Calcium Channel Research Articles

Genetic Insights and Epidemiological Models in Understanding Primary Open Angle Glaucoma

Primary open-angle glaucoma (POAG) is a multifactorial chronic optic neuropathy with significant genetic heterogeneity. The pathogenesis of POAG involves an imbalance between the production and drainage of aqueous humor (AH). Genetic theories suggest that transgenic mice demonstrating the GLU50LYS mutation in optineurin (OPTN) experience retinal ganglion cell apoptosis, while mutant myocilin (MYOC) proteins induce endoplasmic reticulum (ER) stress, leading to an unfolded protein response (UPR) and subsequent apoptosis of trabecular meshwork cells (TMC). Furthermore, the interaction between MYOC and mitochondria in the trabecular meshwork (TM) and astrocytes may lead to mitochondrial membrane depolarization and calcium channel dysregulation, contributing to POAG. Overexpression of MYOC variants (P370L, Q368X) is also implicated, as are epigenetic modifications and signaling pathways such as histone and DNA modification. POAG has been associated with autosomal dominant inheritance, with mutations in MYOC and OPTN being prominent causative factors, although many cases involve multiple genetic loci. Currently, over 20 genetic loci have been linked to POAG, with 14 chromosomal loci (GLC1A to GLC1N) identified, 5 of which contribute to juvenile-onset open-angle glaucoma (JOAG). Of these loci, MYOC, OPTN, WD repeat domain 36 (WDR36), and neurotrophin-4 (NTF4) are the most studied causative genes. The ongoing study of molecular genetics offers potential pathways for future therapeutic advances in the treatment of POAG.

Patterns and factors associated with electrolyte abnormalities among patients with heart failure in Uganda.

Electrolyte abnormalities (EAs) worsen the clinical course of patients with heart failure (HF). The patterns of EAs vary among patients with HF. This study investigated patterns and factors associated with EAs among patients with HF admitted to Hoima Regional Referral Hospital (HRRH) in western Uganda. This hospital-based cross-sectional study used quantitative data of 384 HF patients admitted at HRRH between 21st February and 15th May 2023. Data on sociodemographic, lifestyle, and medical characteristics were collected and presented as descriptive statistics. EAs were considered electrolyte values below or above the reference normal ranges. Bivariate and multiple logistic regression analyses were conducted to establish associations. An association with a p < 0.05 is considered statistically significant. Of 384 HF patients, 342 (89.1%) had EAs. Hypocalcemia was the most common EA, 165 (43.0%). Among the patients, 69 (18.0%) were on diuretics, 185 (48.2%) were on angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and 105 (27.3%) were on calcium channel blockers (CCBs). Additionally, 264 (68.8%) had a history of hypertension, and 20 (5.2%) demonstrated good drug adherence. Patients with good drug adherence had lower odds of EAs (Adjusted Prevalence Odds Ratio [Adjusted POR] = 0.2, 95% CI: 0.1-0.7, p = 0.009). Those on diuretics had higher odds of EAs compared to those on ACEIs/ARBs and CCBs, with an Adjusted POR of 5.7 (95% CI: 1.3-15.0, p = 0.019). A history of hypertension also increased the odds of EAs (Adjusted POR = 4.0, 95% CI: 1.9-8.4, p < 0.001). The prevalence of EAs in patients with HF at HRRH was high, with hypocalcemia being the most common. Patients with good drug adherence had lower odds of EAs. On the other hand, diuretic use and a history of hypertension were associated with increased odds of EAs.

Structural studies of ion channels: achievements, problems and perspectives

The superfamily of membrane proteins known as P-loop channels encompasses potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. An increasing number of crystal and cryo-EM structures are uncovering both general and specific features of these channels. Fundamental folding principles, the arrangement of structural segments, key residues that influence ionic selectivity, gating, and binding sites for toxins and medically relevant ligands have now been firmly established. The advent of AlphaFold2 (AF2) models represents another significant step in computationally predicting protein structures. Comparison of experimental P-loop channel structures with their corresponding AF2 models shows consistent folding patterns in experimentally resolved regions. Despite this remarkable progress, many crucial structural details, particularly important for predicting the outcomes of mutations and designing new medically relevant ligands, remain unresolved. Certain methodological challenges currently hinder the direct assessment of such details. Until the next methodological breakthrough occurs, a promising approach to analyzing ion channel structures in greater depth involves integrating various experimental and theoretical methods.

