Dual Antiplatelet Therapy Versus Antiplatelet Monotherapy Plus Oral Anticoagulation in Patients with Acute Coronary Syndrome and Coronary Artery Ectasia: Design and Rationale of OVER-TIME Randomized Clinical Trial.

INTRODUCTION: The optimal anti-thrombotic therapy to prevent recurrent ischemic events in patients with acute coronary syndrome and coronary artery ectasia (CAE) remains unclear. AIM: To assess the efficacy and safety of antiplatelet plus anticoagulant therapy versus dual antiplatelet therapy in patients with acute coronary syndromes and coronary artery ectasia. METHODS: OVER-TIME is an investigator initiated, exploratory, open label, single center, randomized clinical trial comparing dual antiplatelet therapy (acetyl-salicylic acid plus a P2Y12 inhibitor) with the combination of an antiplatelet monotherapy (a P2Y12 inhibitor) plus a low dose anticoagulant (rivaroxaban, 15mg oral dose) for the prevention of recurrent ischemic events among patients with CAE. We aim to enroll approximately 60 patients with CAE and acute coronary syndromes. After recruitment, patients are randomized to (a) standard of care (dual antiplatelet regimen) or (b) the combination of antiplatelet monotherapy and low dose anticoagulant. Patients will be followed for at least 12 months. The OVER-TIME study aims to assess the efficacy of the regimen in prevention of major cardiovascular events and its security in bleeding events in acute coronary syndromes among patients with CAE. Expected results and conclusions: OVER-TIME is the first randomized controlled trial to assess different antithrombotic strategies in patients with CAE and acute coronary syndrome, and its results will offer preliminary data for the prevention of major cardiovascular events and bleeding events in this group of patients. TRIAL REGISTRATION NUMBER: NCT05233124 (ClinicalTrials.gov), date of registration: February 10, 2022.

Is There Association between Altered Adrenergic System Activity and Microvascular Endothelial Dysfunction Induced by a 7-Day High Salt Intake in Young Healthy Individuals.

This study aimed to test the effect of a 7-day high-salt (HS) diet on autonomic nervous system (ANS) activity in young healthy individuals and modulation of ANS on microvascular endothelial function impairment. 47 young healthy individuals took 7-day low-salt (LS) diet (3.5 g salt/day) followed by 7-day high-salt (HS) diet (~14.7 g salt/day). ANS activity was assessed by 24-h urine catecholamine excretion and 5-min heart rate variability (HRV). Skin post-occlusive reactive hyperemia (PORH) and acetylcholine-induced dilation (AChID) were assessed by laser Doppler flowmetry (LDF). Separately, mental stress test (MST) at LS and HS condition was conducted, followed by immediate measurement of plasma metanephrines' level, 5-min HRV and LDF microvascular reactivity. Noradrenaline, metanephrine and normetanephrine level, low-frequency (LF) HRV and PORH and AChID significantly decreased following HS compared to LS. MST at HS condition tended to increase HRV LF/HF ratio. Spectral analysis of PORH signal, and AChID measurement showed that MST did not significantly affect impaired endothelium-dependent vasodilation due to HS loading. In this case, 7-day HS diet suppressed sympathetic nervous system (SNS) activity, and attenuated microvascular reactivity in salt-resistant normotensive individuals. Suppression of SNS during HS loading represents a physiological response, rather than direct pathophysiological mechanism by which HS diet affects microvascular endothelial function in young healthy individuals.

Corneal Ectasia Induced by Prostaglandin Analogues.

Our purpose is to document the first case of unilateral mild corneal ectasia developed in an apparently nonpredisposed cornea after topical latanoprost treatment, and its regression after treatment withdrawal. We describe a 44-year-old man with visual impairment in his left eye (OS) and a past medical history of myopic refraction and ocular hypertension with latanoprost treatment, the rest of ocular examination was normal. A decrease in visual acuity was observed with a refractive change. Corneal tomography showed features of mild corneal ectasia in his OS. Topical prostaglandin analogue therapy was removed and replaced by other antiglaucoma topical treatment. Corneal tomography returned to normal, an improvement in the quality of vision was observed and refractive astigmatism recovered to baseline values. This case illustrates that topical latanoprost does affect the matrix metalloproteinases balance in corneal extracellular matrix, and subsequently may produce a corneal weakening. Corneal biomechanical features and corneal stiffness do probably recover after topical prostaglandin analogues withdrawal.

von Willebrand factor deficiency does not influence angiotensin II-induced abdominal aortic aneurysm formation in mice.

