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The American Journal of Case Reports May 2024BACKGROUND Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin...
A Rare Case of Congenital Nephrogenic Diabetes Insipidus Associated with Aquaporin 2 Gene Mutation and Subsequent Acute Lymphoblastic Leukemia: Impact of Steroids on Kidney Function.
BACKGROUND Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin receptor 2, or it can be secondary to kidney disease or electrolyte imbalance. The clinical signs of NDI include polyuria, compensatory polydipsia, hypernatremic dehydration, and growth retardation without prompt treatment. In this report, we present the case of a patient with congenital NDI who was later diagnosed with acute lymphoblastic leukemia (ALL). With dexamethasone treatment, he had uncontrolled polyuria and polydipsia. Our aim was to concentrate on the impact of steroids on the kidneys. CASE REPORT Our patient presented at the age of 9 months with signs of severe dehydration that were associated with polyuria. His laboratory examinations revealed hypernatremia and decreased urine osmolality. He was diagnosed with NDI and his exome sequence revealed a homozygous mutation at the nucleotide position AQP2 NM_000486.6: c.374C>T (p.Thr125Met). He was treated with hydrochlorothiazide and amiloride. Then, at age 19 months, he presented with gastroenteritis and a complete blood count (CBC) showed high white blood cell count and blast cells. He was diagnosed with (ALL) and began receiving chemotherapy, during which again developed polydipsia and polyuria, which could not be controlled with an increased dosage of hydrochlorothiazide. CONCLUSIONS We report a rare case of NDI caused by a missense mutation in the aquaporin 2 gene. One year later, the child developed ALL, and treatment with dexamethasone led to an uncompensated state of polydipsia and polyuria.
Topics: Humans; Male; Diabetes Insipidus, Nephrogenic; Aquaporin 2; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Infant; Dexamethasone; Mutation; Glucocorticoids
PubMed: 38769718
DOI: 10.12659/AJCR.943597 -
International Journal of Molecular... Mar 2024Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical...
Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1-ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.
Topics: Humans; Benzamidines; Amiloride; Molecular Docking Simulation; Acid Sensing Ion Channels; Pain
PubMed: 38612396
DOI: 10.3390/ijms25073584 -
Bone & Joint Research Apr 2024Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium...
AIMS
Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro.
METHODS
MG63 and U2OS cells were treated with benzamil for 24 hours. Cell viability was evaluated with the MTS/PMS assay, colony formation assay, and flow cytometry (forward/side scatter). Chromosome condensation, the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cleavage of poly-ADP ribose polymerase (PARP) and caspase-7, and FITC annexin V/PI double staining were monitored as indicators of apoptosis. Intracellular calcium was detected by flow cytometry with Fluo-4 AM. The phosphorylation and activation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) were measured by western blot. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), SOD1, and SOD2 were also assessed by western blot. Mitochondrial status was assessed with tetramethylrhodamine, ethyl ester (TMRE), and intracellular adenosine triphosphate (ATP) was measured with BioTracker ATP-Red Live Cell Dye. Total cellular integrin levels were evaluated by western blot, and the expression of cell surface integrins was assessed using fluorescent-labelled antibodies and flow cytometry.
RESULTS
Benzamil suppressed growth of osteosarcoma cells by inducing apoptosis. Benzamil reduced the expression of cell surface integrins α5, αV, and β1 in MG63 cells, while it only reduced the expression of αV in U2OS cells. Benzamil suppressed the phosphorylation and activation of FAK and STAT3. In addition, mitochondrial function and ATP production were compromised by benzamil. The levels of anti-apoptotic proteins XIAP, Bcl-2, and Bcl-xL were reduced by benzamil. Correspondingly, benzamil potentiated cisplatin- and methotrexate-induced apoptosis in osteosarcoma cells.
CONCLUSION
Benzamil exerts anti-osteosarcoma activity by inducing apoptosis. In terms of mechanism, benzamil appears to inhibit integrin/FAK/STAT3 signalling, which triggers mitochondrial dysfunction and ATP depletion.
PubMed: 38569602
DOI: 10.1302/2046-3758.134.BJR-2023-0289.R1 -
Experimental Physiology May 2024It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the...
It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.
