A unique autopsy case of ascending aortic dissection caused by giant cell arteritis without drug therapy

Giant cell arteritis is a granulomatous inflammation of large and medium‐sized arteries, occurring predominantly in older women. In this case, a 76‐year‐old woman was hospitalized for examination because of a high C‐reactive protein (CRP) level, but nothing remarkable was found on thoracicoabdominal computed tomography (CT) or head magnetic resonanse imaging (MRI). On the 46th day from the first visit, she died suddenly due to cardiac tamponade. On pathological autopsy, we found the cause of death to be acute aortic dissection (Stanford type A) due to giant cell arteritis occurred in the ascending aorta. Histologically, granulomatous vasculitis with giant cells was recognized in the ascending aorta, thoracic descending aorta and abdominal aorta and their branches. Interestingly, similar granulomatous vasculitis was also found in the medium and small vessels of other plural organs, including the heart, liver, uterine corpus, and its appendages. To our knowledge, giant cell arteritis with multiple‐organ granulomatous changes has not been reported before. We herein reported a unique autopsy case of giant cell arteritis in a patient not treated with medication.     

Reevaluation of stringent low iodine diet in outpatient preparation for radioiodine examination and therapy

To decrease total body iodine is a key point in preparation for radioiodine study and therapy. We introduced a stringent self-managed low iodine diet (LID) and compared the outcome to that of the conventional restricted iodine diet (RID) for outpatients. We measured urine iodine to creatinine ratios (I/Cr) in patients prepared with RID for one week, LID for one week, or LID for two weeks. Mean urinary iodine excretion after RID for one week (n = 210) was 182.2 microg/gCr (range, 13-986 microg/gCr; standard deviation (SD) = 158.5) not reaching below the recommended level (I/Cr<100 microg/gCr). Urinary iodine excretion after LID for one week (n = 15) showed a lower mean urinary iodine level (I/Cr 119.4 microg/gCr; range, 23-218 microg/gCr; SD = 55.9) than RID for one-week, and two-week LID (n = 17) showed an even lower mean level (I/Cr 63.1 microg/gCr; range, 7-134 microg/gCr; SD = 38.7). The one-week LID period adequately (recommended level of I/Cr being less than 100 microg/gCr) prepared 26% of the patients, while two-weeks on the diet adequately prepared 70% of the patients. Furthermore, none of the two-week LID patients had I/Cr>150 microg/gCr, although a significantly greater number of one-week LID patients (19%) did. Our self-managed, outpatient LID successfully induced iodine deficiency, and two-week LID may be recommended for preparation in radioiodine study and therapy for thyroid cancer.     

Frontal white matter anisotropy and symptom severity of late-life depression: a magnetic resonance diffusion tensor imaging study

OBJECTIVES: To investigate the disruption of neural circuits in the frontal lobes and limbic structures in late-life depressed patients compared with healthy controls, and to examine the correlation between the degree of microstructural abnormalities of white matter and clinical symptom severity in late-life depression. METHODS: Thirteen patients with late-life depression and matched control subjects underwent diffusion tensor imaging. Fractional anisotropy (FA), an index of the integrity of white matter tracts, was determined in the white matter of frontal, temporal, and occipital brain regions and the corpus callosum. RESULTS: A significant reduction was found in white matter FA values of widespread regions of the frontal and temporal lobes of depressed patients. Also, there was some evidence suggesting that white matter FA values of the inferior frontal brain region are inversely related to severity of depression. CONCLUSIONS: These results suggest the possible loss of integrity within frontal and temporal white matter fibre tracts and implicate the orbitofrontal circuit in symptom severity in late-life depression.     

The association of esophageal hiatus hernia with Mallory-Weiss syndrome

The incidence of esophageal hiatus hernia in Mallory-Weiss syndrome was analyzed from endoscopic findings in order to clarify the association with Mallory-Weiss syndrome. Hiatus hernia was diagnosed from findings of both esophagoscopy and gastroscopy. In 23 patients with Mallory-Weiss syndrome confirmed by endoscopy, hiatus hernia was found 21 cases (91.3%), in which 9 (39.1%) were definite hernias and 12 (52.2%) were minor hernias. In 80 control cases of various gastrointestinal diseases, definite hernia was found in 7 cases (8.8%), and minor hernia was found in 13 cases (16.2%). The incidence of hiatus hernia in Mallory-Weiss syndrome was thus significantly higher than that in the control group. The incidence of hiatus hernia evaluated only by esophageal findings was lower than that evaluated by combined findings from the gastric and esophageal directions. These results indicate that evaluation from the gastric direction is an essential procedure for the diagnosis of esophageal hiatus hernia and that hiatus hernia is one of the predisposing factors for the development of Mallory-Weiss syndrome.     