Abdominal aortic aneurysm (AAA) refers to a localized dilation of the abdominal aorta that exceeds the normal diameter by 50%. AAA pathophysiology is characterized by progressive inflammation, vessel wall destabilization and thrombus formation. Our aim was to investigate the potential involvement of von Willebrand factor (VWF), a thrombo-inflammatory plasma protein, in AAA pathophysiology using a dissection-based and angiotensin II infusion-induced AAA mouse model. AAA formation was induced in both wild-type and VWF-deficient mice by subcutaneous implantation of an osmotic pump, continuously releasing 1000 ng/kg/min angiotensin II. Survival was monitored, but no significant difference was observed between both groups. After 28 days, the suprarenal aortic segment of the surviving mice was harvested. Both AAA incidence and severity were similar in wild-type and VWF-deficient mice, indicating that AAA formation was not significantly influenced by the absence of VWF. Although VWF plasma levels increased after the infusion period, these increases were not correlated with AAA progression. Also detailed histological analyses of important AAA hallmarks, including elastic degradation, intramural thrombus formation and leukocyte infiltration, did not reveal differences between both groups. These data suggest that, at least in the angiotensin II infusion-induced AAA mouse model, the role of VWF in AAA pathophysiology is limited.

Safety and efficacy of the sodium-glucose cotransporter 1 inhibitor mizagliflozin for functional constipation: a randomised, placebo-controlled, double-blind phase 2 trial.

BACKGROUND: Mizagliflozin is a novel oral sodium-glucose cotransporter 1 (SGLT1) inhibitor that increases luminal glucose and water. This study assessed the efficacy and safety of mizagliflozin in patients with functional constipation. METHODS: In this multicentre, randomised, double-blind phase 2 trial at 32 hospitals and community outpatient clinics in Japan, we enrolled patients with functional constipation or constipation-predominant irritable bowel syndrome, aged 20 years or older. Patients were randomly assigned (1:1:1), by use of an independent centralised registration system and dynamic allocation method, to receive mizagliflozin 5 mg, mizagliflozin 10 mg, or placebo, orally once daily for 4 weeks. Patients, investigators, staff, and the sponsor were blinded to the group assignments. The primary outcome was the change from baseline in the number of spontaneous bowel movements per week after 1 week. Efficacy analysis was done in all patients except those who deviated from good clinical practice, did not receive at least one dose of the study drug, withdrew before starting treatment, were ineligible, or for whom the primary outcome could not be assessed, and safety was assessed in all patients except those who deviated from good clinical practice, who did not receive the study drug, or who withdrew before receiving treatment. This trial is registered with ClinicalTrials.gov, number NCT02281630, and is completed. FINDINGS: Between Oct 15, 2014, and March 7, 2015, 258 patients with functional constipation were randomly assigned: 86 patients per group. Two patients from the placebo group and three from the 10 mg mizagliflozin group were excluded because the primary outcome could not be assessed, and one patient from the 5 mg mizagliflozin group was excluded for not receiving the study drug; therefore 84 patients in the placebo group, 85 in the 5 mg mizagliflozin group, and 83 in the 10 mg mizagliflozin group were included in the full analysis population. Mean change from baseline in the number of spontaneous bowel movements per week after 1 week with mizagliflozin 5 mg (3·85 [SD 3·96]) and mizagliflozin 10 mg (5·85 [6·01]) was significantly greater than those in the placebo group (1·80 [1·80]; p<0·0001 for both comparisons). The most common adverse events were nasopharyngitis (one [1%] of 86 patients in the placebo group, seven [8%] of 85 on mizagliflozin 5 mg, and five [6%] of 86 on mizagliflozin 10 mg), diarrhoea (none on placebo, four [5%] patients on mizagliflozin 5 mg, and eight [9%] on mizagliflozin 10 mg), and abdominal distention (three [3%] on placebo, four [5%] on mizagliflozin 5 mg, and seven [8%] on mizagliflozin 10 mg). Only diarrhoea and abdominal distention were deemed to be related to mizagliflozin treatment, whereas nasophanyngitis might not be related to mizagliflozin treatment, on the basis of clinical evaluation. INTERPRETATION: The SGLT1 inhibitor mizagliflozin showed favourable efficacy and tolerability at 5 mg and 10 mg doses in patients with functional constipation, providing a potential alternative therapy to available drugs. FUNDING: Kissei Pharmaceutical.

