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Frontiers in Physiology 2023Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention...
Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention of acute mountain sickness, may prevent altitude-induced deterioration of postural control in older persons. In this parallel-design trial, 95 healthy volunteers, 40 years of age or older, living <1,000 m, were randomized to preventive therapy with acetazolamide (375 mg/d) or placebo starting 24 h before and during a 2-day sojourn at 3,100 m. Instability of postural control was quantified by a balance platform with the center of pressure path length (COPL) as primary outcome while pulse oximetry (SpO) was monitored. Effects of altitude and treatment on COPL were evaluated by ordered logistic regression. www.ClinicalTrials.gov NCT03536429. In participants taking placebo, ascent from 760 m to 3,100 m increased median COPL from 25.8 cm to 27.6 cm (odds ratio 3.80, 95%CI 2.53-5.70) and decreased SpO from 96% to 91% (odds ratio 0.0003, 95%CI 0.0002-0.0007); in participants taking acetazolamide, altitude ascent increased COPL from 24.6 cm to 27.3 cm (odds ratio 2.22, 95%CI 1.57-3.13), while SpO decreased from 96% to 93% (odds ratio 0.007, 95%CI 0.004-0.012). Altitude-induced increases in COPL were smaller with acetazolamide vs. placebo (odds ratio 0.58, 95%CI 0.34-0.99) while drops in SpO were mitigated (odds ratio 19.2, 95%CI 9.9-37.6). In healthy individuals, 40 years of age or older, postural control was impaired after spending a night at 3,100 m. The altitude-induced deterioration of postural control was mitigated by acetazolamide, most likely due to the associated improvement in oxygenation.
PubMed: 38250659
DOI: 10.3389/fphys.2023.1274111 -
Annals of Medicine and Surgery (2012) Feb 2024Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia...
INTRODUCTION AND IMPORTANCE
Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia without episodes of weakness or paralysis. One of the sodium channel myotonia has been classified as acetazolamide-responsive myotonia because of the effectiveness of acetazolamide as an antimyotonic drug.
CASE PRESENTATION
The child presented with generalized muscle hypertrophy and stiffness involving arms, thighs, calves, chest, and back muscles with unusually prominent trapezius muscle. The parents described the warm-up phenomenon as an improvement in stiffness as the day passes and with repetitive action. Percussion myotonia was illustrated in the thenar eminence and trapezius muscle. Characteristic 'dive-bomber' sound was present in electromyography, and whole-exome sequencing revealed a novel Ile239Thr mutation in the gene. Acetazolamide was prescribed for the condition, and regular follow-up shows an excellent clinical response.
CLINICAL DISCUSSION
This case presents a pure myotonic phenotype without episodes of weakness or paralysis. Generalized myotonia with muscle hypertrophy and demonstrating warm-up phenomenon resembles myotonia congenita (a chloride channelopathy). However, genetic analysis revealed a novel Ile239Thr mutation involving gene indicating this case to be a sodium channelopathy.
CONCLUSION
This case limelight sodium channel myotonia with a novel Ile239Thr mutation in gene that phenotypically resembles myotonia congenita but genetically belongs to sodium channelopathy highlighting the poor correlation between genotypes and phenotypes in non-dystrophic myotonia. Acetazolamide can be a safe and cost-effective antimyotonic drug in sodium channel myotonia.
PubMed: 38333241
DOI: 10.1097/MS9.0000000000001673 -
Asia-Pacific Journal of Ophthalmology...The presence of peripapillary intraretinal fluid (IRF) has a broad differential diagnosis, including several types of neovascular and pachychoroid-related diseases....
PURPOSE
The presence of peripapillary intraretinal fluid (IRF) has a broad differential diagnosis, including several types of neovascular and pachychoroid-related diseases. However, the clinician may encounter cases without signs of neovascular or pachychoroid disease, or any other previously described diagnosis. For these patients, we propose the term NOn-Pachychoroid PEripapillary Schisis (NOPPES) of the retina, and we discuss the differential diagnosis.