Alterations in store-operated calcium entry in neurodegenerative pathologies: history, facts, perspectives

Neurodegenerative disorders, along with cardiovascular and oncological pathologies, are one of the most actual issues facing modern medicine. Therefore, the study of the molecular mechanisms of their pathogenesis and the search for new drug targets is highly demanded. Neuronal calcium signalling has attracted close attention, as altered calcium homeostasis has been demonstrated in the pathogenesis of various neurodegenerative diseases. In this review, we focus on one of the most ubiquitous and important pathways for calcium uptake: store-operated calcium entry. Here we describe studies demonstrating disturbances in store-operated calcium entry in various neurodegenerative pathologies, including Alzheimer’s, Parkinson’s and Huntington’s diseases. Also, we analyse the molecular determinants underlying these disturbances and propose ways for pharmacological correction of altered calcium signaling. The information summarized in the review will allow us to consider store-operated calcium channels as promising targets for the drug development in order to treat neurodegenerative pathologies and outline further promising directions for the investigation.

Antihypertensive Medication Category Prescriptions and Blood Pressure Control in African Surinamese and Ghanaian Migrants with Hypertension in Amsterdam, The Netherlands: The HELIUS Study.

West African (WA) migrants in Europe have higher hypertension rates than the host populations. For African migrants, guidelines recommend diuretics and/or calcium channel blockers (CCB) for primary cardiovascular disease prevention, but data on antihypertensive medication (AHM) prescription patterns or related hypertension control rates are lacking. We assessed AHM prescription patterns and its relation to hypertension control among hypertensive WA migrants in the Netherlands compared to the host population. Cross-sectional data from WA or Dutch origin participants from the HELIUS study were used. Participants with treated hypertension and without diabetes, cardiovascular disease, or microalbuminuria were selected. We used logistic and linear regression analyses to assess the association between AHM categories and hypertension control rates (systolic blood pressure (BP) ≤ 140 mmHg and diastolic BP ≤ 90 mmHg) and the systolic BP levels. We compared 999 WA participants and 314 Dutch participants. Hypertension control rates were lower in the WA origin compared to Dutch origin participants (44.3% versus 58.0%, p < 0.001). For WA participants, prescription rates for any AHM category were: CCB (54.8%), diuretics (18.5%) beta-blocking agents (27.3%) and renin-angiotensin system blockers (52.6%). Prescription rates were higher for CCB and similar for diuretics compared to the Dutch participants. Neither CCB nor diuretics were associated with better control rates. Compared to Dutch participants, West African participants had similar diuretic prescriptions but significantly higher prescriptions for CCB. However, neither medications was associated with better hypertension control. Future research should explore physician and patient factors to improve hypertension control.

Effect of Calcium on the Characteristics of Action Potential Under Different Electrical Stimuli

This study investigates the role of calcium ions in the release of action potentials by comparing two models based on the framework: the standard HH model and a HH + Ca model that incorporates calcium ion channels. Purkinje cells’ responses to four types of electrical current stimuli—constant direct current, step current, square wave current, and sine current—were simulated to analyze the impact of calcium on action potential characteristics. The results indicate that, under the constant direct current stimulation, the action potential firing frequency of both models increased with the escalating current intensity, while the delay time of the first action potential decreased. However, when the current intensity exceeded a specific threshold, the peak amplitude of the action potential gradually diminished. The HH + Ca model exhibited a longer delay in the first action potential compared to the HH model but maintained an action potential release under stronger currents. In response to the step current, both models showed an increased action potential frequency with a higher current, but the HH + Ca model generated subthreshold oscillations under weak currents. With the square wave current, the action potential frequency increased, though the HH + Ca model experienced suppression under high-frequency weak currents. Under the sine current, the action potential frequency rose, with the HH + Ca model showing less depression near the sine peak due to calcium’s role in modulating membrane potential. These findings suggest that calcium ions contribute to a more stable action potential release under varying stimuli.