Methadone use and asymptomatic common bile duct dilation: Re-examining the link.

Opiates have long been implicated in causing common bile duct (CBD) dilation but few studies have been done to look at the association between synthetic opiates - methadone - and asymptomatic CBD dilation. The mechanism by which methadone could cause CBD dilation is poorly understood, but it has been postulated that increase in biliary pressures from contraction of the sphincter of Oddi is likely. In the below article, we review all the evidence pertaining towards methadone causing common bile duct dilation.

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

Comparison of Two Neutral Oral Contrast Agents in Pediatric Patients: A Prospective Randomized Study.

Purpose To prospectively compare small bowel distention provided by, as well as patient acceptance of, two different neutral (negative) oral contrast materials used for cross-sectional enterography in a pediatric population. Materials and Methods In this noninferiority study, 66 pediatric patients undergoing clinical computed tomographic (CT) or magnetic resonance (MR) enterography were randomized to receive either a flavored beverage for neutral abdominal and pelvic imaging (Breeza; Beekley Medical, Bristol, Conn) or a low-density barium sulfate suspension. Patients were blinded to the oral contrast material administered and were asked to rate taste, texture, and their perceived health state (where 0 was very bad and 10 was very good). Ingested volume of the prescribed weight-based oral contrast material preparation was recorded. Maximum small bowel diameter was measured in all four abdominal quadrants. Mean bowel diameter as well as taste, texture, and health state scores were compared between cohorts by using t tests; proportions were compared by using Fisher exact tests. Results Thirty-three patients each received Breeza and barium sulfate suspension, respectively. No difference was found in age (Breeza, 13.5 years ± 2.6 [standard deviation]; barium sulfate suspension, 13.9 years ± 2.8; P = .49), sex distribution (15 girls each; P > .99), or health state (P = .21) between cohorts. Twenty-eight of 33 (84.8%) and 17 of 33 (51.5%) patients completed the Breeza and barium sulfate suspension preparations, respectively (P = .007). Breeza received higher scores for taste (6.1 ± 2.5 vs 2.7 ± 2.5; P < .0001) and texture (7.3 ± 2.3 vs 3.6 ± 2.9; P < .0001). No difference was found in bowel distention between Breeza and barium sulfate suspension (1.63 cm ± 0.24 vs 1.69 cm ± 0.25; P = .44). Conclusion The neutral oral contrast materials Breeza and low-density barium sulfate suspension provide similar small bowel distention. Patients receiving Breeza are more likely to ingest the entire prescribed volume.

Magnetic resonance cholangiogram patterns and clinical profiles of ketamine-related cholangiopathy in drug users.

BACKGROUND & AIMS: Recreational ketamine use has emerged as an important health and social issue worldwide. Although ketamine is associated with biliary tract damage, the clinical and radiological profiles of ketamine-related cholangiopathy have not been well described. METHODS: Chinese individuals who had used ketamine recreationally at least twice per month for six months in the previous two years via a territory-wide community network of charitable organizations tackling substance abuse were recruited. Magnetic resonance cholangiography (MRC) was performed, and the findings were interpreted independently by two radiologists, with the findings analysed in association with clinical characteristics. RESULTS: Among the 343 ketamine users referred, 257 (74.9%) were recruited. The mean age and ketamine exposure duration were 28.7 (±5.8) and 10.5 (±3.7) years, respectively. A total of 159 (61.9%) had biliary tract anomalies on MRC, categorized as diffuse extrahepatic dilatation (n = 73), fusiform extrahepatic dilatation (n = 64), and intrahepatic ductal changes (n = 22) with no extrahepatic involvement. Serum alkaline phosphatase (ALP) level (odds ratio [OR] 1.007; 95% CI 1.002-1.102), lack of concomitant recreational drug use (OR 1.99; 95% CI 1.11-3.58), and prior emergency attendance for urinary symptoms (OR 1.95; 95% CI 1.03-3.70) had high predictive values for biliary anomalies on MRC. Among sole ketamine users, ALP level had an AUC of 0.800 in predicting biliary anomalies, with an optimal level of ≥113 U/L having a positive predictive value of 85.4%. Cholangiographic anomalies were reversible after ketamine abstinence, whereas decompensated cirrhosis and death were possible after prolonged exposure. CONCLUSIONS: We have identified distinctive MRC patterns in a large cohort of ketamine users. ALP level and lack of concomitant drug use predicted biliary anomalies, which were reversible after abstinence. The study findings may aid public health efforts in combating the growing epidemic of ketamine abuse. LAY SUMMARY: Recreational inhalation of ketamine is currently an important substance abuse issue worldwide, and can result in anomalies of the biliary system as demonstrated by magnetic resonance imaging. Although prolonged exposure may lead to further clinical deterioration, such biliary system anomalies might be reversible after ketamine abstinence. Clinical trial number: NCT02165488.

