex that is downregulated in STZ-diabetic aortic ECs and restored by insulin treatment. MGO elevation might furthermore contribute to diabetes endothelial dysfunction and TRPV4 downregulation. By contrast, MGO induced the loss of contractility persistence, possibly due to MGO’s acting as a TRPM8 agonist

Calix[4]pyrrole macrocycle: Extraction of fluoride anions from aqueous media

Solid-phase extraction of fluoride anions by calixpyrrole macrocycle (CP) from aqueous media has been studied using the batch method. Various significant extraction parameters like initial concentration of the anion, extraction time, concentration of the calixpyrrole, pH and temperature were evaluated. Langmuir, Freundlichand, Dubinin-Redushkevish (D-R) isotherms and coefficients were used to analyze the equilibrium data. The amount of fluoride anion extracted per unit of the CP was found to be 0.40 mg/g at 298 K from 19 mg/L aqueous solution of fluoride anions. The mean free energy calculated from D-R model for the removal of fluoride anions by the CP was found to be 10.0 kJ/mol, indicating that chemisorption is involved in the extraction process. The data were also fitted to kinetic models such as pseudo first order and pseudo second order. The removal of fluoride anions increased with increasing temperature indicating the endothermic nature of the extraction process. The present method has been compared with the previous methods

Methylglyoxal, A Metabolite Increased in Diabetes is Associated with Insulin Resistance, Vascular Dysfunction and Neuropathies

The published manuscript is available at EurekaSelect via http://www.eurekaselect.com/openurl/content.php?genre=article&doi=10.2174/1389200217666151222155216 © 2018 Bentham Science PublishersBackground: Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO). Methods: Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review. Results: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1. Conclusion: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.Peer reviewedFinal Accepted Versio

Correcting hypophosphataemia in a paediatric patient with Sanjad-Sakati syndrome through a single oral dose of potassium phosphate intravenous solution.

Sanjad-Sakati syndrome is an autosomal recessive disorder that is quite common in Kuwait. Among a wide range of complications in Sanjad-Sakati syndrome patients is the vulnerability to infections and subsequent hypophosphataemia. Hypophosphataemia is a metabolic alteration that contributes to numerous consequences such as cardiac arrhythmia. Therefore, if hypophosphataemia is left unresolved, it may culminate in death. A 20-month-old boy of 2.5 kg body weight diagnosed with Sanjad-Sakati syndrome was initially admitted to the paediatric intensive care unit after recovering from COVID-19, and then shifted to the general ward. He was diagnosed with recurrent pneumonia and urinary tract infection. After 9 days, the patient showed severe hypophosphataemia with serum phosphate concentration reaching 0.33 mmol/L. Despite the availability of potassium phosphate intravenous solution, it was difficult to administer potassium phosphate intravenously because of the small body size and low body weight of the patient. Therefore, 0.6 mL potassium phosphate containing 2.4 mEq of potassium and 5.3 mEq of phosphate was administered through a nasogastric tube. The patient showed rapid response after a single dose through the nasogastric tube. Such an intervention in Sanjad-Sakati syndrome patients shows possible advantages of shifting drug administration from intravenous to oral route that includes a convenient route of administration, whether in the intensive care unit or in the general ward. Moreover, shifting drug administration from the intravenous to oral route overcomes the risk of cannula-induced infection and reduces nurses' workload

Paediatric poisoning in Kuwait-Al Adan joint hospital: The need for functional poisoning control centre in Kuwait.

Poisoning is a major global health concern. Every year, unintentional poisoning contributes to 106,683 deaths globally. In Kuwait, paediatric poisoning cases comprise approximately 50% of total poisoning cases. Despite the extensive importance and the long history of poison control centres (PCCs) and the emphasis of the World Health Organization (WHO) to establish a PCC in Kuwait, no functional PCC exists in Kuwait. Here we reported 82 poisoning cases between July and December 2020, revealing a 100% increase in comparison to the official figures published in 2004 and 2005. No fatalities were reported, and all cases were discharged home within 12 h of their visit to the casualty. Children aged 2 to < 4 years comprised the most reported poisoning cases with approximately 45% of the total. The number of male child poisoning cases was approximately two-fold of female children. The most common poisoning agent was silica gel granules (9%) followed by medicines - reported as paracetamol (7%), diclofenac (7%), multivitamin gummies (7%) and vitamin C (5%). Among other causes of poisoning were ingestion of salbutamol nebulizer solution (4%), oral contraceptives and insecticides (4%). These findings reveal the importance of establishing a functional PCC in Kuwait to minimise the unnecessary visits following ingestion of expired orange juice and henna, that may encounter further contraction of infections, especially with the current state of the COVID-19 pandemic. Moreover, a functional PCC would provide comprehensive data and hence further intervention such as shifting the dosage form of salbutamol from nebulizer solution to metered dose inhaler with a spacer, in addition to increasing public awareness towards minimizing such a dramatic increase in casualty visits because of -suspected poisoning

Correcting hypokalaemia in a paediatric patient with Bartter syndrome through oral dose of potassium chloride intravenous solution.