DESIGN
A retrospective chart study set in a tertiary referral center for retinal diseases in Amsterdam, the Netherlands.
METHODS
Using multimodal imaging, cases suspected of peripapillary pachychoroid syndrome were reviewed. Cases without signs of neovascular or pachychoroid disease were included in this study. These cases were discussed in a group of senior retinal specialists to establish a diagnosis, and if there was no evidence for any previously described diagnostic entity, these cases were categorized as NOPPES.
RESULTS
Four cases of NOPPES were identified, 3 female patients and 1 male patient, aged between 58 and 75 years. Two patients were myopic, and 1 patient had a mild hyperopia. Three out of 4 cases showed unilateral peripapillary IRF, and 1 case had bilateral IRF. No improvement was seen after intravitreal bevacizumab or aflibercept, nepafenac eye drops, oral acetazolamide, vitrectomy with internal limiting membrane peeling, or surgery for carotid stenosis. One case showed a reduction in IRF after starting prednisolone eye drops.
CONCLUSIONS
We describe NOPPES, a new form of peripapillary schisis-like IRF. NOPPES seems relatively therapy-resistant. More research is needed to delineate the clinical spectrum of NOPPES and its pathogenesis and treatment.
Topics: Humans; Male; Female; Middle Aged; Aged; Retrospective Studies; Diagnosis, Differential; Tomography, Optical Coherence; Retina; Ophthalmic Solutions; Fluorescein Angiography
PubMed: 37974318
DOI: 10.1097/APO.0000000000000645 -
Journal of Neuromuscular Diseases 2024The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1...
BACKGROUND
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation.
METHODS
Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected.
RESULTS
A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude.
CONCLUSIONS
The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.
Topics: Adult; Female; Humans; Middle Aged; Electromyography; Italy; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Point Mutation
PubMed: 38427496
DOI: 10.3233/JND-230134 -
Scientific Reports Mar 2024The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin...
The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin prophylaxis. One hour prior to hypobaric hypoxia exposure, male SD rats were orally supplemented with quercetin (50 mg/kg BW) and acetazolamide (50 mg/kg BW) and exposed them to 25,000 ft. (7,620 m) in a simulated environmental chamber for 12 h at 25 ± 2 °C. Different biochemical parameters like renin activity, aldosterone, angiotensin I, ACE 2 were determined in plasma. As a conventional response to low oxygen conditions, oxidative stress parameters (ROS and MDA) were elevated along with suppressed antioxidant system (GPx and catalase) in plasma of rats. Quercetin prophylaxis significantly down regulated the hypoxia induced oxidative stress by reducing plasma ROS & MDA levels with efficient enhancement of antioxidants (GPx and Catalase). Further, hypoxia mediated regulation of renin and ACE 2 proves the outstanding efficacy of quercetin in repudiating altercations in RAAS cascade due to hypobaric hypoxia. Furthermore, differential protein expression of HIF-1α, NFκB, IL-18 and endothelin-1 analyzed by western blotting approves the biochemical outcomes and showed that quercetin significantly aids in the reduction of inflammation under hypoxia. Studies conducted with Surface Plasmon Resonance demonstrated a binding among quercetin and ACE 2 that indicates that this flavonoid might regulate RAAS pathway via ACE 2. Henceforth, the study promotes the prophylaxis of quercetin for the better adaptability under hypobaric hypoxic conditions via modulating the RAAS pathway.
Topics: Rats; Male; Animals; Quercetin; Renin; Catalase; Aldosterone; Rats, Sprague-Dawley; Reactive Oxygen Species; Hypoxia; Antioxidants; Oxidative Stress; Angiotensin I; Kidney
PubMed: 38556603
DOI: 10.1038/s41598-024-58134-3 -
Pharmaceutics Mar 2024Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and...
Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and bicarbonate. It is a membrane-bound protein with an extracellular catalytic center that is predominantly overexpressed in solid hypoxic tumors. Sulfamates and sulfonamides, for example acetazolamide (AZA), have been used to inhibit hCA IX in order to improve the response to solid hypoxic tumors. In the present study, we propose a new drug targeting approach by attaching the natural cytotoxic substances betulin and betulinic acid (BA) via a linker to sulfonamides. The conjugate was designed with different spacer lengths to accumulate at the target site of hCA IX. Computational and cell biological studies suggest that the length of the linker may influence hCA IX inhibition. Cytotoxicity tests of the newly synthesized bifunctional conjugates 3, 5, and 9 show effective cytotoxicity in the range of 6.4 and 30.1 µM in 2D and 3D tumor models. The hCA IX inhibition constants of this conjugates, measured using an in vitro enzyme assay with -nitrophenyl acetate, were determined in a low µM-range, and all compounds reveal a significant inhibition of hypoxia-induced CA activity in a cell-based assay using the Wilbur-Anderson method. In addition, the cells respond with G1 increase and apoptosis induction. Overall, the dual strategy to produce cytotoxic tumor therapeutics that inhibit tumor-associated hCA IX was successfully implemented.
PubMed: 38543295
DOI: 10.3390/pharmaceutics16030401 -
Sleep Medicine Feb 2024The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory...
RATIONALE
The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory polysomnography (PSG) data. Thus, we used PSG data to examine the: 1) association between OSA, and its severity, with IIH and 2) sex differences in OSA severity in those with and without IIH.
METHODS
We retrospectively analyzed diagnostic PSG data from January 2015 to August 2023 for patients who were diagnosed with IIH by a neuro-ophthalmologist using the modified Dandy criteria. We selected three age, sex, and body mass index (BMI) matched controls for each IIH patient. We examined potential associations of IIH with OSA using regression. Sex differences were analyzed using ANOVA.
RESULTS
Of 3482 patients who underwent PSG, we analyzed 78 IIH patients (16 males) and 234 matched controls (48 males). Five (6.4 %) IIH and 39 (16.7 %) control patients had OSA, defined as AHI≥15. After adjusting for age, sex, BMI, and comorbidities, IIH was negatively associated with the presence of OSA (OR 0.29, 95%CI 0.10-0.87, p = 0.03). However, models that adjusted for acetazolamide use, with or without comorbidities, showed no significant relationship with OSA (OR 0.31, p = 0.20). Males with IIH had a significantly higher age (p = 0.020), OSA severity (p = 0.032), and arousal index (p = 0.046) compared to females with IIH.
CONCLUSIONS
IIH treated with acetazolamide was not an independent risk factor for OSA presence or severity. The presence of IIH treated with acetazolamide likely does not warrant routine screening for OSA, but related risk factors may identify appropriate patients.
Topics: Humans; Male; Female; Retrospective Studies; Polysomnography; Pseudotumor Cerebri; Acetazolamide; Sleep Apnea, Obstructive
PubMed: 38245928
DOI: 10.1016/j.sleep.2024.01.013 -
Cureus Mar 2024Idiopathic intracranial hypertension (IIH) is a rare condition characterized by increased intracranial pressure, with an unknown cause. However, the pathophysiology of...
Idiopathic intracranial hypertension (IIH) is a rare condition characterized by increased intracranial pressure, with an unknown cause. However, the pathophysiology of antibiotic-induced IIH remains unclear. The clinical symptoms include headache, visual disturbances, and vomiting. The diagnosis is confirmed by an elevated intracranial pressure (ICP) with normal CSF study and cerebral imaging. Management includes discontinuing the offending antibiotic and reducing ICP with medications such as acetazolamide or diuretics. Therefore, surgical intervention may be necessary in severe cases. In this article, we report the case of a 19-year-old patient, admitted with symptoms of intracranial hypertension syndrome, occurring three days after receiving antibiotics (gentamicin, penicillin). Physical examination revealed bilateral optic disc edema. Cerebral magnetic resonance imaging (MRI) revealed indirect signs of intracranial hypertension. The CSF pressure measurement was approximately 290 mmHg, while CSF and other laboratory blood tests were normal. The patient received methylprednisolone bolus and topiramate (50 mg/day). A month later, the clinical outcome showed regression of headaches and regression of the papilledema.
