Transient Abnormalities Research Articles

Proteomic profiling of extracellular vesicles in takotsubo syndrome

Abstract Background/Purpose Takotsubo syndrome (TS) is an acute form of heart failure characterized by transient regional wall motion abnormalities triggered by a stressful event. The mechanisms underlying its development and recovery are poorly understood, resulting in a lack of disease-specific treatments and diagnostic markers. Extracellular vesicles (EVs) play a significant role in cellular communication and have been shown to be important in various diseases. Their involvement in cardiac conditions like TS is an emerging area of research. The primary objective of this study is to isolate and characterize EVs, as well as profile their proteomic profile, from the heart tissue of rats induced with TS. Methods Rats underwent TS induction through the infusion of 1 mg/kg isoprenaline over 15 minutes (TS24h), or were given saline (control). High-resolution echocardiography verified apical ballooning at 6 hours. After 24 hours, heart tissues from apical and basal segments were collected and processed. EV isolation involved tissue slicing, enzymatic digestion, and differential centrifugation steps, including a final iodixanol cushion separation for large and small EVs (Figure 1). Tandem mass tags and mass spectrometry were utilized for global proteomics and any differentially expressed proteins (DEPs) were identified. Analytical techniques such as volcano plots, heatmaps, enrichment analysis, and protein clustering/networks were employed. The strongest clusters (lowest False Discovery Rate and highest intensity) were selected, and their Gene Ontology (GO) terms/pathways were identified. Results Pure, cup-shaped, vesicles ranging from 50-800nm were successfully isolated (figure 1). EVs from apex of control and TS24h hearts had lower protein concentrations compared to their corresponding basal segments. Global proteomic analysis revealed a distinct protein profile in EVs from the apical segment of TS hearts at 24 hours. A total of 256 (TS24h-apex vs control-apex) and 561 proteins (TS24h-apex vs TS24h-base) were differentially expressed. No DEPs were observed when comparing the basal segments of TS24h and control hearts. Functional enrichment analysis of the DEPs showed an abundant change of biological processes related to metabolic lipid processes, inflammatory response, complement activation, reorganization of extracellular matrix. A downregulation was seen for biological processes related to mitochondrial ATP synthesis coupled electron transport and muscle contraction. Conclusion This study demonstrates a distinct EV protein profile in the apical segments of TS hearts, with marked changes in proteins related to metabolic lipid processes, inflammation, and mitochondrial activity. This extensive catalogue of novel proteins sets the stage for future research aimed at identifying potential therapeutic targets and diagnostic biomarkers, and enabling proof-of-concept studies in TS.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies

BackgroundSHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects.MethodsTwo randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg).ResultsSixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed.ConclusionsA single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development.Trial registrationNCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease

BackgroundColony-stimulating factor 1 receptor (CSF1R)–dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.MethodsIn this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.ResultsA total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.ConclusionsTargeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.)

Takotsubo Syndrome: Differences between Peripartum Period and General Population.

Takotsubo syndrome (TTS) was first described in postmenopausal women with transient regional wall motion abnormalities. The trigger is usually an emotional or physical stress. The catecholamine hypothesis seems to be the most prevailing. The main difference between TTS and acute coronary syndromes is that there is no obstructive coronary disease to explain the regional abnormalities. In this form, the left ventricle resembles the fishing jar which is used to trap octopus in Japan. However, to date more atypical forms are recognized. Also, the syndrome is not limited to older women. Nowadays, TTS is presented even in pregnancy and postpartum females. Our experience revealed cases of patients during these periods and some of them suffered from reverse Takotsubo. Additionally, the initial diagnosis in some patients was other than TTS. Due to these findings, we suggest that this type of TTS is not very rare but underestimated. For this reason, further studies are needed to support and explain this condition.

Development of a small animal model replicating core characteristics of takotsubo syndrome in humans.

Adequate animal models are necessary to understand human conditions, such as takotsubo syndrome (TS) characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models. We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 g and aged 7-8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored the regional wall motion over 30 days to correlate with histological changes. Increasing the isoprenaline dose and the infusion time significantly enhanced akinesia (P < 0.01), resulting in pronounced apical ballooning observed in three-dimensional imaging. Akinesia peaked at 6 h post-infusion, with recovery observed at 24 h; most rats recovered from akinetic segments within 48-72 h. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases, with a 16.7% mortality rate. Histological examinations confirmed that myocardial injury occurred, independent of apical ballooning. This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model's reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation.

"Spasms in Silence": A case of coronary vasospasm-induced ventricular fibrillation.