Topics: Animals; Furosemide; Acetazolamide; Amiloride; Diuretics; Sheep; Female; Kidney Cortex; Kidney Medulla; Oxygen; Hemodynamics; Oxygen Consumption
PubMed: 38551893
DOI: 10.1113/EP091479 -
Therapeutic Advances in Chronic Disease 2024The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied.
BACKGROUND
The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied.
OBJECTIVE
To analyze the efficacy between different mineralocorticoid receptor antagonists (MRAs) and epithelial sodium channel (ENaC) inhibitors in a network meta-analysis (NMA) framework, while also evaluating adverse events.
DESIGN
Systematic review and NMA.
DATA SOURCES AND METHODS
The systematic review and NMA was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, MEDLINE, the Cochrane library, and Excerpta Medica database (EMBASE) were searched for randomized controlled trials (RCTs) involving adult patients with primary hyperaldosteronism until 23 June 2023. Studies that compared the efficacy and side effects of different medical treatments of primary hyperaldosteronism were included. The primary outcomes included the effect on blood pressure, serum potassium, and major adverse cardiovascular events. The secondary outcomes were adverse events related to MRAs (hyperkalemia and gynecomastia). Frequentist NMA and pairwise meta-analysis were conducted.
RESULTS
A total of 5 RCTs comprising 392 participants were included. Eplerenone, esaxerenone, and amiloride were compared to spironolactone and demonstrated comparable effect on the reduction of systolic blood pressure. In comparison to spironolactone, eplerenone exhibited a less pronounced effect on reducing diastolic blood pressure [-4.63 mmHg; 95% confidence interval (CI): -8.87 to -0.40 mmHg] and correcting serum potassium (-0.2 mg/dL; 95% CI: -0.37 to -0.03 mg/dL). Spironolactone presented a higher risk of gynecomastia compared with eplerenone (relative risk: 4.69; 95% CI: 3.58-6.14).
CONCLUSION
The present NMA indicated that the blood pressure reduction and potassium-correcting effects of the three MRAs may demonstrate marginal differences, with confidence levels in the evidence being very low. Therefore, further research is needed to explore the efficacy of these MRAs, especially regarding their impact on mortality and cardiovascular outcomes.
TRIAL REGISTRATION
PROSPERO (CRD: 42023446811).
PubMed: 38511069
DOI: 10.1177/20406223241239775 -
International Journal of Surgery Case... Apr 2024Heterotopic ossification is forming a new bone in tissues that do not normally ossify. HO was first reported in 1901 by Askanazy and Lubarsh in a case report study. The...
INTRODUCTION AND IMPORTANCE
Heterotopic ossification is forming a new bone in tissues that do not normally ossify. HO was first reported in 1901 by Askanazy and Lubarsh in a case report study. The range of HO is wide from minute foci to large clinically significant ossification. The incidence of HO in abdominal scars is extremely low.
CASE PRESENTATION
We present an 84-year-old man referred to our hospital after an unsuccessful elective colostomy reversal in a local hospital. The colostomy was made for fecal diversion after sigmoidectomy due to treatment of sigmoid volvulus about three months ago. The patient had a past medical history of hypertension for 8 years under treatment of amiloride.
CLINICAL DISCUSSION
In general appearance, the patient was not ill or toxic. Vital signs were normal. Postoperatively Patient did not defecate. In his physical examination was not found abdominal tenderness or rebound tenderness. The patient underwent laparotomy which revealed significant retroperitoneal adhesion and colostomy was reversed. Accidentally was found a dense structure with bone-like consistency in the abdominal wall close to the scar was resected. The specimen Pathologic examination showed metaplastic bone deposition with mature bone trabeculae and heterotopic ossification was confirmed.
CONCLUSION
We report a rare case of HO that was identified at the abdominal wall. Heterotopic ossification can lead to serious complications. However, in symptomatic patients, surgical excision is an acceptable treatment, unlike in asymptomatic patients.
PubMed: 38460290
DOI: 10.1016/j.ijscr.2024.109469 -
BioRxiv : the Preprint Server For... Feb 2024The ENaC gamma subunit is essential for homeostasis of Na , K , and body fluid. Dual subunit cleavage before and after a short inhibitory tract allows dissociation of...