PubMed: 38567240
DOI: 10.7759/cureus.55424 -
Frontiers in Oncology 2023Multiple myeloma (MM) is an incurable cancer of malignant plasma cells that engraft in the bone marrow (BM). It is more than likely that the poorly investigated physical...
INTRODUCTION
Multiple myeloma (MM) is an incurable cancer of malignant plasma cells that engraft in the bone marrow (BM). It is more than likely that the poorly investigated physical parameters of hypoxia and pH in the tumor microenvironment (TME) is critical for MM survival. Here, we explore the effects of a hypoxic environment on pH regulation and its role in MM survival.
METHODS
We used in vitro models of MM, in which the culturing medium was modified to specific pH and pO2 levels and then measured the effects on cell survival that was correlated with changes in intracellular (pHi) and extracellular pH (pHe). In a MM xenograft model, we used PET/CT to study hypoxia-mediated effects on tumor growth.
RESULTS
Hypoxia-mediated apoptosis of MM cells is correlated with acidic intracellular pHi (less than < 6.6) that is dependent on HIF activity. Using a polyamide HIF responsive element binding compound, a carbonic anhydrase inhibitor (acetazolamide), and an NHE-1 inhibitor (amiloride) acidified the pHi and lead to cell death. In contrast, treatment of cells with an alkalization agent, Na-lactate, rescued these cells by increasing the pHi (pH > 6.6). Finally, treatment of mice with acetazolamide decreased cell growth in the tumor nodules.
DISCUSSION
Targeting hypoxia and HIF have been proposed as an anti-tumor therapy but the clinical efficacy of such strategies are modest. We propose that targeting the pHi may be more effective at treating cancers within a hypoxic TME.
PubMed: 38023253
DOI: 10.3389/fonc.2023.1268421 -
Surgical Neurology International 2024This study aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after superficial temporal artery to middle cerebral artery (STA-MCA)...
BACKGROUND
This study aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis for moyamoya disease.
METHODS
This study included 25 patients with moyamoya disease who underwent STA-MCA anastomosis combined with indirect bypass onto their 34 hemispheres. About 1 mL of CSF was collected before and after bypass procedures to measure CSF partial pressure of oxygen (PO), CSF partial pressure of carbon dioxide (PCO), and CSF pH with a blood gas analyzer. As the controls, the CSF was collected from 6 patients during surgery for an unruptured cerebral aneurysm. PO and PCO were expressed as the ratio to partial pressure of oxygen (PO) and partial pressure of carbon dioxide (PCO), respectively.
RESULTS
PO/PO was 0.79 ± 0.14 in moyamoya disease, being lower than 1.10 ± 0.09 in the controls ( < 0.0001). PCO/PCO was 0.90 ± 0.10 in moyamoya disease, being higher than 0.84 ± 0.07 in the controls ( = 0.0261). PO/PO was significantly lower in pediatric patients than in adult patients and in the hemispheres with reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide than in those with normal CBF but reduced CVR. STA-MCA anastomosis significantly increased PO/PO from 0.79 ± 0.14 to 0.86 ± 0.14 ( < 0.01) and reduced PCO/PCO from 0.90 ± 0.10 to 0.69 ± 0.16 ( < 0.0001). There was no difference in CSF pH between moyamoya disease and the controls.
CONCLUSION
PO/PO was significantly lower in moyamoya disease than in the controls. Its magnitude was more pronounced in pediatric patients than in adult patients and depends on the severity of cerebral ischemia. STA-MCA anastomosis carries dramatic effects on CSF gas tensions in moyamoya patients. CSF may be a valuable biomarker to monitor the pathophysiology of cerebral ischemia/hypoxia in moyamoya disease.
PubMed: 38840605
DOI: 10.25259/SNI_281_2024