A 56-year-old man presented following an aborted cardiac arrest. His initial ECGs showed episodes of transient repolarization abnormalities. Coronary vasospasm can be a precipitant for ventricular arrhythmia in these patients, underpinning the importance of continuous ECG for accurate diagnosis and management.

SCARY ECG IN TAKOTSUBO CARDIOMYOPATHY

Abstract Takotsubo cardiomyopathy (TTC) is characterized by a transient ventricular wall motion abnormality and shares common features with acute coronary syndrome (ACS) with a wide spectrum of triggers, such as both emotional or physical, activating common toxic catecholamines–mediated pathways. TTC might be associated with severe clinical complications. We report a case of a 74–year female patient with circulatory shock with mixed phenotype, distributive due to sepsis and cardiogenic due to TTC. The patient presented to the emergency department with severe hypotension, pathological qSOFA score and clinical and laboratory findings consistent with severe sepsis. ECG showed diffuse lambda ST–segment elevation, also called “shark fin”(fig.1). According to hemodynamically unstable scenario and ECG pattern, emergency coronary angiography was performed, showing absence of coronary artery disease(fig. 2). Echocardiography revealed severe LV systolic disfunction (EF 20–25%) with apical ballooning and severe systolic anterior motion (SAM) of the anterior mitral leaflet eliciting dynamic LVOTO with peak gradient greater than 90 mmHg; fig. 3) and severe MR. Patient was treated with cautious fluid administration, hemotrasfusion and empiric large spectrum antibiotic therapy. According to TTC working diagnosis, even if septic state was thought to contribute to cardiogenic shock, norepinephrine was not administered due to concerns for LVOTO and SAM. After overcoming of dramatic first phase and after hemodynamic steadiness was achieved, beta blockade and ACEi were progressively administered. Seriate transthoracic echocardiogram revealed progressive improvement of LV systolic function, regression of apical ballooning, SAM and LVOTO. ECG monitoring showed regression of ischemic ST elevation. ST elevation has been described in about 56% of TTC cases, however with amplitude tipically lower than in STEMI. Lambda–wave ST elevation has been rarely reported. Vasospasm, local intermittent microvascular constriction, catecholamine–induced metabolic toxicity, transmural systolic wall tension and its the mechano–electric feedback can explain scaring ECG–pattern. Despite its rare prevalence in TTC “shark fin” pattern appears to relate to adverse outcome and it should be used as an early marker of potential further clinical deterioration, suggesting more intensive monitoring to avoid delays in possible therapy escalation.

Are changes in olanzapine-induced liver enzyme levels associated with GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms?

Olanzapine treatment sometimes produces transient liver biochemistry abnormalities, and such drug-induced liver injuries are mainly monitored by measuring blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas alpha-glutathione-S-transferase (α-GST) is not routinely measured in clinics, even though it can serve as an earlier and more specific biomarker of liver damage. Susceptibility to drug-induced liver injury can much depend on the gene polymorphisms regulating the activity of DNA detoxification and repair enzymes. The aim of this study was to evaluate which of the three liver enzymes - α-GST, ALT, and AST - is the most sensitive biomarker of olanzapine-induced liver injury and how their blood levels are affected by the GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms in 30 olanzapine-treated patients. Contrary to our hypothesis, the increase in serum α-GST levels was not significantly greater than that of the transaminases. ALT turned out to be an earlier biomarker of liver injury than the other two enzymes. No significant association was found between gene polymorphisms and liver enzyme levels, save for GSTP1 Ile/Val + Val/Val and ALT, which points to this genotype as a risk factor for drug-induced liver injury. Future studies might help to identify the underlying mechanisms of transient liver enzyme increase associated with this genotype.

The effects of choline supplementation in mothers with hypothyroidism on the alteration of cognitive-behavioral, long-term potentiation, morphology, and apoptosis in the hippocampus of pre-pubertal offspring rats.

The mother's thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long-lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive-behavioral function, long-term potentiation (LTP), and morphological changes as well as apoptosis in pre-pubertal offspring rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase-3 stained cells in choline-receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats.

Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging.

Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach.

