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Cells Dec 2023Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells...
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors.
Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death. We show that both apoptotic pathways are activated in BVSMCs by oligomeric Aβ42 and and mitochondrial respiration is severely impaired. Importantly, the CAIs methazolamide (MTZ) and acetazolamide (ATZ) prevent the pro-apoptotic effects in BVSMCs, while reducing caspase 3 activation and Aβ deposition in the arterial walls of TgSwDI animals, a murine model of cerebral amyloid angiopathy (CAA). This study reveals new molecular targets and a promising therapeutic strategy against BVSMC dysfunction in AD, CAA, and ARIA (amyloid-related imaging abnormalities) complications of recently FDA-approved anti-Aβ antibodies.
Topics: Animals; Mice; Carbonic Anhydrase Inhibitors; Amyloid beta-Peptides; Endothelial Cells; Muscle, Smooth, Vascular; Alzheimer Disease; Cerebral Amyloid Angiopathy; Mitochondria; Receptors, Death Domain
PubMed: 38132159
DOI: 10.3390/cells12242840 -
Cardiology Research Apr 2024Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have... (Review)
Review
Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have assessed the upfront combination of acetazolamide and hydrochlorothiazide with loop diuretics in hospitalized patients with acute decompensated heart failure without loop diuretic resistance. We reviewed two recent randomized controlled trials on the upfront use of acetazolamide and thiazide diuretics in acute decompensated heart failure, respectively. When the two trials on acetazolamide are considered together, adding oral or intravenous acetazolamide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and natriuresis. However, the effects were significantly higher in patients with serum bicarbonate ≥ 27 mmol/L and those with higher baseline glomerular filtration rate (GFR). Similarly, when the two trials on thiazide diuretics are considered together, adding hydrochlorothiazide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and weight loss. However, it increases the risk of impaired renal function. When all the trials are considered together, the upfront use of acetazolamide may be helpful in carefully selected patients, including patients with underlying elevated bicarbonate levels (≥ 27 mmol/L) and those with good renal function (GFR > 50). Conversely, though the upfront use of thiazide diuretic added to intravenous furosemide improved diuretic response in acute decompensated heart failure, it causes an increased risk of worsening renal function and lack of clear evidence of reducing hospital length of stay.
PubMed: 38645830
DOI: 10.14740/cr1627 -
Journal of Cataract and Refractive... Jul 2023A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both...
A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both eyes and cupped nerves. She had a family history of glaucoma in her father. She was started on latanoprost in both eyes and was referred for a glaucoma evaluation. On initial evaluation, her IOP was 25 mm Hg in the right eye and 26 mm Hg in the left eye. Central corneal thickness measured 592 µm in the right eye and 581 µm in the left eye. Her angles were open to gonioscopy without any peripheral anterior synechia. She had 1+ nuclear sclerosis with a corrected distance visual acuity (CDVA) of 20/25 in the right eye and 20/30- in the left eye and uncorrected near visual acuity of J1+ in each eye. Her nerves were 0.85 mm in the right eye and 0.75 mm in the left eye. Optical coherence tomography (OCT) showed retinal nerve fiber layer thinning and a dense superior arcuate scotoma into fixation in her right eye, and superior and inferior arcuate scotomas in her left eye (Figures 1 and 2JOURNAL/jcrs/04.03/02158034-202307000-00019/figure1/v/2023-06-26T195222Z/r/image-tiffJOURNAL/jcrs/04.03/02158034-202307000-00019/figure2/v/2023-06-26T195222Z/r/image-tiff, Supplemental Figures 1 and 2, available at http://links.lww.com/JRS/A882 and http://links.lww.com/JRS/A883). She was successively trialed on fixed combination brimonidine-timolol, dorzolamide, and netarsudil, in addition to her latanoprost, but her IOP remained in the mid- to upper 20s in both eyes. The addition of acetazolamide lowered the pressure to 19 mm Hg in both eyes, but she tolerated it poorly. Methazolamide was also attempted with similar side effects. We elected to perform left eye cataract surgery combined with 360-degree viscocanaloplasty and insertion of a Hydrus microstent (Alcon Laboratories, Inc.). Surgery was uncomplicated with IOP of 16 mm Hg on postoperative day 1 with no glaucoma medications. However, by postoperative week 3, IOP returned to 27 mm Hg, and despite restarting latanoprost-netarsudil and finishing her steroid taper, IOP remained at 27 mm Hg by postoperative week 6. Brimonidine-timolol was added back to her left eye regimen and at postoperative week 8, IOP had elevated to 45 mm Hg. Maximizing her therapy with the addition of topical dorzolamide and oral methazolamide brought her IOP back down to 30 mm Hg. At that point, the decision was made to proceed with trabeculectomy of the left eye. The trabeculectomy was uneventful. However, postoperative attempts to augment filtration were rendered less successful by extremely thick Tenon layer. At her most recent follow-up the pressure in the left eye was mid-teens with brimonidine-timolol and dorzolamide. Her right eye IOP is in the upper 20s on maximum topical therapy. Knowing her postoperative course in the left eye, how would you manage the right eye? In addition to currently available options, would you consider a supraciliary shunt such as the MINIject (iSTAR) if such a device were U.S. Food and Drug Administration (FDA)-approved?