Mouse liver blood flow is regulated by hepatic stellate cells in response to the sympathetic neurotransmitter norepinephrine

BackgroundThere is no clear information on the regulation of liver blood flow by the autonomic nervous system. We conducted this study to investigate whether quiescent hepatic stellate cells (qHSCs) regulate liver blood flow in response to the sympathetic neurotransmitter norepinephrine (NE). MethodsqHSCs isolated from mice were cultured in Dulbecco's modified Eagle medium without fetal bovine serum for 1 day on collagen gel. NE-induced qHSC contraction was evaluated using the quantitative single-cell contraction measurement method that we had developed previously. For the measurement of liver perfusion pressure in situ, a buffer solution was perfused from the portal vein in mice. ResultsNE-induced a reversible contraction of qHSCs. This contraction was suppressed by the nonmuscle myosin II inhibitor blebbistatin, the myosin light chain kinase inhibitor ML-9, the Rho kinase inhibitor H-1152, the calmodulin inhibitor W-7, the store-operated calcium channel inhibitor YM-58483, and the IP3 receptor inhibitor xestospongin C. In contrast, the transient receptor potential C channel inhibitor SKF96365 did not affect the NE-induced contraction. ConclusionThese results suggest that qHSCs contract in response to NE. New & noteworthyThe present study provides direct evidence for the first time that norepinephrine (NE) induces a reversible contraction of isolated single quiescent hepatic stellate cells (qHSCs) and further suggests that the NE-mediated qHSC contraction participates in the regulation of liver blood flow in vivo.

Distribution and calcium signaling function of somatostatin receptor subtypes in rat pituitary

The somatostatin (SST) receptor family controls pituitary hormone secretion, but the distribution and specific roles of these receptors on the excitability and voltage-gated calcium signaling of hormone producing pituitary cells have not been fully characterized. Here we show that the rat pituitary gland expressed Sstr1, Sstr2, Sstr3, and Sstr5 receptor genes in a cell type-specific manner: Sstr1 and Sstr2 in thyrotrophs, Sstr3 in gonadotrophs and lactotrophs, Sstr2, Sstr3, and Sstr5 in somatotrophs, and none in corticotrophs and melanotrophs. Most gonadotrophs and thyrotrophs spontaneously fired high-amplitude single action potentials, which were silenced by SST without affecting intracellular calcium concentrations. In contrast, lactotrophs and somatotrophs spontaneously fired low-amplitude plateau-bursting action potentials in conjunction with calcium transients, both of which were silenced by SST. Moreover, SST inhibited GPCR-induced voltage-gated calcium signaling and hormone secretion in all cell types expressing SST receptors, but the inhibition was more pronounced in somatotrophs. The pattern of inhibition of electrical activity and calcium signaling was consistent with both direct and indirect inhibition of voltage-gated calcium channels, the latter being driven by cell type-specific hyperpolarization. These results indicate that the action of SST in somatotrophs is enhanced by the expression of several types of SST receptors and their slow desensitization, that SST may play a role in the electrical resynchronization of gonadotrophs, thyrotrophs, and lactotrophs, and that the lack of SST receptors in corticotrophs and melanotrophs keeps them excitable and ready to responses to stress.

Transcriptomic imputation identifies tissue-specific genes associated with cervical myelopathy

Degenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology. To determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy. Retrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank. In a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature. We identified 16 genes significantly associated with DCM across five different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention. The inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects. Understanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM.

Multi-target Phenylpropanoids Against Epilepsy.

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.

Vasospasm in Pediatric Subarachnoid Hemorrhage.