Evaluation of Brain MRI Findings in Patients Referred with Seizures

Introduction: Seizures are one of the common and warning signs of brain diseases, which doctors often use CT-scan or MRI for diagnose. The present study was conducted with the aim of evaluation of brain MRI of the patients referred with seizures in order to determine their brain lesions and involvement.&#x0D; Methods: The study was carried out using a retrospective cross-sectional descriptive method. All the patients with seizures referred for MRI to the Radiology Department of Shahid Sadoughi Hospital in Yazd City, Iran during 2016-2020 were examined. By referring to the archives of the radiology department, the records and MRI of the patients referred with seizures were extracted. Then, the data were extracted from the Hospital Information System and the patients' files; after that they were analyzed with SPSS version 16.&#x0D; Results: The present study was conducted on 105 patients with seizures for brain MRI. 48.6% (51 people) of patients were male and 51.4% (54 people) were female. The average age of the patients was 34.17 ± 10.50 years. MRI was normal in 59% of the patients. 16.2% Non-Specific, 6.7% Mass and 4.8% evidence of Encephalomalacia were also reported. The most lesions with 10.5% were related to left frontal lobe and 2.9% were related to right frontal lobe. 99% of seizures were unspecified convulsion and 1% were postprocedural disorder of nervous system. There was no significant relationship between the gender of the patients and their diagnosis (P&gt;0.471).&#x0D; Conclusion: Wide abnormalities such as mass, edema, encephalomalacia and demyelination are observed in the MRI of the patients with seizures and are often located in the frontal lobe. In general, seizures can cause transient and reversible brain abnormalities in MRI.

Severe Leptospirosis With non-Oliguric Renal Failure With ‘Myocarditis’ Mimicking Acute Coronary Syndrome: A Rare Presentation From Northern India

Leptospirosis is a globally distributed zoonosis with a broad clinical spectrum. Thisthe disease mostly affectsliver and kidney tissues. Other organs can be affected by leptospirosis-induced vasculitis. In addition, cardiacmanifestations are common, and the presence of transient ECG abnormalities can be found in 50-60 % of thepatients(1). Early diagnosis and adequate supportive therapy are crucial for the appropriate management ofsymptoms. In this article, we present a case of leptospirosis with myocarditis with hypokalemia and non-oliguricacute renal failure. All clinical findings gradually regressed after treatment.

Acute cardiovascular manifestations with multisystem inflammatory syndrome in children due to COVID-19 infection: A single-center prospective observational study

Abstract Background: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the COVID-19 pandemic. A majority of children have significantly raised levels of NT pro-BNP, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. Cardiac involvement may include rhythm disturbance, depressed myocardial function, valvar regurgitation, and/or coronary artery inflammation. This hospital-based prospective study was aimed to evaluate cardiovascular manifestations in cases of multisystem inflammatory syndrome in children (MIS-C). Subjects and Methods: The current study was a prospective observational study that included 100 children admitted to the pediatric intensive care unit after getting the requisite clearance from the institutional ethics committee; informed written consent of parents was taken before the start of the study. Results: The mean age of the study participants was 8.9 ± 3.9 years with 62% male children. Ninety-four percentage had MIS-C with KD phenotype while only 6% of kids developed shock. Abnormal electrocardiography (ECG) was found in 41%, pericardial effusion in 16%, left ventricular dysfunction (LVD) in 42%, and coronary lesions found in 30% of patients. Abnormal NT-proBNP (&gt;125 pg/ml) was noted in 90% of children. Abnormal cTnT was seen in 89%, and 91% of children had abnormal BNP. The present study found a mortality of 6%. Conclusions: MIS-C with KD phenotype is the most common presentation with raised cardiac injury markers. Abnormal ECG LVD and coronary lesions are transient common cardiac abnormalities which get resolved within 3 months of treatment.

Comparação de fórmulas para cálculo da taxa de filtração glomerular estimada e seus limiares diagnósticos para doença renal crônica em pessoas idosas: um estudo transversal

Abstract Objective To evaluate and compare the CKD-EPI, BIS1 and MDRD formulas and diagnostic thresholds of 45 and 60 ml/min/1.73m2 in older patients. Method A cross-sectional, descriptive, analytical observational study was conducted. Patients aged ≥65 years treated at a referral outpatient clinic between January 2020 and June 2022, were assessed. Patients with only one creatinine level or with transient GFR abnormalities were excluded. Results The GFR estimates using the CKD-EPI formula were higher than both the BIS1 and MDRD formulas in patient groups aged 65-74 years and 75-84 years. In the group of patients aged 85-94 years, the CKD-EPI showed no difference when compared with the MDRD, yielding higher estimates only compared with the BIS1. Greater dispersion was found between the CKD-EPI and BIS1, showing less agreement between these formulas, as confirmed by the Kappa test (76.7%), while there was almost perfect agreement between the CKD-EPI and MDRD. Conclusion The BIS1 formula showed stronger correlation of the decrease in eGFR with advancing age, reflecting the physiological renal aging process and serving as a potentially useful tool for estimating GFR in older adults. The formula can help provide a more accurate diagnosis of CKD and aid planning of interventions to slow the progression of CKD and predict the risk of mortality from cardiovascular diseases.

