Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)-4 (C-590T), IL-4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL-10 (C-627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patient's attitude, indoor environment, and so on, were also investigated in this study. Our study was retrospective, and the correlation was analyzed by our defined clinical scores divided into three terms: worst symptoms, recent symptoms and general amelioration at the most recent examination during the disease course. Our results indicated that IL-10 AA, the genotype with lower IL-10 production, is associated with higher IgE levels in the serum (p < 0.0001, estimate; 0.912). Marginal liver abnormalities were observed in the subject group with both FA and AE (p < 0.1191, estimate; 0.1490). Our defined clinical scores enabled evaluation of various aspects of disease severity. Based on the scores, while no single SNP selected in this study determined severity, the combination of the SNP with laboratory data and environmental factors appeared to determine severity.     

St. Jude Medical valve replacement: clinical experience with 1,039 patients

St. Jude Medical valve replacement was performed in 1,039 patients; 320 had aortic (AVR), 543 mitral (MVR), and 176 had double valve replacement (DVR). There were 44(4.2%) early deaths. Follow-up extended in 995 patients from 10 to 130 months, with a cumulative period of 2,730 patients-years. The overall survival rates of AVR, MVR, and DVR patients at 10 years were 60.5%, 89.6%, 90.3% respectively. The linearized incidences of valve thrombosis, thromboembolism, anticoagulation-related hemorrhage, prosthetic valve endocarditis, and significant hemolysis were as follows: 0.11%/pt-yr, 1.33%/pt-yr, 0.04%/pt-yr, 0.18%/pt-yr, and 0.11%/pt-yr, respectively. There were no structural failure after 10 years follow-up. Reoperation (explant and re-replacement or suture repair) was required in 10 patients. Seven of them had periprosthetic leakage, 2 had valve thrombosis, and one underwent reoperation because of a technical error. Actuarially over 98% of patients were free of valve-related mortality at 10 years. St. Jude Medical valve is an excellent alternative for use in the surgical treatment of valvular heart disease.     

Definition of carcinoma of the gastric cardia

Summary This study concerns the definition of carcinoma of the gastric cardia. The topography of the esophagogastric mucosal junction (mucosal EGJ) was investigated with an endoscope in 182 patients who were free of hiatal hernias, ulcers, and neoplasms in the esophagus and stomach. The relationship between the EGJ and the cardiac gland area was then examined histologically in 56 resected specimens containing intact EGJs and cardia gland areas. Furthermore the cancerous center was determined; the shortest distance between the cancerous center and the EGJ and the amount of esophageal invasion were measured in 102 resected carcinomas located close to the junction; the carcinomas contained the EGJ and were good enough for pathohistological examination. The EGJ was located 0.5–1.0 cm proximal to the His angle (the gastric cardia) in radiological and endoscopic examinations. Histologically the cardiac gland area was found to straddle the EGJ at a range of about 1 cm proximal and 2 cm distal to the junction. Among the upper stomach carcinomas, most of the tumors (87.5%) whose center was located within 2 cm from the EGJ invaded the esophagus. In conclusion, carcinoma of the gastric cardia is defined as a lesion with its center located within 1 cm proximal and 2 cm distal to the EGJ.

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Definition des Kardiacarcinoms

Zusammenfassung Diese Untersuchung befaßt sich mit der Definition von Carcinomen der Kardia. An 182 Patienten, die weder Hiatushernien, Ulcera noch Neoplasien des Oesophagus bzw. des Magens aufwiesen, wurde die Lage des Übergangs von der Oesophagus- zur Magenmucosa (esophagogastric mucosal junction, EGJ) endoskopisch untersucht. Dann wurde die Beziehung zwischen EGJ und dem Drüsengebiet der Kardia histologisch anhand von 56 Resektaten mit intaktem EGJ und Kardiadrüsenzone untersucht. Außerdem wurde an 102 resezierten Carcinomen mit Sitz in der Nähe des gastrooesophagealen Übergangs die kürzeste Ent fernung zwischen Carcinomzentrum und EGJ und das Ausmaß der Oesophagusinfiltration bestimmt; die Proben schlossen den EGJ ein und konnten pathohistologisch beurteilt werden. Bei der radiologischen und endoskopischen Untersuchung fand sind der EGJ 0,5–1,0 cm vom His-Winkel entfernt. Die histologische Untersuchung zeigte, daß die Kardiadrüsenzone sich vom EGJ etwa 1 cm nach proximal und 2 cm nach distal erstreckt. Die meisten Tumoren des oberen Magens (87,5%), deren Zentrum innerhalb von 2 cm vom EGJ entfernt lag, infiltrierten in den Oesophagus. Ein Kardiacarcinom ist demzufolge als Läsion zu definieren, deren Zentrum innerhalb von 1 cm proximal und 2 cm distal des EGJ liegt.