Pharmacokinetics of AT-2266 Administered Orally to Mice, Rats, Dogs, and Monkeys

The pharmacokinetics of AT-2266 (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine- 3-carboxylic acid) were studied in various experimental animals and compared in a number of aspects with those of norfloxacin. Both agents were administered orally. The mean peak plasma levels of AT-2266 in mice, rats, and dogs (given a single dose of 50 mg/kg for mice and rats and 25 mg/kg for dogs) were 2.39, 1.63, and 5.00 mug/ml, respectively, with elimination half-lives of 2.24, 2.81, and 5.76 h. The respective mean plasma levels of norfloxacin at similar dosages were 0.510, 0.410, and 0.700 mug/ml; elimination half-lives were 1.40, 2.35, and 6.06 h. In dogs repeatedly dosed with 25 mg of AT-2266 per kg every 12 h, the mean peak plasma levels after the third and fifth doses were about 1.4 times those after the first dose. The binding rates of AT-2266 and norfloxacin to plasma of mice, rats, and dogs and to human serum ranged from 27.6 to 40.2% and 39.8 to 44.2%, respectively. In rats receiving a single dose of 50 mg/kg, the respective mean peak levels of AT-2266 in plasma, lung, muscle, and kidney were 2.47, 4.60, 5.35, and 33.9 mug/ml or g, whereas those of norfloxacin were 0.234, 0.390, 0.272, and 2.05 mug/ml or g. AT-2266 was widely distributed in tissues of dogs and monkeys after repeated dosage. The respective 24-h recoveries of AT-2266 from urine of mice, rats, and dogs after single doses of 50, 50, and 25 mg/kg were 56.6, 40.5, and 64.1%, and recoveries of norfloxacin at these doses were 4.40, 2.91, and 5.34%. The respective 24-h recoveries of AT-2266 from bile and feces of rats given a single dose of 50 mg/kg were 2.47 and 52.7%. Bioautography of plasma and urine indicated that AT-2266 was metabolized to but a slight degree. The results indicate that AT-2266 is better than norfloxacin in oral absorption and similar to the latter in stability to metabolic inactivation.     

Dietary instructions focusing on meal-sequence and nutritional balance for prediabetes subjects: An exploratory,cluster-randomized,prospective, open-label,clinical trial

BackgroundAlthough lifestyle modifications are known to be effective in type 2 diabetes (T2D) as well as in prediabetes, adherence to a healthy diet is difficult for some, and interventions of lifestyle modifications need to be revised occasionally. Meal sequence has been gaining attention as a part of a healthy diet among T2D individuals to improve glycemia and body weight. In addition, a dietary instruction program, SMART Washoku®, which can help individuals to consume a more nutritionally balanced diet, has been developed.MethodsThe current exploratory trial was designed to examine the effects of dietary instructions focusing on meal sequence and nutritional balance in individuals with prediabetes in the Japanese national health check-up and guidance program. Participants were cluster-randomized into three groups: Group A, receiving a conventional health guidance program (n = 11); Group B, receiving health guidance with dietary instructions focusing on meal sequence (n = 18); and Group C, receiving health guidance with dietary instructions focusing on nutritional balance (n = 13). Participants received health guidance education and various measurements before and 6 months after the instructions.ResultsBody weight in Group B was significantly reduced compared to that in Group A, with similar adherence, while the effects on glycemia were similar between the two Groups. Body weight reduction was greater in Group C compared to that in Group A, although adherence in Group C was significantly lower than that in Group A.ConclusionThe group receiving health guidance with dietary instructions focusing on meal sequence exhibited similar adherence and greater reduction in body weight than the group receiving conventional health guidance.     