А rare case of Тakoтsubo cardiomyopathy complicated with high-grade AV block and ventricular tachycardia

Takotsubo cardiomyopathy or broken heart syndrome is a stress-induced cardiomyopathy with clinical, laboratory and ECG resemblance to acute coronary syndrome. Major differences stem from transient segmental wall motion abnormalities beyond the territory of a single coronary artery and the lack of obstructive coronary disease during angiography. Overall the condition is considered as a benign one with a favourable outcome, however there are reports of complicated clinical course by cardiogenic shock, apical thrombus, death and arrhythmias. The latter are reported to occur in 13% of the cases with ventricular arrhythmias (ventricular tachycardia, ventricular &amp;#64257; brillation, torsades de pointes) as a leading &amp;#64257; nding and in minor percentage &amp;ndash; high-grade AV block. Despite advances in our knowledge and experience there are still no strict guidelines for the management of conduction disorders. We present the case of a 78-year old lady with an apical variant of Takotsubo, complicated by syncope, complete AV block, new left bundle branch block, paroxysmal atrial &amp;#64257; brillation, ventricular tachycardia and implantation of a permanent pacemaker. During the hospitalization she developed acute cardiac failure with echocardiographic evidence of left ventricular systolic dysfunction and an apical thrombus. The presented case demonstrates the complexity of the condition and the necessity of strict follow-up and timely therapy.&amp;nbsp;

Central diabetes insipidus after transnasal adenomectomy:trends in development and recovery, clinical and laboratory characteristics

Background: Currently, there is an increase in the incidence of chiasmosellar neoplasms and respective neurosurgical interventions. The postoperative period may be complicated by vasopressin synthesis and secretion disorders. Both the development and abortion of the fluid and electrolyte disorders can be delayed. Due to a tendency for an earlier discharge of the patients, a proportion of the disorders remain unaddressed. There is no data on the evolution and time to regress of transient abnormalities in the published studies with a long-term postoperative follow-up.&#x0D; Aim: To assess the incidence, evolution and regression trends, clinical and laboratory characteristic of postoperative central diabetes insipidus (CDI).&#x0D; Materials and methods: The single center retrospective comparative study included 150 patients who had undergone transnasal adenomectomy for Cushings disease, acromegaly, prolactinomas, and hormonally inactive pituitary adenomas. Clinical and laboratory assessments were performed pre- and postoperatively. In the event of CDI, treatment with desmopressin was administered. Ninety six (96) patients aged 20 to 65 years (median age 43 [35; 54] years) were followed for at least 60 months after the procedure.&#x0D; Results: Median time to the onset of permanent CDI (pCDI) was Day 5 [1; 9.5] after surgery, that of transient CDI (tCDI) Day 1 [1; 4.5] with its remission by Day 30 [1.5; 199]. The maximally delayed onset was on Day 86 for the pCDI and Day 61 for tCDI; that to the remission of tCDI, 738 days. At discharge from the hospital, postoperative CDI was present in 34/150 patients (23%; 95% CI 1730), and in 25/150 of the patients (16%; 95% CI 1224) the disorder resolved. At 5 to 7 years after surgery, the prevalence of pCDI was 16% (95% CI 1024), that of tCDI 35% (95% CI 2745), 49% (95% CI 3959) of the patients had no abnormalities (respective absolute patient numbers being 15, 34, and 47 of 96 followed for at least 60 months). At Days 1 to 7 after surgery, the patients with pCDI and tCDI had more frequent complaints of dry mouth and thirst than those without the disorder. These complaints were verified by higher 24-hour fluid intake and diuresis at the day of surgery and Days 5 to 7 thereafter, compared to those in the patients without the disorders. At Days 57 after surgery, urine sodium and urine specific gravity were significantly lower, as was urine osmolality at all postoperative stages, compared to those in the patients without the disorders.&#x0D; Conclusion: Within 2 years after transnasal adenomectomy, the incidence of postoperative CDI is gradually decreasing (from 23% to 16%). Due to potentially delayed manifestation of water and electrolyte imbalance, it is recommended that these parameters should be monitored at least for 2,5 months after the discharge from hospital. Due to potentially delayed remission (12 months and more), follow-up and monitoring for 1.5 years is reasonable, with periodic assessment of sodium levels, fluid intake and excretion, and attempts to withdraw desmopressin.

Takotsubo syndrome: unravelling the enigma of the broken heart syndrome?-a narrative review.