Bartter syndrome is a rare autosomal recessive disorder characterized by hypokalaemia. Hypokalaemia is defined as low serum potassium concentration ˂3.5 mmol/L, which may lead to arrhythmia and death if left untreated. The aim of this case report was to normalize serum potassium concentration without the need for intravenous intervention. A 5-month-old male of 2.7 kg body weight diagnosed with Bartter syndrome was admitted to the general paediatric ward with acute severe hypokalaemia and urinary tract infection. The main challenge was the inability to administer drugs through intravenous route due to compromised body size. Therefore, we shifted the route of administration to the nasogastric tube/oral route. A total of 2 mL of concentrated intravenous potassium chloride (4 mEq potassium) were dissolved in distilled water and administered through nasogastric tube. Serum potassium concentration was rapidly normalized, which culminated in patient discharge. In conclusion, shifting drug administration from intravenous to oral route in a paediatric patient with Bartter syndrome includes numerous advantages such as patient convenience, minimized risk of cannula-induced infection, and reduced nurse workload

Diabetic dyslipidaemia is associated with alterations in eNOS, caveolin-1 and endothelial dysfunction in streptozotocin treated rats

This is the peer reviewed version of the following article: Yousif A. Shamsaldeen, Rosemary Ugur, Christopher D. Benham, and Lisa A. Lione, ‘Diabetic dyslipidaemia is associated with alterations in eNOS, caveolin‐1, and endothelial dysfunction in streptozotocin treated rats’, Diabetes Metabolism Research and Reviews, e2995, March 2018, which has been published in final form at https://doi.org/10.1002/dmrr.2995. Under embargo until 22 February 2019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Background: Diabetes is a complex progressive disease characterised by chronic hyperglycaemia and dyslipidaemia associated with endothelial dysfunction. Oxidised LDL (Ox-LDL) is elevated in diabetes and may contribute to endothelial dysfunction. The aim of this study was to relate the serum levels of Ox-LDL with endothelial dysfunction in streptozotocin (STZ)-diabetic rats and to further explore the changes in endothelial nitric oxide synthase (eNOS) and caveolin-1 (CAV-1) expression in primary aortic endothelial cells (ECs). Methods: Diabetes was induced with a single intraperitoneal injection of STZ in male Wistar rats. During the hyperglycaemic diabetes state serum lipid markers, aortic relaxation and aortic ECs eNOS and CAV-1 protein expression was measured. Results: Elevated serum Ox-LDL (STZ 1486 ± 78.1 pg/ml vs control 732.6 ± 160.6pg/ml, p<0.05) was associated with hyperglycaemia (STZ 29 ± 0.9 mmol/L vs control: 7.2 ± 0.2 mmol/L, p<0.001) and hypertriglyceridemia (STZ 9.0 ± 1.5 mmol/L vs control: 3.0 ± 0.3 mmol/L, p<0.01) in diabetic rats. A significant reduction was observed in STZ-diabetic aortic endothelial cell eNOS and CAV-1 of 40% and 30% respectively, accompanied by a compromised STZ-diabetic carbachol-induced vasodilation (STZ 29.6 ± 9.3% vs control 77.2 ± 2.5%, p<0.001). Conclusions: The elevated serum Ox-LDL in hyperglycaemic STZ-diabetic rats may contribute to diabetic endothelial dysfunction, possibly through downregulation of endothelial CAV-1 and eNOS.Peer reviewe

Targeting the Bacterial Protective Armour:Challenges and Novel Strategies in the Treatment of Microbial Biofilm

Infectious disease caused by pathogenic bacteria continues to be the primary challenge to humanity. Antimicrobial resistance and microbial biofilm formation in part, lead to treatment failures. The formation of biofilms by nosocomial pathogens such as Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Klebsiella pneumoniae (K. pneumoniae) on medical devices and on the surfaces of infected sites bring additional hurdles to existing therapies. In this review, we discuss the challenges encountered by conventional treatment strategies in the clinic. We also provide updates on current on-going research related to the development of novel anti-biofilm technologies. We intend for this review to provide understanding to readers on the current problem in health-care settings and propose new ideas for new intervention strategies to reduce the burden related to microbial infections

Targeting the Bacterial Protective Armour; Challenges and Novel Strategies in the Treatment of Microbial Biofilm

Infectious disease caused by pathogenic bacteria continues to be the primary challenge to humanity. Antimicrobial resistance and microbial biofilm formation in part, lead to treatment failures. The formation of biofilms by nosocomial pathogens such as Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Klebsiella pneumoniae (K. pneumoniae) on medical devices and on the surfaces of infected sites bring additional hurdles to existing therapies. In this review, we discuss the challenges encountered by conventional treatment strategies in the clinic. We also provide updates on current on-going research related to the development of novel anti-biofilm technologies. We intend for this review to provide understanding to readers on the current problem in health-care settings and propose new ideas for new intervention strategies to reduce the burden related to microbial infections