Cerebral vasospasm (CV) is a common severe complication of subarachnoid hemorrhage (SAH), a severe type of intracranial bleeding that is uncommon in children. The purpose of this article is to review the current literature regarding this potentially devastating complication. CV may be asymptomatic and is less common in children compared to adults. Several molecular phenomena, including inflammatory ones, contribute to its pathophysiology. Better collateral circulation and higher cerebral blood flow are protective factors in children. When clinically apparent, CV may manifest as a change in the child's neurologic status or vital signs. CV can be diagnosed using brain vessel imaging, such as computed tomography angiography, magnetic resonance angiography, digital subtraction angiography, transcranial Doppler ultrasonography, and computed tomography perfusion. A reduction of < 50% in the artery's caliber confirms the diagnosis. Besides general supportive measures and causative treatment of SAH, CV management options include the administration of calcium channel blockers and neurointerventional approaches, such as intra-arterial vasodilators and balloon angioplasty. Long-term outcomes in children are usually favorable.

A survival case of high-dose amlodipine intoxication with non-cardiogenic pulmonary edema: a case report

Introduction: Dihydropyridines calcium channel blockers at high dose can have conduction abnormalities, reduced inotropism, and non-cardiogenic pulmonary oedema (NCPE) which otherwise, at standard dosage have only vascular selectivity. They remain one of the commonly used anti-hypertensive exhibiting very lethal outcomes (50% mortality rates) in its overdose. Case presentation: The authors present a case of a 21-year-old male with amlodipine intoxication with 43 tabs of 10 mg (total of 430 mg) ingestion manifested by loss of consciousness, hypotension, tachycardia, and respiratory distress. Discussion: An amlodipine overdose causes refractory hypotension due to vasodilation and impaired cardiac metabolism and contractility. Further amlodipine toxicity can result in NCPE that manifests clinically as respiratory distress and low oxygen levels due to lung injury caused by inflammation and increased vascular permeability. Conclusion: This case report emphasizes the significance of early recognition and prompt treatment of amlodipine intoxication, which can result in serious complications like fluid overload and respiratory distress.

Cardiovascular profile drugs and the state of periodontal tissues

People with CVD, mostly over 50 years of age, regularly take medications such as beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), statins and acetylsalicylic acid (ASA). Periodontal tissue disease (PTD) occurs in the age group 35–44 years in 60% of cases, in the group of people 65–74 years – about 70%, that is, in that period of life when cardiovascular disease (CVD) begins to develop and progress. Some cardioprotective drugs, such as antihypertensives, cause xerostomia. Medication-induced xerostomia is one of the common causes of oral health problems in older adults who are on long-term drug therapy. Xerostomia is a common debilitating condition that causes problems such as dysphagia, loss of taste, and oral pain, as well as increasing the risk of tooth decay and oral infections. Drug-induced gingival overgrowth is an abnormal hypertrophy of the gingiva that can be caused by a number of medications, including calcium channel blockers. Drug-induced gingival overgrowth is characterized by the accumulation of connective tissue that primarily affects the anterior regions of the upper and lower jaw, and also causes problems with oral hygiene, which leads to susceptibility to infections and periodontal disease and can lead to tooth loss. Anticoagulants used in CVD due to the risk of bleeding require special approaches in the prevention and therapy of periodontal tissue disease. The possibilities of using statins in PTD due to their pleiotropic properties, independent of hypolipidemic action. The review article is devoted to the influence of drugs of cardiovascular profile on the state of periodontal tissues and mechanisms of development of side effects, as well as the possibilities of using statins taking into account their pleiotropic effects.

Paraneoplastic Neurologic Syndromes Associated With Merkel Cell Carcinoma.