Takotsubo syndrome (TTS) is a condition characterized by transient ventricular regional wall motion abnormalities, without causative coronary artery disease, typically triggered by emotional or physical stress. TTS is more common in post-menopausal women, closely resembling acute coronary syndrome (ACS) in its clinical presentation, with multiple proposed underlying pathophysiological mechanisms and no evidence-based treatments. This review aims to provide a comprehensive summary of the latest research, encompassing the pathophysiology, diagnostic findings, prognosis, and treatment options for TTS patients. Relevant literature from 1990 to June 2023 on TTS epidemiology, physiopathology, diagnosis, clinical manifestations, treatment, and prognosis was retrieved through PubMed research. Only English publications were included. TTS is an increasingly recognized cardiovascular disorder, a significant release of catecholamines is thought to be a key contributing element, yet its exact mechanism remains unclear. Notably, TTS poses significant short and long-term risks akin to ACS. Initial treatment should focus on ruling out ACS and providing standard care for subsequent left ventricular dysfunction and complications. Research hints at a potential role for Angiotensin-converting enzyme inhibitors and Angiotensin II receptor blockers in improving long-term prognosis in TTS patients. Significant knowledge gaps still exist in our understanding of the pathophysiology, treatment options, and areas for improvement in diagnosing and prognosticating this intriguing condition. Further research is therefore needed.

Takotsubo Cardiomyopathy in the setting of Urosepsis

Takotsubo cardiomyopathy is a rare cardiac condition associated with transient left ventricular apical wall motion abnormalities in association with stress but without any signifcant coronary artery disease. We present a case of takotsubo cardiomyopathy presenting as acute pulmonary edema in the background of urosepsis.

Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201)

Background: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic cell transplant (alloHCT) that affects multiple organs with inflammatory and fibrotic pathology, leading to significant patient burden and mortality. Colony-stimulating factor 1 receptor (CSF-1R)-dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab (SNDX-6352) is an investigational, high-affinity anti-CSF-1R monoclonal antibody that targets monocytes and macrophages. We previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase 1/2 study (NCT03604692) in patients with cGVHD. Methods: This pivotal phase 2, open-label, randomized, multicenter study evaluated axatilimab at 3 different doses in alloHCT patients with recurrent or refractory cGVHD (AGAVE-201; NCT04710576). Eligible patients were randomized 1:1:1 to receive intravenous (IV) axatilimab at 0.3 mg/kg every 2 weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Randomization was stratified by severity of cGVHD and prior use of ibrutinib, ruxolitinib, or belumosudil. Concomitant use of corticosteroids, calcineurin inhibitors, or mammalian target of rapamycin inhibitors (sirolimus or everolimus) was allowed. Axatilimab treatment could be continued as long as there was clinical benefit as assessed by the investigator. The primary efficacy endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks) as defined by the NIH 2014 consensus criteria; the efficacy boundary of the ORR is based on the lower bound of the 95% CI exceeding 30%. The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score with a threshold of ≥7 points. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs). Results: A total of 241 patients were enrolled across 121 study sites and 239 (99.2%) patients were treated with axatilimab at the data cutoff of 7 April 2023. Patients were heavily pretreated with a median of 4 prior lines of therapy, including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Demographics and disease characteristics were balanced among the 3 dose cohorts (Table 1). ORR (95% CI) was 74% (63, 83) with 0.3 mg/kg Q2W, 67% (55, 77) with 1 mg/kg Q2W, and 50% (39, 61) with 3 mg/kg Q4W (Table 1). Median duration of response (DOR) has not been reached in any of the cohorts, with 60%, 60% and 53% of patients maintaining response at 12 months in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W cohorts, respectively, in the first 6 cycles. Drug discontinuation owing to TEAEs occurred in 6% of patients with 0.3 mg/kg Q2W, 22% with 1 mg/kg Q2W, and 18% with 3 mg/kg Q4W. The most common TEAEs are summarized in Table 2. Fatal TEAEs occurred in 1.3%, 8.6%, and 7.6% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. The frequency of TRAEs and grade ≥ 3 TRAEs were dose dependent, consistent with CSF-1R inhibition-mediated macrophage clearance. Most infections were mild, with 3 reported cytomegalovirus infections, including reactivations, in the higher dose cohorts. Conclusions: The AGAVE-201 pivotal trial met its primary endpoint for all doses studied. Axatilimabtreatment of refractory cGVHD in heavily pretreated patients resulted in robust clinical activity and durable responses in all 3 dose cohorts, with the highest ORR and least toxicity at the 0.3 mg/kg Q2W dose. Adverse events consisted primarily of transient laboratory abnormalities and other on-target effects known to be associated with CSF-1R block.

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.