The ENaC gamma subunit is essential for homeostasis of Na , K , and body fluid. Dual subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (P ), . Cleavage proximal to the tract occurs at a furin recognition sequence ( RKRR in mouse). Loss of furin-mediated cleavage prevents activation of the channel by proteolysis at distal sites. We hypothesized that RKRR mutation to QQQQ ( ) in 129/Sv mice would reduce ENaC P , impair flow-stimulated flux of Na (J ) and K (J ) in perfused collecting ducts, reduce colonic amiloride-sensitive short circuit current (I ), and impair Na , K , and body fluid homeostasis. Immunoblot of mouse kidney lysates confirmed loss of a band consistent in size with the furin-cleaved proteolytic fragment. However, male mice on a low Na diet did not exhibit altered ENaC P or flow-induced J , though flow-induced J modestly decreased. Colonic amiloride-sensitive I in mice was not altered. males, but not females, exhibited mildly impaired fluid volume conservation when challenged with a low Na diet. Blood Na and K were unchanged on a regular, low Na , or high K diet. These findings suggest that biochemical evidence of gamma subunit cleavage should not be used in isolation to evaluate ENaC activity. Further, factors independent of gamma subunit cleavage modulate channel P and the influence of ENaC on Na , K , and fluid volume homeostasis in 129/Sv mice, .
PubMed: 38405735
DOI: 10.1101/2024.02.12.579964 -
Biochimica Et Biophysica Acta.... Apr 2024Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the...
Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the formation of pro-secretory ion transport characterised by elevated basal Cl current. Studies using human sinonasal epithelial cells treated with HDM extract report a higher protease activated receptor-2 (PAR-2) agonist-induced calcium mobilisation that may be related to airway sensitisation by allergen-associated proteases. Herein, this study aimed to investigate the effect of HDM on Ca signalling and inflammatory responses in asthmatic airway epithelial cells. Primary bronchial epithelial cells (hPBECs) from asthma donors cultured at air-liquid interface were used to assess electrophysiological, Ca signalling and inflammatory responses. Differences were observed regarding Ca signalling in response to PAR-2 agonist 2-Furoyl-LIGRLO-amide (2-FLI), and equivalent short-circuit current (I) in response to trypsin and 2-FLI, in ALI-asthma and healthy hPBECs. HDM treatment led to increased levels of intracellular cations (Ca, Na) and significantly reduced the 2-FLI-induced change of I in asthma cells. Apical HDM-induced Ca mobilisation was found to mainly involve the activation of PAR-2 and PAR-4-associated store-operated Ca influx and TRPV1. In contrast, PAR-2, PAR-4 antagonists and TRPV1 antagonist only showed slight impact on basolateral HDM-induced Ca mobilisation. HDM trypsin-like serine proteases were the main components leading to non-amiloride sensitive I and also increased interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) from asthma hPBECs. These studies add further insight into the complex mechanisms associated with HDM-induced alterations in cell signalling and their relevance to pathological changes within asthma.
Topics: Humans; Animals; Alarmins; Trypsin; Asthma; Epithelial Cells; Allergens; Pyroglyphidae
PubMed: 38367901
DOI: 10.1016/j.bbadis.2024.167079 -
European Journal of Pharmaceutics and... Apr 2024Over the last 10 years there is an increasing need for the design of personalised medicines at the point of care (PoC) that meet the specific needs of individual...
Over the last 10 years there is an increasing need for the design of personalised medicines at the point of care (PoC) that meet the specific needs of individual patients. A plethora of technologies has been introduced for making affordable personalised pharmaceutical products, which however, do not address manufacturing and regulatory challenges. Here we introduce a novel ultra-compact tablet press which was used for the design and compression of rosuvastatin-aspirin and amiloride-lysonipril bilayer tablets respectively. By applying precision dosing, it was feasible to manufacture tablets of different dose strengths and control features such as hardness, friability and disintegration times. The compaction of on-demand personalised multidrug pills that meet quality standards could revolutionised the treatment of patients at the point of care.
Topics: Humans; Chemistry, Pharmaceutical; Point-of-Care Systems; Tablets; Technology, Pharmaceutical; Physical Phenomena; Drug Compounding
PubMed: 38360119
DOI: 10.1016/j.ejpb.2024.114220