To define the clinical and immunologic profile of patients with paraneoplastic neurologic syndromes (PNSs) associated with Merkel cell carcinoma (MCC). Retrospective analysis was conducted on patients with suspected MCC-related PNS assessed at the French Reference Center, and cases were identified by a systematic review of the literature (MEDLINE, Embase) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 17 patients were identified in our center and 30 in the systematic review, resulting in an overall cohort of 47 patients. The median age was 65 years (range 41-90), and 30 of 46 (65%) were men. Lambert-Eaton myasthenic syndrome (LEMS) (14/47, 29%), rapidly progressive cerebellar syndrome (11/47, 23%), and encephalomyelitis (EM) (8/47, 17%) were the most common associated clinical phenotypes. The most frequently associated neural antibodies (Abs) were voltage-gated calcium channel (VGCC)-Abs (14/45, 31%), followed by Hu-Abs (8/45, 17%) and neurofilament (NF)-Abs (8/45, 17%). Patients with NF-Abs only exhibited CNS disorders (8/8, 100%) and often had antibodies against >1 NF subunit (6/8, 75%). At onset, 26 of 43 patients (60%) had no identifiable primary skin tumor but had lymph node metastasis; these patients were more frequently men (21/26, 80%, vs 7/17, 41%; p = 0.007), had more frequently VGCC-Abs (12/26, 46%, vs 2/17, 11%, p = 0.02) predominantly among those with LEMS, and presented reduced mortality than patients with a known primary tumor (5/25, 20%, vs 8/15, 53%; p = 0.02). MCC-related PNSs present as a heterogeneous clinical spectrum including central and/or peripheral nervous system disorders such as LEMS, RCPS, and EM, mainly associated with VGCC-Abs, NF-Abs, and Hu-Abs. NF-Abs were only seen among patients with CNS disorders. At onset, the absence of a primary skin tumor but presence of lymph node metastasis is frequently observed, and this particular clinical presentation is linked to reduced mortality, highlighting distinctive clinical and immunologic features of MCC-related PNS.

Amlodipine increases risk of primary open-angle glaucoma

BackgroundThe use of calcium channel blockers is associated with primary open-angle glaucoma (POAG) in a statistically meaningful but minor way. In general, those who had received calcium channel blocker medication were at a 23% increased risk of developing glaucoma in comparison to those who had never taken the antihypertensive drugs. We wished to confirm this association and examine POAG genes that might be involved, since the genetics has not yet been analyzed.MethodsWe used MedWatch and UK Biobank data to evaluate the effects of amlodipine on POAG and intraocular pressure (IOP). We analyzed three POAG-associated single-nucleotide polymorphisms: rs9913911, an intron variant in growth arrest-specific 7 (GAS7), one of the genes that influences IOP; rs944801, an intron variant within CDKN2B-AS1, and rs2093210, an intron variant within SIX6, known to be associated with vertical cup-disc ratio, an important optic nerve head parameter that is often used to define or diagnose glaucoma.ResultsAmlodipine use in MedWatch doubled the prevalence of POAG, from 0.0805 to 0.177%, a small but significant increase. Multivariate analysis by logistic regression of UK Biobank data revealed that POAG risk was significantly increased with age, male sex, major alleles of rs9913911 (GAS7) and rs944801 (CDKN2B-AS1), and minor allele of rs2093210 (SIX6). Amlodipine increased POAG risk by 16.1% (P = 0.032). Amlodipine has not been associated with increased IOP. We confirmed this lack of association and in addition found that GAS7, associated with IOP, was not associated with POAG risk and amlodipine. But CDKN2B-AS1 and SIX6, POAG genes not associated with IOP, were associated with POAG and amlodipine.ConclusionsAmlodipine, a frequently prescribed drug and first line treatment for hypertension, has a potentially hazardous relationship with POAG. Knowledge of this link can guide the prescribing of alternate drugs for hypertensive individuals who have glaucoma or are at risk for it. Diuretics and β-blockers are not associated with POAG or increased IOP and could be substituted for amlodipine in hypertensive patients at risk POAG.Trial registrationNone.Graphical

Amlodipine-induced gingival hyperplasia in a Nepalese patient experiencing high dosages: a case report

