The renal distal convoluted tubule (DCT) plays a key role in magnesium homeostasis with genetic and drug-induced causes of hypomagnesemia affecting this segment. The importance of the renal TRPM6 channel subunit of the TRPM6/7 magnesium channel in magnesium homeostasis is unclear due to discrepant findings in knockout mice. Furthermore, the apical potassium channel Kv1.1 has been proposed to drive magnesium entry through TRPM6/7 along DCT, with limited experimental evidence. To clarify the roles of TRPM6 and Kv1.1 we generated mice with inducible DCT-specific TRPM6 knockout (DCT-TRPM6 KO) or renal tubule Kv1.1 knockout (tubule-Kv1.1 KO). Using a newly generated antibody, we found that TRPM6 expression is restricted to early DCT (DCT1), consistent with single cell transcriptomic data. DCT-TRPM6 KO displayed lower plasma [Mg[2+]] on diets with normal (0.21% w/w) or reduced (0.08% w/w) magnesium content. In contrast, plasma [Mg[2+]] did not differ to controls in tubule-Kv1.1 KO mice on diets containing 0.08% w/w or 0.04% w/w magnesium. There were no differences in other blood chemistry values for either knockout. GFR, lithium clearance, and natriuretic responses to furosemide, hydrochlorothiazide, or amiloride did not differ in tubule-Kv1.1 KO mice. Immunofluorescence and single molecule fluorescent in situ hybridization revealed Kv1.1 expression in mouse and human in glomeruli and along the S3 segment of the proximal tubule, but not along DCT. In summary, renal TRPM6 plays a critical role in magnesium homeostasis under baseline conditions. Kv1.1 is not expressed along DCT and is not required for magnesium homeostasis or normal renal function at baseline.

A rapid and sensitive direct injection (DI) method is proposed for the monitoring of 235 organic microcontaminants (OMCs), including those listed in the recently adopted Directive (EU) 2024/3019 and the 5th Watch List, in treated wastewater (WW) and drinking water (DW), using ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS/MS). No pre-concentration stages were applied thanks to the advantages of a state-of-the-art triple quadrupole (QqQ) instrument, minimizing sample handling up to a filtration step. The polarity switching mode was used for the analysis of the selected OMCs from different classes (pharmaceuticals, antibiotics, pesticides, artificial sweeteners, metabolites and transformation products) in a single injection. LC-MS/MS parameters, including injection volume, capillary voltage, source temperature and mobile phase composition, were optimized. The proposed method was successfully validated in urban WW effluents and DW at 10, 100 and 1000 ng/L. Trueness (average expressed as relative recovery) was in the range of 72-127% and inter and intra-day precision (expressed as relative standard deviation, RSD) was always ≤21%. Limits of quantification (LOQs) were in the range of 0.5-500 ng/L for WW and 0.1-100 ng/L for DW. The suitability of the method was demonstrated by analysing 28 WW samples from 2 wastewater treatment plants (WWTPs) and 10 DW samples from different locations. 150 OMCs with sum of concentrations ranging from 17.7 to 239.9 μg/L were detected in WW samples and 0.1 to 1.0 μg/L in DW samples, respectively. All of 12 compounds included in EU Directive 2024/3019 were detected in WW samples with individual concentrations ranging from 46 (metoprolol) to 6667 ng/L (hydrochlorothiazide).

Hypertension (HTN) is a major global health burden and a leading risk factor for cardiovascular morbidity and mortality. Although numerous studies have explored host genetic factors and molecular mechanisms underlying HTN, increasing evidence indicates that gut microbiota dysbiosis also contributes to disease development. However, the specific microbial genes involved in HTN pathogenesis and their potential therapeutic targeting remain largely unexplored. This study aimed to identify HTN-associated differentially abundant bacterial genes (DAGs), prioritize bacterial key genes (bKGs) from among them, and repurpose potential therapeutic agents targeting these bKGs using an integrated bioinformatics framework. A total of 167 stool (fecal) microbiome samples, comprising 72 samples from HTN patients and 95 samples from HCs, were analyzed using publicly available 16 S rRNA sequencing data. After quality processing and clustering at 97% similarity, 95,361 representative operational taxonomic units were obtained. Microbial diversity analysis revealed significant alterations in community composition between HTN and HC groups. Differential abundance analysis identified 24 significantly altered bacterial genera associated with HTN. Functional prediction analysis further revealed 28 differentially abundant metabolic pathways and 631 differentially abundant bacterial genes (DAGs) potentially involved in HTN pathogenesis. From these DAGs, protein-protein interaction network analysis prioritized ten hub genes as bKGs (alsB, ampC, gsiB, araC, coaA, dnaB, fruA, ssuA, minE and tsx) representing potential microbial therapeutic targets. Structure-based molecular docking identified five approved drugs, namely Azilsartan, Eplerenone, Candesartan, Conivaptan, and Telmisartan, as top-ranked compounds exhibiting strong binding affinities toward the proposed targets. ADMET evaluation suggested favorable pharmacokinetic and safety profiles for Azilsartan, Eplerenone, and Candesartan. Furthermore, molecular dynamics simulation analyses confirmed that Eplerenone and Candesartan exhibited greater structural stability and sustained binding interactions, suggesting their potential as promising therapeutic candidates for HTN management. Therefore, this study identifies microbial gene signatures potentially involved in HTN and proposes a microbiome-guided drug repurposing strategy targeting bacterial functional pathways. These findings provide novel insights into microbiota-host interactions in HTN and highlight promising therapeutic candidates that warrant further experimental and clinical validation.

