Japanese version of the MD Anderson Symptom Inventory: a validation study

Cancer patients frequently suffer from a myriad of symptoms. The development and application of comprehensive assessment tools is essential to the effective management of these symptoms. The M.D. Anderson Symptom Inventory (MDASI), developed in English, is a brief, self-rating multiple symptom assessment scale that consists of 13 symptom items and 6 interference items. We examined the validity and reliability of the Japanese version of this scale (MDASI-J) by evaluating 252 randomly selected cancer patients. They were asked to self-administer the MDASI-J and the European Organization for Research and Treatment of Cancer QLQ-C 30. Construct, criterion, convergent and discriminant validity, and reliability of the MDASI-J were evaluated and compared with corresponding data obtained in the previous study conducted in the United States. The results indicated that the MDASI-J is a valid and practical measure for assessing multiple symptoms in Japanese cancer patients. Both factor analysis and cluster analysis showed the consistency of the statistical structure of the English and Japanese versions, indicating the cross-cultural validity of the scale.     

Establishment of cell lines stably expressing HNA-1a, -1b, and -2a antigen with low background reactivity in flow cytometric analysis

BACKGROUND: Antibodies to neutrophil antigens have been implicated in neonatal alloimmune neutropenia, autoimmune neutropenia, and transfusion-related acute lung injury. Most often, neutrophil-specific antibodies are directed toward human neutrophil antigen (HNA)-1 (Fcgamma receptor 3b) and HNA-2a (CD177) in these disorders. STUDY DESIGN AND METHODS: To detect the alloantibodies in the serum samples, a panel of cell lines was established in which the HNA-1a, HNA-1b (polymorphisms of HNA-1), or HNA-2a gene was transduced with a retrovirus vector to confer stable transgene expression in K562 cells that exhibited low background reactivity to human serum samples obtained from healthy donors in flow cytometric analysis. RESULTS: It was shown that several well-characterized human serum samples containing antibodies against HNA-1a, -1b, and -2a were unambiguously identified by the established panel cell lines and observed a lower background reactivity and longer shelf life of the K562 panel cell lines compared with isolated neutrophils, which have been used for the cell panel to identify antibodies against HNA in human serum samples. CONCLUSION: These results indicate that the K562 panel cell lines provide a good panel for detecting HNA-reactive neutrophil antibodies in human serum samples.     

Effects of streptozotocin-induced diabetes on leg muscle contractile properties and motor neuron morphology in rats

Skeletal muscle fiber subtypes are differentially sensitive to diabetes-related pathology; For example, fast-twitch muscles exhibit severe decreases in contraction force while slow-twitch muscles demonstrate prolonged half-relaxation time. However, such alterations have only been examined after a relatively short period following diabetes onset, with no information available regarding muscle damage caused by longer disease periods (>20 weeks). This study examined alterations in the contractile properties of the medial gastrocnemius (fast-twitch) and soleus (slow-twitch) muscles, as well as morphological changes in their motor neurons 12 and 22 weeks after diabetes onset. Adult male Wistar rats were divided into diabetic (12- or 22-week post-streptozotocin injection) and age-matched control groups. Electrically evoked maximum twitch and tetanic tension were recorded from leg muscles. Additionally, motor neuron number and cell body size were examined. At 12 weeks after diabetes onset, decreases in twitch force were observed predominantly in medial gastrocnemius muscles, while soleus muscles exhibited prolonged half-relaxation time. However, these differences became ambiguous at 22 weeks, with decreased twitch force and prolonged half-relaxation time observed in both muscles. On the other hand, reduction in soleus motor neurons was observed 12 weeks after diabetes onset, while medial gastrocnemius motor neurons were diminished at 22 weeks. These data indicate that experimental diabetes induces differential damage to medial gastrocnemius and soleus muscles as well as motor neurons. These diabetes-induced differences may partly underlie the differential deficits observed in gastrocnemius and soleus.     

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.     

Relationship between the pixel value in digital subtraction angiography and iodine concentration: study in high iodine concentration with original phantom

Quantitative digital subtraction angiography (DSA) image analysis based on densitometry is widely accepted and used. For the densitometoric DSA image analysis, it is required that there is a linear relationships between the pixel values on DSA images (DSA values) and contrast medium iodine concentration or the thickness of the vessels or the chambers filled with contrast material. We studied on relationship between the DSA value and iodine concentration especially in high iodine concentration. As for the relationship between DSA values and iodine concentration on the DSA images at low concentration, DSA phantom had a good linear relationship. However, the relationship at the high iodine concentration, DSA phantom sometimes lost this linear relationship. Our results suggested that it was necessary to identify relationship between DSA values and iodine concentration in each DSA system, especially in high iodine concentration setting, for densitometoric DSA image analysis.     

Estimated number of off‐target candidate sites for antisense oligonucleotides in human mRNA sequences

Antisense oligonucleotide (ASO) therapeutics are single‐stranded oligonucleotides which bind to RNA through sequence‐specific Watson–Crick base pairings. A unique mechanism of toxicity for ASOs is hybridization‐dependent off‐target effects that can potentially occur due to the binding of ASOs to complementary regions of unintended RNAs. To reduce the off‐target effects of ASOs, it would be useful to know the approximate number of complementary regions of ASOs, or off‐target candidate sites of ASOs, of a given oligonucleotide length and complementarity with their target RNAs. However, the theoretical number of complementary regions with mismatches has not been reported to date. In this study, we estimated the general number of complementary regions of ASOs with mismatches in human mRNA sequences by mathematical calculation and in silico analysis using several thousand hypothetical ASOs. By comparing the theoretical number of complementary regions estimated by mathematical calculation to the actual number obtained by in silico analysis, we found that the number of complementary regions of ASOs could be broadly estimated by the theoretical number calculated mathematically. Our analysis showed that the number of complementary regions increases dramatically as the number of tolerated mismatches increases, highlighting the need for expression analysis of such genes to assess the safety of ASOs.     

Pathogenesis of gastric and duodenal ulcer in the elderly

In the elderly, H. pylori infection and nonsteroidal anti-inflammatory drug(NSAID) use are most important risk factors for peptic ulcer disease. It is now recognized that, in patients with H. pylori infection, nonatrophic antral-predominant gastritis results in increased acid secretion, which is seen in duodenal ulcer patients, whereas corpus-predominant gastritis and pangastritis result in decreased acid secretion, that are seen in patients with proximal gastric ulcer and gastric cancer. These physiological changes are considered to be related to disease outcome. On the other hand, NSAIDs induced gastrointestinal toxicity is primarily due to the inhibition of mucosal prostaglandin synthesis in the gastric mucosa, which subsequently impairs the gastric cytoprotective factors. These two factors may independently, or even synergistically, cause the development of peptic ulcer disease in the elderly.     

Lumped parameter model for hemodynamic simulation of congenital heart diseases

The recent development of computer technology has made it possible to simulate the hemodynamics of congenital heart diseases on a desktop computer. However, multi-scale modeling of the cardiovascular system based on computed tomographic and magnetic resonance images still requires long simulation times. The lumped parameter model is potentially beneficial for real-time bedside simulation of congenital heart diseases. In this review, we introduce the basics of the lumped parameter model (time-varying elastance chamber model combined with modified Windkessel vasculature model) and illustrate its usage in hemodynamic simulation of congenital heart diseases using examples such as hypoplastic left heart syndrome and Fontan circulation. We also discuss the advantages of the lumped parameter model and the problems for clinical use.