Introduction and importance: Amlodipine is a third-generation calcium channel blocker used in the treatment of hypertension. One of the side effects associated with amlodipine is gingival hyperplasia mostly occurring at a higher dose (10 mg). There are very few cases of gingival hyperplasia associated with amlodipine at a lower dose (5 mg) or short-term administration. Case presentation: A 51-year-old male patient with diagnosed hypertension sought medical attention for gingival swelling and bleeding from the gums while brushing. He had been under amlodipine 5 mg for 12 months, which was increased to 10 mg for the last 2 months. The history and physical examination were consistent with amlodipine-induced gingival hyperplasia. The first line of treatment consisted of discontinuation of amlodipine and substitution with another class of anti-hypertensive. Clinical discussion and conclusion: The presented case highlights the challenge of balancing economic considerations with potential side effects in the use of amlodipine for hypertension in low-income countries like Nepal. Given its availability at no cost or minimal expense, amlodipine is often initiated as a first-line therapy. However, the decision to increase the dosage to 10 mg/day, influenced by economic constraints and the drug’s affordability, raises the risk of gingival hyperplasia. This case emphasizes the importance of physicians being mindful of potential adverse effects when prescribing higher doses of amlodipine and underscores the need for continued vigilance in managing hypertension in resource-limited settings.

A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings.

L-type Ca2+ channels (CaV1.2/1.3) convey influx of calcium ions that orchestrate a bevy of biological responses including muscle contraction, neuronal function, and gene transcription. Deficits in CaV1 function play a vital role in cardiac and neurodevelopmental disorders. Here, we develop a genetically encoded enhancer of CaV1.2/1.3 channels (GeeCL) to manipulate Ca2+ entry in distinct physiological settings. We functionalized a nanobody that targets the CaV complex by attaching a minimal effector domain from an endogenous CaV modulator-leucine-rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeCL selectively increased L-type current amplitude. In neurons in vitro and in vivo, GeeCL augmented excitation-transcription (E-T) coupling. In all, GeeCL represents a powerful strategy to boost CaV1.2/1.3 function and lays the groundwork to illuminate insights on neuronal and cardiac physiology and disease.

Osteopontin Regulates AQP4 Expression by TRPV4 Activation in Müller Cells: Implications for Retinal Homeostasis.

During the intense neuronal activity in the retina, Müller cells are exposed to a hypotonic environment and activate a regulatory volume decrease (RVD) response, which depends on Aquaporin-4 (AQP4) and the calcium channel Transient Receptor Potential Vanilloid 4 (TRPV4). It was reported that Osteopontin (OPN), a cytokine and component of the extracellular matrix (ECM), may modulate the RVD of Müller cells. In other cell types, OPN participates in cell survival and migration, which Müller cells undergo to maintain retinal homeostasis. Therefore, the aim of this work was to study the putative crosstalk of OPN with AQP4 and/or TRPV4 in the main functions of Müller cells: RVD, morphology maintenance and migration. We used a human Müller cell line (MIO-M1) exposed to OPN and evaluated cell volume and osmotic permeability (Pf) during an osmotic swelling, AQP4 expression, cell morphology and migration. We observed that OPN induced a reduced Pf and RVD by downregulating AQP4 expression, which was prevented by TRPV4 inhibition. OPN also induced significant changes in cell morphology with an increased number of cytoplasmic projections. Finally, OPN reduced the migration of Müller cells, being this effect dependent on TRPV4. We propose that OPN affects water permeability and cell volume regulation of Müller cells by activating TRPV4 to reduce AQP4 expression. This represents a novel mechanism of regulation of water permeability by the ECM in Müller cells. Additionally, OPN-induced changes in morphology and migration of Müller cells may have an impact on retinal physiology.