     

Fractalkine and inflammatory diseases]

The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T(CE)), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.     

A surgical case of ventricular septal perforation after repairing left ventricular free wall rupture.

A 78-year-old woman with diagnosis of acute myocardial infarction (AMI) in the anteroseptal area fell into cardiogenic shock suddenly just before starting percutaneous coronary intervention (PCI). Echocardiography showed left ventricular free wall rupture, then an emergent operation was performed by sutureless patch repair using collagen fleece with fibrinogen-based impregnation. Eight days later from the initial operation, the onset of ventricular septal perforation (VSP) was recognized. Fifteen days after, the infarct exclusion technique with endocardial patch was performed. She has been doing well 4 months after the operation without residual shunt. To our best knowledge, this is the first surgical case report that free wall rupture of left ventricle and VSP which are serious complications after myocardial infarction happened in succession.     

Astasia in a patient with unilateral thalamic infarction: clinical and MRI study]

We report a 82-year-old woman who developed difficulty in standing and sitting in the morning. She had no other complaints and stayed in the bed. The next day, she was admitted to the hospital and neurological examination revealed that she was alert, with no other motor or sensory abnormalities. Finger to nose test, and knee to heel test were normal. No dysdiadochokinesia was seen. Astasia was the only observed abnormal finding. MRI showed a small infarction (14 x 8mm) in the posterolateral portion of the left thalamus (VPL-LP nucleus). During the following 15 days, her imbalance has gradually improved and then disappeared. We diagnosed the patient as astasia occurring from a small unilateral infarction in the thalamus. It is thought that thalamic astasia is caused by the disruption of afferent pathway from the vestibulocerebellum; however, this case is based on just clinical and MRI study, so physiological and pathological studies will be necessary in the future.     

Airway troubles related to the double-lumen endobronchial tube in thoracic surgery

Purpose Several case reports indicate critical respiratory complications in relation to the double-lumen endobronchial tube (DLT). A prospective survey for the airway problems in using the DLT is presented. Methods One hundred adult patients undergoing thoracotomy for lung cancer were investigated. Tube malposition and airway obstruction were searched using a fiber-optic scope. The endobronchial cuff was positioned just below the trachcal carina while the trachea was intubated with a DLT (Rüsch). The distances of displacement, from the tracheal carina to the bronchial cuff, were measured during anesthesia using an epidural catheter, which had marks every 5 mm. The distances for correcting the tube position were measured at both the bronchial cuff and the level of the teethPaO₂,PaCO₂ andSPO₂ were also measured. Results Malposition (displacement over 5 mm from the correct position) was found in 42 patients, and 40 of them were in a withdrawal direction, occurring at the postural change and during one-lung ventilation, especially during manipulation of the lung hilum. Correcting distances at the level of the teeth were 15.3–3-times longer than those at the bronchial cuff. Airway deformities and gradual withdrawal of the bronchial cuff were found in association with surgical manipulation. Obstruction occurred at the tips of the tracheal tube in four patients and the bronchial tube in six patients, and at the tip of both in two patients. Hypoxemia (PaO₂<60 mmHg) occurred in four patients and hypercapnea (PaCO₂>60 mm Hg) in two patients. Conclusion Most of the DLT obstructions were associated with withdrawal malposition. Great attention to DLT displacement and airway deformity is advised.