Software‐assisted morphometric and phenotype analyses of human peripheral blood monocyte‐derived macrophages induced by a microenvironment model of human esophageal squamous cell carcinoma

Human macrophages play important roles in tumor promotion and are called tumor‐associated macrophages (TAMs). We previously demonstrated that human esophageal squamous cell carcinomas (ESCCs) contain TAMs and that these TAMs tend to have tumor‐supporting features. Here we exposed human macrophages to conditioned media of TE‐series human ESCC cell lines (TECMs) to generate an ESCC extracellular stimuli‐influenced TAM model. CD14⁺ peripheral blood monocytes (PBMos) from healthy donors were treated with M‐CSF and with additional IL‐4 or TECM exposure. Morphological changes of the cells and the induction of CD163/CD204 proteins were detected in the TECM‐exposed model TAMs by immunofluorescence. A software‐assisted immunofluorescent cell image analysis showed increased CD163/CD204 positivity in the model TAMs and a weak to moderate positive correlation between the cytoplasmic area and the sum fluorescent intensity of CD204. Morphological changes of the cells were significantly reflected by several cytomorphometric parameters. PBMos were elongated with M‐CSF treatment, then enlarged with TECM exposure. The cytoplasmic aspect ratio was decreased by M‐CSF treatment and slightly increased by TECM exposure. The nuclear‐cytoplasmic ratio decreased during the whole process of cell differentiation. This system is useful for quantitative assessments of TAM‐like morphological changes of macrophages and the induction of CD163/CD204 in a model ESCC microenvironment.     

Associations between coping strategies and insomnia: a longitudinal study of Japanese workers

Study ObjectivesCoping with stress is important because stress disturbs sleep. However, only a few longitudinal studies have investigated the association between coping and insomnia. We examined whether individuals with insomnia symptoms used more maladaptive coping strategies than individuals without insomnia symptoms, and evaluated the association between insomnia symptoms and coping strategies.MethodsIn this prospective cohort study, Japanese workers were enrolled and observed over a 2-year period. During both years, self-administered questionnaires on coping and insomnia symptoms were administered. Coping was assessed using the Brief-Coping Orientation to Problems Experienced, and insomnia symptoms were examined using the Athens Insomnia Scale. Generalized estimating equation modeling identified the effects of coping strategies on insomnia severity.ResultsIn total, 1358 of 1855 workers at baseline were followed up. Individuals with insomnia symptoms showed a higher use of maladaptive coping strategies and less use of humor and instrumental support than individuals without insomnia symptoms. Active coping, humor, emotional support, and instrumental support were negatively associated with insomnia severity. In contrast, venting, substance use, behavioral disengagement, and self-blame were positively associated with insomnia severity.ConclusionsThis study showed that individuals with insomnia symptoms use both adaptive and maladaptive coping strategies and are more likely to use maladaptive strategies than individuals without insomnia symptoms. In the future, interventions focused on educating people about adaptive coping strategies should be conducted to determine whether coping strategies may prevent insomnia symptoms.     

Suppressive effect of short-interfering RNA on hyperglycemia-induced expression of intercellular adhesion molecule-1 on cultured vascular endothelial cells

PURPOSE: The pathology of diabetic retinopathy involves endothelial dysfunction, in which leukocyte adhesion to the vascular endothelium via intercellular adhesion molecule-1 (ICAM-1) may play a key role. Short-interfering RNAs (siRNAs) are unique modulators of gene expression in mammalian cells. The purpose of this study was to evaluate the enhanced effect of hyperglycemia and the attenuating effect of siRNAs on ICAM-1 expression in cultured endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were seeded onto 24-well culture plates. The following day, ICAM-1-specific siRNAs were transfected using Lipofectamine 2000. Glucose (15, 30, or 45 mM) or interleukin-1ss as a positive control was added to the medium to stimulate ICAM-1. After 48 hours, the HUVECs were collected to measure the ICAM-1 expression by enzyme-linked immunosolvent assay. Fluoresceinated siRNAs were transfected into HUVECs to confirm transfection of the siRNAs into HUVECs by fluorescein microscopy. RESULTS: Glucose enhanced the ICAM-1 expression in a dose-dependent manner. ICAM-1 expression stimulated by hyperglycemia decreased significantly in the HUVECs transfected with corresponding siRNAs. Transfection of siRNAs was confirmed with enhanced fluorescence in HUVECs incubated with control siRNAs. CONCLUSIONS: These results suggested that hyperglycemia stimulated protein expression of ICAM-1 and that siRNAs suppressed gene expression of ICAM-1 in HUVECs. The RNA-targeting approach using siRNAs may provide a novel therapeutic option for diabetic retinopathy.     

Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo

Background  The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required. Methods  We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments. Results  In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment. Conclusion  Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.