Tocolysis and Neurodevelopment of Children Born Very Preterm

Neurodevelopmental outcomes of very preterm children exposed to tocolytics are not well described. To investigate whether tocolysis administered after spontaneous preterm labor is associated with neurodevelopmental outcomes at 5.5 years and to assess whether the type of tocolytic drug is associated with neurodevelopmental outcomes among infants exposed. This prospective, national, population-based cohort study used data from the French Etude Épidémiologique sur les Petits Âges Gestationnels-2 cohort. Children who were alive and participated in an assessment at 5.5 years and whose mothers experienced spontaneous preterm labor without an infectious context and delivered at 24 to 31 weeks were eligible for this study. Recruitment occurred from March to December 2011. Follow-up at age 5.5 years was conducted from September 2016 to December 2017. Data analysis was performed from July 2023 through April 2024. The primary analysis examined tocolytics (yes vs no), and the secondary analysis examined the type of tocolytic (atosiban vs calcium channel blockers [CCBs]). The composite outcome neurodevelopmental disabilities included cerebral palsy; visual, hearing, and cognitive deficiencies; developmental coordination disorders; or behavioral problems. A total of 1055 mothers (mean [SD] age, 29.2 [5.7] years) had preterm labor without fever and gave birth to 1320 children (704 male [weighted percentage, 53.3%; 95% CI, 50.6%-56.1%]; mean [SD] gestational age, 28.8 [2.0] weeks). Overall, 776 mothers (weighted percentage, 73.5%; 95% CI, 70.8%-76.2%) received tocolytics; 136 mothers (weighted percentage, 17.9%; 95% CI, 15.3%-20.8%) received only a CCB, and 295 mothers (weighted percentage, 37.6%; 95% CI, 34.2%-41.0%) received only atosiban. From modified Poisson regression with propensity score matching, the risk of overall neurodevelopmental disabilities (mild, moderate, or severe) at 5.5 years did not differ between preterm children exposed and not exposed to tocolytics (relative risk [RR], 1.11; 95% CI, 0.85-1.45; P = .44) or in preterm infants exposed to atosiban compared with those exposed to CCBs (RR, 0.94; 95% CI, 0.67-1.32; P = .71). In this study, tocolytics were not associated with neurodevelopmental disabilities among very preterm children surviving at 5.5 years.

Risk of developing hyperkalemia in patients with hypertension treated with combination antihypertensive therapy - a retrospective register-based study.

The risk of hyperkalemia in relation to different combinations of antihypertensive therapy remains to be elucidated. In this Danish register-based study, we aimed to investigate the risk of developing hyperkalemia in relation to different combinations of antihypertensive therapy. Using incidence density matching, we matched a hyperkalemic patient to five normokalemic patients on eGFR groups, age, sex, and time between study entry and date of potassium measurement. Combination therapies were subdivided into eight groups: beta blockers (BB) + calcium channel blockers (CCB), BB + renin angiotensin system inhibitors (RASi), BB + RASi + mineralocorticoid receptor antagonists (MRA), CCB + RASi, CCB + RASi + thiazides, CCB + thiazides, RASi + thiazides, and other combinations. Multivariable conditional logistic regression was used to estimate the odds of hyperkalemia within 90 days for each of the eight antihypertensive combination therapies. A total of 793 patients with hyperkalemia were matched to 3598 normokalemic patients. In multivariable analysis, odds of developing hyperkalemia when being treated with BB + RASi + MRA was 1.95 (95% CI, 1.39-2.72) compared to RASi + thiazides (reference). CCB + thiazides (OR, 0.76 [95% CI, 0.45-1.28]) and CCB + RASi + Thiazid (OR 0.81 [95% CI, 0.51-1.28]) were among the others not significantly associated with hyperkalemia. Combinations of BB + RASi + MRA were significantly associated with an increased risk of developing hyperkalemia within 90 days of initiating treatment. Patients treated with BB + RASi + MRA within 90 days of treatment initiation, were associated with an increased hyperkalemia risk. When treating hypertensive patients with combination antihypertensive therapy, identifying and monitoring patients with a high risk of dyskalemias is a crucial goal to avoid serious adverse effects and detrimental outcomes related to dyskalemia.