Topics: Humans; United States; Female; Adolescent; Middle Aged; Glaucoma, Open-Angle; Latanoprost; Methazolamide; Timolol; Glaucoma; Treatment Outcome
PubMed: 37390324
DOI: 10.1097/j.jcrs.0000000000001221 -
Anesthesia Depresses Cerebrovascular Reactivity to Acetazolamide in Pediatric Moyamoya Vasculopathy.Journal of Clinical Medicine Jun 2023Measurements of cerebrovascular reactivity (CVR) are essential for treatment decisions in moyamoya vasculopathy (MMV). Since MMV patients are often young or cognitively...
Measurements of cerebrovascular reactivity (CVR) are essential for treatment decisions in moyamoya vasculopathy (MMV). Since MMV patients are often young or cognitively impaired, anesthesia is commonly used to limit motion artifacts. Our aim was to investigate the effect of anesthesia on the CVR in pediatric MMV. We compared the CVR with multidelay-ASL and BOLD MRI, using acetazolamide as a vascular stimulus, in all awake and anesthesia pediatric MMV scans at our institution. Since a heterogeneity in disease and treatment influences the CVR, we focused on the (unaffected) cerebellum. Ten awake and nine anesthetized patients were included. The post-acetazolamide CBF and ASL-CVR were significantly lower in anesthesia patients (47.1 ± 15.4 vs. 61.4 ± 12.1, = 0.04; 12.3 ± 8.4 vs. 23.7 ± 12.2 mL/100 g/min, = 0.03, respectively). The final BOLD-CVR increase (0.39 ± 0.58 vs. 3.6 ± 1.2% BOLD-change (mean/SD), < 0.0001), maximum slope of increase (0.0050 ± 0.0040%/s vs. 0.017 ± 0.0059%, < 0.0001), and time to maximum BOLD-increase (~463 ± 136 and ~697 ± 144 s, = 0.0028) were all significantly lower in the anesthesia group. We conclude that the response to acetazolamide is distinctively different between awake and anesthetized MMV patients, and we hypothesize that these findings can also apply to other diseases and methods of measuring CVR under anesthesia. Considering that treatment decisions heavily depend on CVR status, caution is warranted when assessing CVR under anesthesia.
PubMed: 37445429
DOI: 10.3390/jcm12134393 -
Journal of the American Society of... Jul 2023Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes...
SIGNIFICANCE STATEMENT
Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes mellitus. The molecular mechanisms remain elusive. Our study reveals that thiazides attenuate insulin secretion through inhibition of the mitochondrial carbonic anhydrase isoform 5b (CA5b) in pancreatic β cells. We furthermore discovered that pancreatic β cells express only one functional carbonic anhydrase isoform, CA5b, which is critical in replenishing oxaloacetate in the mitochondrial tricarboxylic acid (TCA) cycle (anaplerosis). These findings explain the mechanism for thiazide-induced glucose intolerance and reveal a fundamental role of CA5b in TCA cycle anaplerosis and insulin secretion in β cells.
BACKGROUND
Thiazide diuretics are associated with glucose intolerance and new-onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in β cells.
METHODS
We performed static insulin secretion experiments with islets of wild-type, Sodium/chloride co-transporter (NCC) (SLC12A3), and sodium-driven chloride/bicarbonate exchanger (NDCBE) (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knockdown of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in β cells. CA isoform 5b (CA5b) KO mice were then used to assess the role of the putative thiazide target CA5b in β -cell function and in mediating thiazide sensitivity in vitro and in vivo .
RESULTS
Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and Min6 cells at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO 2 /HCO 3- -dependent, not additive to unselective CA inhibition with acetazolamide, and independent of extracellular potassium. By contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC or NDCBE. CA expression profiling with subsequent knockdown of individual CA isoforms suggested mitochondrial CA5b as a molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxaloacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and thiazides did not alter insulin secretion in CA5b KO islets.
