Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1

Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D₃ to 24,25(OH)₂D₃ ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396^w/w mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors.     

Pharmacokinetics of Rocuronium in Children Aged 4-11 Years

Background: Rocuronium is a new nondepolarizing muscle relaxant with a rapid onset and intermediate duration of action. Although the pharmacokinetics of rocuronium have been determined in adults and the elderly, similar data are lacking in children. Accordingly, rocuronium's pharmacokinetics were determined in children aged 4-11 yr.

Methods: Rocuronium (600 micro gram/kg) was administered to 20 children aged 4-11 yr anesthetized with nitrous oxide and less or equal to 1% halothane, and four plasma samples were obtained over 4 h to determine rocuronium concentrations. The pharmacokinetics of rocuronium were determined using two sparse-sampling population approaches, mixed- effects modeling, and naive pooled data analysis.

Results: With mixed-effects modeling, weight-normalized plasma clearance varied with weight (P < 0.01), being 79.4 ml *symbol* min sup -1 + 3.13 ml *symbol* kg sup -1 *symbol* min sup -1. Neither weight- normalized distributional clearance (2.67 ml *symbol* kg sup -1 *symbol* min sup -1), weight-normalized central compartment volume (106 ml/kg), nor weight-normalized volume of distribution at steady-state (224 ml/kg) varied with weight, height, or age. Similar results were obtained with the naive pooled data approach.     

Therapeutic efficacy and safety of chamomile for state anxiety,generalized anxiety disorder,insomnia, and sleep quality: A systematic review and meta‐analysis of randomized trials and quasi‐randomized trials

This systematic review and meta‐analysis aimed to study the efficacy and safety of chamomile for the treatment of state anxiety, generalized anxiety disorders (GADs), sleep quality, and insomnia in human. Eleven databases including PubMed, Science Direct, Cochrane Central, and Scopus were searched to retrieve relevant randomized control trials (RCTs), and 12 RCTs were included. Random effect meta‐analysis was performed by meta package of R statistical software version 3.4.3 and RevMan version 5.3. Our meta‐analysis of three RCTs did not show any difference in case of anxiety (standardized mean difference = ?0.15, 95% CI [?0.46, 0.16], P = 0.4214). Moreover, there is only one RCT that evaluated the effect of chamomile on insomnia and it found no significant change in insomnia severity index (P > 0.05). By using HAM‐A scale, there was a significant improvement in GAD after 2 and 4 weeks of treatment (mean difference = ?1.43, 95% CI [?2.47, ?0.39], P = 0.007), (MD = ?1.79, 95% CI [?3.14, ?0.43], P = 0.0097), respectively. Noteworthy, our meta‐analysis showed a significant improvement in sleep quality after chamomile administration (standardized mean difference = ?0.73, 95% CI [?1.23, ?0.23], P < 0.005). Mild adverse events were only reported by three RCTs. Chamomile appears to be efficacious and safe for sleep quality and GAD. Little evidence is there to show its effect on anxiety and insomnia. Larger RCTs are needed to ascertain these findings.     

Brugada syndrome associated with out-of-hospital cardiac arrest: A case report

BACKGROUNDBrugada syndrome (BrS) is an inherited disease characterized by an electrocardiogram (ECG) with a coved-type ST-segment elevation in the right precordial leads (V1-V3), which predisposes to sudden cardiac death (SCD) due to polymorphic ventricular tachycardia or ventricular fibrillation in the absence of structural heart disease. We report the case of a 29-year-old man with out-of-hospital cardiac arrest. BrS is associated with a high incidence of SCD in adults, and increasing the awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving.CASE SUMMARYA 29-year-old man suffered from out-of-hospital cardiac arrest, and after defibrillation, his ECG demonstrated a coved-type elevated ST segment in V1 and V2. These findings were compatible with type 1 Brugada pattern, and ECG of his brother showed a type 2 Brugada pattern. The diagnosis was BrS, NYHF IV, multiple organ dysfunction syndrome, sepsis, and hypoxic ischemic encephalopathy. The patient had no arrhythmia episodes after discharge throughout a follow-up period of 36 mo. CONCLUSIONIncreasing awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving.     

Respiratory function in vineyard and orchard workers

A group of 174 male vineyard and orchard workers was studied for the prevalence of acute and chronic respiratory symptoms and lung function changes. In addition, 115 male control workers were studied for the prevalence of chronic respiratory symptoms. There was a significantly higher prevalence of dyspnea and chest tightness in exposed compared to control workers. In particular, exposed nonsmokers had significantly higher prevalences of dyspnea and chest tightness than controls; this was found for exposed nonsmokers with both short (≤10 years) and long (>10 years) exposure. Smokers exposed for more than 10 years had significantly higher prevalences of chronic cough, chronic phlegm, chronic bronchitis, and chest tightness than smokers with shorter exposures (p < 0.01 or p < 0.05). Workers employed for more than 10 years had higher prevalences of most of the acute (shift-related) symptoms than those workers with shorter employment; however, the differences were significant only for cough in smokers (p < 0.05). Significantly lower than predicted FVC values were measured in smokers and nonsmokers after both short and long duration of employment. Differences between measured and predicted FEV₁, FEF₅₀, and FEF₂₅ were significant for workers employed for more than 10 years. A separate analysis of individual data as a percent of predicted values demonstrated that many workers had FVC (5.2%), FEV₁ (6.3%), FEF₅₀ (27.6%), and FEF₂₅ (40.2%) lower than 70% of predicted values. These data suggest that vineyard and orchard workers may develop acute and chronic respiratory symptoms and lung function changes which are, in part, related to environmental factors and to cigarette consumption. Am. J. Ind. Med. 31:250–255, 1997. © 1997 Wiley-Liss, Inc.     

Three-Dimensional Myocardial Perfusion Maps by Contrast Echocardiography

We evaluated the clinical applicability of a system for three-dimensional (3-D) display of a perfusion map following myocardial contrast echocardiography (MCE). The system was used in 12 patients (9 males and 3 females, mean age 52 ± 10 years) undergoing interventional treatment of chronic total coronary occlusion. In each patient three standard apical views were acquired at baseline with sonicated Iopamidol^R injections into the left coronary artery (LCA) and into the right coronary artery (RCA). Following successful recanalization of the occluded artery MCE was repeated. The patients tolerated the procedure well. Acquisition of three standard apical views provided sufficient information for the reconstruction of 3-D perfusion maps containing the 16 standard left ventricular (LV) segments. Side-by-side display of the perfusion maps obtained following LCA and RCA echocontrast injections allowed us to classify the myocardial segments (192) into three groups: (1) those supplied by one major artery (124); (2) those supplied by collaterals from contralateral or both major arteries (58); and (3) segments supplied by none of the major arteries (10). Decreased opacification was observed in 50 segments of group 2. Following successful intervention we were able to visualize the redistribution of blood flow delivered to the LV myocardium by each major coronary artery in 3-D format. We conclude that this 3-D approach, which can easily be performed with currently available ultrasound equipment, allows an estimate of the contribution of each major coronary artery to LV perfusion before and after coronary angioplasty.