Corneal Collagen Cross-Linking Complications.

Corneal cross-linking was approved by United States Food and Drug Administration for the treatment of progressive keratoconus in April 2016. As this approach becomes more widely used for the treatment of keratoconus and post-laser in situ keratomileusis (LASIK) ectasia, the medical community is becoming more familiar with potential complications associated with this procedure. This article aims to review the reported complications of collagen cross-linking for the treatment of keratoconus and post-LASIK ectasia.

Dilatation of the ductus arteriosus by diazoxide in fetal and neonatal rats.

BACKGROUND: Diazoxide, an ATP-sensitive potassium channel opener, is the main therapeutic agent for treating hyperinsulinemic hypoglycemia. The aim of this study was to determine the in vivo ductus arteriosus (DA)-dilating effects of diazoxide in fetal and neonatal rats. METHODS: Near-term rat pups delivered via cesarean section were housed at 33°C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were injected i.p. with diazoxide (10 and 100 mg/kg) 4 h before delivery, and the neonatal DA diameter was measured at 0, 30, or 60 min after birth. The newborn rats were also injected i.p. with diazoxide (10 and 100 mg/kg) at birth or 60 min after birth. DA was measured at 0, 30, or 60 min after injection. In the fetal investigation, the effect of diazoxide was studied via simultaneous application of indomethacin (10 mg/kg) and L-nitroarginine methyl ester (L-NAME) on gestational days 21 and 19. RESULTS: The control rats had rapid postnatal DA constriction (diameter, 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Diazoxide had a dose-dependent inhibitory effect on postnatal DA constriction. Prenatal diazoxide (10 mg/kg) inhibited postnatal DA closure (0.20 mm at 60 min after birth). The diazoxide injection (10 mg) at birth inhibited postnatal DA closure (0.14 mm at 60 min after birth). Diazoxide injection in 60-min-old rats dilated the constricted DA at 60 min (0.10 mm vs. 0.02 mm in the controls). In the fetal investigation, diazoxide inhibited the fetal DA constrictive effect of indomethacin and L-NAME. CONCLUSION: Diazoxide attenuates postnatal DA constriction and dilates a closing DA in fetal and neonatal rats.

[Secondary megaureter: A rare complication of Deflux® endoscopic management of vesicoureteral reflux in children]. / Le méga-uretère secondaire : une complication rare du traitement endoscopique du reflux vésico-urétéral par Deflux® chez l'enfant.

Endoscopic management is the gold standard for symptomatic low-grade vesicoureteral reflux (VUR) in children. Deflux® (hyaluronic acid/dextranomer) injection is highly effective and has very few complications. We report on two cases of secondary megaureter after Deflux® injections. In the first case, a boy presented with Grade 4 VUR. He received a bilateral Deflux® injection with a total of three syringes. The postoperative ultrasound was normal. However, a check-up ultrasound 3 years later showed a significant ureteropyelocalyceal dilatation, with stasis and decreased renal function on scintigraphy, the reason why antireflux surgery (Cohen procedure) was performed. In the second case, a girl diagnosed with bilateral VUR at birth received bilateral injections with one syringe on each side at the age of 12 months. One month later, the ultrasound showed a dilation of the distal ureters (diameter of the right ureter, up to 10mm; left ureter, up to 6.7mm). The child underwent surgery 8 months later (Cohen procedure) because of iterative pyelonephritis and persistent ureter dilatation. Only one previous case has been described in the literature. In our experience, this complication has occurred only twice in 452 injections (4‰). In conclusion, endoscopic treatment with hyaluronic acid/dextranomer injection is a minimally invasive procedure that improves the situation in cases of VUR. It has few complications. Other than failure, there is a low risk of secondary expansion requiring, in our opinion, ultrasound verification over the long term.