CONCLUSIONS
Thiazides attenuate insulin secretion via inhibition of the mitochondrial CA5b isoform in β cells of mice.
Topics: Mice; Animals; Insulin Secretion; Thiazides; Sodium Chloride Symporter Inhibitors; Glucose Intolerance; Chlorides; Islets of Langerhans; Glucose; Diabetes Mellitus; Carbonic Anhydrases; Sodium; Insulin; Insulin-Secreting Cells
PubMed: 36927842
DOI: 10.1681/ASN.0000000000000122 -
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 -
Neurologia I Neurochirurgia Polska 2024Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH... (Review)
Review
INTRODUCTION
Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH population, as the occurrence of a leak can mask the typical IIH symptoms and signs, complicating the diagnosis. Treatment of leaks in this population can also be challenging, with the risk of rhinorrhea recurrence if intracranial hypertension is not adequately treated.
OBJECTIVE
The aim of this narrative review was to examine current literature on the association between spontaneous CSF rhinorrhea leaks and IIH, focusing on key clinical features, diagnostic approaches, management strategies, and outcomes.
MATERIAL AND METHODS
A literature search was executed using the PubMed and Scopus databases. The search was confined to articles published between January 1985 and August 2023; extracted data was then analysed to form the foundation of the narrative review.
RESULTS
This search yielded 26 articles, comprising 943 patients. Average age was 46.8 ± 6.5 years, and average body mass index was 35.8 ± 4.8. Most of the patients were female (74.33%). Presenting symptoms were rhinorrhea, headaches and meningitis. The most common imaging findings were empty sella and encephalocele. The standard treatment approach was endoscopic endonasal approach for correction of CSF rhinorrhea leak, and shunt placement was also performed in 128 (13%) patients. Recurrences were observed in 10% of cases.
CONCLUSIONS
The complex relationship between spontaneous CSF leaks and IIH is a challenge that benefits from multidisciplinary evaluation and management for successful treatment. Treatments such as endoscopic repair, acetazolamide, and VP/ /LP shunts reduce complications and recurrence. Personalised plans addressing elevated intracranial pressure are crucial for successful outcomes.
Topics: Humans; Female; Adult; Middle Aged; Male; Pseudotumor Cerebri; Cerebrospinal Fluid Rhinorrhea; Intracranial Hypertension; Acetazolamide; Endoscopy; Cerebrospinal Fluid Leak; Retrospective Studies
PubMed: 38393958
DOI: 10.5603/pjnns.98054 -
Drugs in Context 2023Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a... (Review)
Review
Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.
PubMed: 38188263
DOI: 10.7573/dic.2023-6-5 -
Journal of Critical Care Medicine... Jul 2023Acute angle closure glaucoma (AACG) is an ophthalmological emergency, and can lead to the devastating consequence of permanent vision loss if not detected and treated...
INTRODUCTION
Acute angle closure glaucoma (AACG) is an ophthalmological emergency, and can lead to the devastating consequence of permanent vision loss if not detected and treated promptly. We present a case of an atypical presentation of unilateral AACG on post operative day (POD) 1, after a prolonged operation under general anaesthesia (GA).
CASE PRESENTATION
A 65-year-old female underwent a 16 hour long operation for breast cancer and developed an altered mental status with a left fixed dilated pupil on POD 1. She was intubated to secure her airway in view of a depressed consciousness level and admitted to the intensive care unit. Initial blood investigations and brain imaging were unremarkable. On subsequent review by the ophthalmologist, a raised intraocular pressure was noted and she was diagnosed with acute angle closure glaucoma. She was promptly started on intravenous acetazolamide and pressure-lowering ophthalmic drops. Her intraocular pressure normalized in the next 24 hours with improvement in her mental status to baseline.
CONCLUSION
AACG needs to be consistently thought of as one of the top differentials in any post-operative patient with eye discomfort or abnormal ocular signs on examination. A referral to the ophthalmologist should be made promptly once AACG is suspected.
PubMed: 37588183
DOI: 10.2478/jccm-2023-0016 -
Current Heart Failure Reports Apr 2024Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in... (Review)
Review
PURPOSE OF REVIEW
Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.
RECENT FINDINGS
We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
Topics: Humans; Heart Failure; Sodium Potassium Chloride Symporter Inhibitors; Quality of Life; Diuretics; Hospitalization
PubMed: 38300391
DOI: 10.1007/s11897-024-00644-2