Gordon syndrome (Pseudohypoaldosteronism type II) is a rare autosomal dominant disorder characterized by hyperkalemia, hypertension, and metabolic acidosis. Among the four causative genes, CUL3 mutations produce the most severe phenotype, yet endocrine manifestations beyond growth delay remain poorly described. We report a 22-year-old male who presented with chronic hyperkalemia, hypertension, insulin resistance with steatohepatitis, and testicular hypoplasia with elevated gonadotropins, consistent with compensated primary testicular dysfunction. Genetic analysis identified a de novo heterozygous CUL3 c.1207-26A>G splice-site mutation resulting in exon 9 skipping. Treatment with hydrochlorothiazide normalized blood pressure and serum potassium while improving metabolic and hormonal abnormalities. Notably, these improvements reversed upon treatment discontinuation. This case suggests that certain endocrine manifestations in CUL3-related Gordon syndrome may be secondary to chronic electrolyte imbalance rather than direct genetic effects, highlighting the importance of comprehensive endocrine evaluation and sustained thiazide therapy in affected patients.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an uncommon but recognized complication of herpes zoster (varicella-zoster virus, VZV) infection, and diagnostic uncertainty may arise when hyponatremia develops after antiviral therapy is initiated. We report an 89-year-old patient with hypertension, chronic kidney disease stage 3, hyperlipidemia, and prior left nephrectomy for renal cell carcinoma who presented with right neck and upper arm pain, weakness, and a unilateral dermatomal vesicular eruption consistent with herpes zoster. Oral acyclovir was started at 800 mg five times daily. During hospitalization, serum sodium declined from 136 mEq/L to a nadir of 123 mEq/L despite discontinuation of hydrochlorothiazide. The patient remained clinically euvolemic, with urine sodium of 134 mEq/L and urine osmolality of 570 mOsm/kg, supporting SIADH. Thyroid-stimulating hormone and morning cortisol were normal. Fluid restriction < 1.2 L/day was ineffective. As the patient became symptomatic, and hypertonic saline (with removal of fluid restriction) produced no improvement, a single dose of tolvaptan produced rapid correction of serum sodium and improvement in mentation. The patient was subsequently maintained on sodium chloride tablet supplementation, fluid restriction, and a high-protein diet, with serum sodium improving to 135-136 mEq/L. This case describes severe hypotonic euvolemic hyponatremia meeting biochemical criteria for SIADH in the setting of localized herpes zoster, after consideration of concurrent hydrochlorothiazide exposure and temporally associated oral acyclovir.

Primary hyperparathyroidism occurs in up to 95% of patients with multiple endocrine neoplasia type 1 (MEN1). However, only a few cases of parathyroid carcinoma have been reported, and only one case of intrathyroidal parathyroid carcinoma. We describe the case of a 41-year-old male with a history of MEN1 and primary hyperparathyroidism who developed hypercalcemia to 13.1 mg/dL (SI: 3.3 mmol/L) (reference range [RR], 8.6-10.3 mg/dL [SI: 2.2-2.6 mmol/L]) with parathyroid hormone (PTH) 454 pg/mL (SI: 48.1 pmol/L) (RR, 15-65 pg/mL [SI: 1.6-6.9 pmol/L]). Neck ultrasonography showed a highly suspicious intrathyroidal 3.6 cm nodule. The patient had a lobectomy, and final pathology showed a 3.1 × 1.6 × 1.2 cm parathyroid carcinoma. After the surgery, calcium dropped to 6.0 mg/dL (SI: 1.5 mmol/L) with PTH of 11 pg/mL (SI: 1.2 pmol/L) requiring oral calcium supplements, calcitriol, and hydrochlorothiazide. Laboratory tests at 12 months on these medications showed calcium of 9.3 mg/dL (SI: 2.3 mmol/L) and PTH 21 pg/mL (SI: 2.2 pmol/L) indicating recovery of parathyroid function without recurrence, and calcitriol was discontinued. This case illustrates that a high index of suspicion for malignancy should be maintained for intrathyroidal parathyroid adenoma in the setting of severe hypercalcemia, especially in MEN1.

Sulfonamides are widely prescribed in clinical practice. Although rare, these have been shown to trigger an idiosyncratic reaction characterized by an acute myopic shift, likely caused by ciliochoroidal effusion and anterior rotation of the ciliary body, resulting in forward displacement of the iris-lens diaphragm. We report the case of a patient who developed blurred vision and acute myopia on cycloplegic refraction after initiating hydrochlorothiazide. The symptoms resolved completely after discontinuation of the medication. Although most of the literature highlights this reaction in association with topiramate, it is important to note that any sulfonamide can potentially lead to a similar clinical presentation.

Extemporaneous compounding plays a critical role in providing individualized pharmacotherapy for pediatric patients who require cardiovascular medications not available in commercially manufactured liquid formulations. This study evaluated the chemical, physical, and microbiological stability of clopidogrel, hydrochlorothiazide, nifedipine, propranolol, and spironolactone oral suspensions prepared in Flavor Sweet™ SF/Flavor Plus™ (1:1) (also marketed in Europe as Syra Sweet SF/Syra Plus), a widely used vehicle in pharmacy compounding. All formulations were prepared using a standardized protocol and stored at room temperature and refrigerated conditions for up to 90 days. Stability-indicating UHPLC methods were validated and applied to quantify drug content and monitor pH and physical characteristics throughout the study. Antimicrobial Effectiveness Testing was performed in accordance with USP <51>. Hydrochlorothiazide, nifedipine, propranolol, and spironolactone retained 90-110% of labeled content for at least 90 days under both storage conditions, while clopidogrel showed temperature-dependent degradation and met stability criteria for up to 90 days only under refrigeration. All formulations maintained consistent pH values and exhibited no visual changes. Microbiological evaluation confirmed effective preservative performance across all samples, with no microbial proliferation and full compliance with USP <51> acceptance criteria.