Ameliorative effect of green tea against contrast-induced renal tubular cell injury.

INTRODUCTION: Reactive oxygen species are a mediator of kidney damage by contrast media, and green tea is a potent-free radical scavenger. This study was designed to examine whether green tea could protect against the nephrotoxicity induced by contrast media. MATERIALS AND METHODS: Forty rats were randomly divided into 4 groups. Group 1 was control; group 2 received contrast medium (intravenous iodixanol, 10 mL/kg, as a single dose); group 3 received contrast medium and then green tea extract for 3 days (10 mg/kg/d, intraperitoneal); and group 4 first received green tea and then contrast medium. Histological changes (degeneration, vacuolization of tubular renal cells, dilatation of tubular lumen, and presence of debris in the lumens) were assessed and recorded as scores from zero to 4. The sum of scores were used as the overal renal injury level. RESULTS: Groups 3 and 4 with green tea treatment had significantly higher overall scores than the control group, but significantly lower scores than group 2 with contrast medium only. A similar trend was seen for dilatation and degeneration levels. Vacuolization level was not significantly lower in the green tea groups as compared to the contrast medium group. Debris level was not significantly lower in group 3 than group 2. The differences were not significant between groups 3 and 4.   Conclusions. We observed beneficial effect of green tea against nephrotoxicity of contrast media. Green tea extract may offer an inexpensive and nontoxic intervention strategy in patients with a risk for nephrotoxicity with contrast media.

Réplica al artículo «Rotura de aneurisma iliaco durante el preacondicionamiento con levosimendán previo a cirugía de revascularización coronaria, ¿fue levosimendán el factor más influyente?» / Reply to article 'Iliac aneurysm rupture during preconditioning with levosimendan for coronary artery graft, it was levosimendan the most influencing factor?'

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Ketamine-related cholangiopathy: a retrospective study on clinical and imaging findings.

PURPOSE: Ketamine is a commonly abused recreational drug in Southeast Asia. There are emerging reports on ketamine abuse causing liver injury and biliary dilatation. This retrospective study aims to investigate the clinical and radiological features of this condition. METHODS: A retrospective search in the database of our institute was performed from January 2008 to February 2014 for patients who were ketamine abusers, with deranged liver function and/or epigastric pain, and had computed tomography of the abdomen or magnetic resonance cholangiopancreatography. Patient demographics, clinical data, and radiological findings were reviewed. RESULTS: Twenty-six patients (11 male and 15 female) were included in this study. Eighteen (69 %) patients had fusiform dilatation of the common bile ducts (CBDs) without evidence of intrinsic or extrinsic obstruction, and non-dilated intrahepatic ducts. The degree of CBD dilatation correlated with duration of abuse. In five patients who achieved abstinence, the CBD dilatation showed improvement. CONCLUSIONS: Ketamine-related cholangiopathy manifested as fusiform dilatation of the CBD without evidence of obstructive lesions. Severity of CBD dilatation appears to be correlated with the duration of ketamine, and the condition is potentially reversible in abstinent patients.

Development of a safety biomarker signature to detect hepatic sinusoidal dilation associated with an anti-DLL4 biotherapeutic.

CONTEXT: Biomarkers of lesion-specific drug induced liver toxicity are currently lacking. OBJECTIVE: To develop a biomarker signature using routine clinical pathology parameters that predict hepatic sinusoidal dilation related to anti-DLL4 biotherapeutics. METHODS: Random forest and factor analysis was used to construct a signature of routine laboratory tests to detect microscopically confirmed sinusoidal dilation of the liver. RESULTS: A biomarker signature was developed comprising two scores (S1 and S2) with area under the curve (AUC) for sinusoidal dilation prediction of 0.81, 0.85 and 0.96 in three rat studies and 0.48 and 0.81 in two monkey studies. CONCLUSION: A unique, two-dimensional signature of liver parameters and red blood cell parameters could detect sinusoidal dilation in multiple preclinical species.