Esophageal ulcer related to zinc deficiency following a total gastrectomy.

A 76-y-old Japanese man who had undergone gastrectomy 4.5 y earlier experienced 2 wk of sore throat, heartburn, and difficulty swallowing. Endoscopy showed deep, craterlike, longitudinal ulcers in the lower and middle esophagus. Immunohistochemistry and blood tests were negative for herpes simplex virus and cytomegalovirus infections. The patient reported no other symptoms affecting the gastrointestinal tract. Although his symptoms ameliorated after initial hospitalization and treatment, they re-emerged a few days after being discharged. Fifty-one days after being first admitted, he complained of glossalgia. The serum zinc level was found to be 38 µg/dL, which was below the reference range; the patient was diagnosed with zinc deficiency. After oral zinc administration, the patient was relieved of the symptoms, and his pain was alleviated. Upper gastrointestinal endoscopy after symptom relief showed improvement in the esophageal ulcers. He has continued taking zinc supplementations, and has not developed similar symptoms in the 5 y since being treated. To the best of our knowledge, this is the first case report of esophageal ulcers related to zinc deficiency.

Reproducibility and reliability of performance indicators to evaluate the therapeutic effectiveness of biofeedback therapy after elbow surgery: An observational case series.

Electromyographic biofeedback (EMG-BF) therapy provides information on the state of contraction of the targeted muscles and relaxation of their antagonists, which can facilitate early active range of motion (RoM) after elbow surgery. Our aim in this study was to calculate the minimum detectable change (MDC) during EMG-BF therapy, initiated in the early postoperative period after elbow surgery.This study is an observational case series. EMG-BF of muscle contraction and relaxation was provided during active elbow flexion and extension exercises. Patients completed 3 sets of 10 trials each of flexion and extension over 4 weeks. The total range of flexion-extension motion and scores on the Japanese Society for Surgery of the Hand version of the disability of the arm, shoulder, and hand questionnaire and the Japanese version of the Patient-Rated Elbow Evaluation were obtained at baseline and weekly during the 4-week intervention period. A prediction formula was developed from the time-series data obtained during the intervention period, using the least-squares method. The estimated value was calculated by removing the slope from the prediction formula and adding the initial scores to residuals between the measured scores and predicted scores individually. Systematic error, MDC at the 95th percentile cutoff (MDC95), repeatability of the measures, and the change from the baseline to each time-point of intervention were assessed.The MDC95 was obtained for all 3 outcome measures and the range of values was as follows: RoM, 8.3° to 22.5°; Japanese version of the Patient-Rated Elbow Evaluation score, 17.6 to 30.6 points; and disability of the arm, shoulder, and hand questionnaire subscale: disability and symptoms score, 14.2 to 22.9 points.The efficacy of EMG-BF after elbow surgery was reflected in earlier initiation of elbow RoM after surgery and improvement in patient-reported upper limb function scores. The calculated MDC95 cut-offs could be used as reference values to assess the therapeutic effects of EMG-BF in individuals.

Current characteristics and management of ST elevation and non-ST elevation myocardial infarction in the Tokyo metropolitan area: from the Tokyo CCU network registered cohort.

Limited data exists on ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) managed by a well-organized cardiac care network in a metropolitan area. We analyzed the Tokyo CCU network database in 2009-2010. Of 4329 acute myocardial infarction (AMI) patients including STEMI (n = 3202) and NSTEMI (n = 1127), percutaneous coronary intervention (PCI) was performed in 88.8 % of STEMI and 70.4 % of NSTEMI patients. Mean onset-to-door and door-to-balloon times in STEMI patients were shorter than those in NSTEMI patients (167 vs 233 and 60 vs 145 min, respectively, p < 0.001). Coronary artery bypass graft surgery was performed in 4.2 % of STEMI and 11.4 % of NSTEMI patients. In-hospital mortality was significantly higher in STEMI patients than NSTEMI patients (7.7 vs 5.1 %, p < 0.007). Independent correlates of in-hospital mortality were advanced age, low blood pressure, and high Killip classification, statin-treated dyslipidemia and PCI within 24 h were favorable predictors for STEMI. High Killip classification, high heart rate, and hemodialysis were significant predictors of in-hospital mortality, whereas statin-treated dyslipidemia was the only favorable predictor for NSTEMI. In conclusion, patients with MI received PCI frequently (83.5 %) and promptly (door-to-balloon time; 66 min), and had favorable in-hospital prognosis (in-hospital mortality; 7.0 %). In addition to traditional predictors of in-hospital death, statin-treated dyslipidemia was a favorable predictor of in-hospital mortality for STEMI and NSTEMI patients, whereas hemodialysis was the strongest predictor for NSTEMI patients.

Informatics framework of traditional Sino-Japanese medicine (Kampo) unveiled by factor analysis.

Kampo, an empirically validated system of traditional Sino-Japanese medicine, aims to treat patients holistically. This is in contrast to modern medicine, which focuses in principle on treating the affected parts of the body of the patient. Kampo medicines formulated as combinations of crude drugs are prescribed based on a Kampo-specific diagnosis called Sho (in Japanese), defined as the holistic condition of each patient. Therefore, the medication system is very complex and is not well understood from a modern scientific perspective. Here, we show the informatics framework of Kampo medication by multivariate factor analysis of the elements constituting Kampo medication. First, the variation of Kampo formulas projected by principal component analysis (PCA) indicated that the combination patterns of crude drugs were highly correlated with Sho diagnoses of Deficiency and Excess. In an opposite way, partial least squares projection to latent structures (PLS) regression analysis could also predict Deficiency/Excess only from the composed crude drugs. Secondly, to chemically verify the correlation between Deficiency/Excess and crude drugs, we performed mass spectrometry (MS)-based metabolome analysis of Kampo prescriptions. PCA and PLS regression analysis of the metabolome data also suggested that Deficiency/Excess could be theoretically explained based on the variation in chemical fingerprints of Kampo medicines. Our results show that factor analysis of Kampo concepts and of the metabolomes of Kampo medicines enables interpretation of the complex system of Kampo. This study will theoretically form the basis for establishing traditionally and empirically based medications worldwide, leading to systematically personalized medicine.

Combination of liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry with 13C-labeling for chemical assignment of sulfur-containing metabolites in onion bulbs.

Phytochemicals containing heteroatoms (N, O, S, and halogens) often have biological activities that are beneficial to humans. Although targeted profiling methods for such phytochemicals are expected to contribute to rapid chemical assignments, thus making phytochemical genomics and crop breeding much more efficient, there are few profiling methods for the metabolites. Here, as an ultrahigh performance approach, we propose a practical profiling method for S-containing metabolites (S-omics) using onions (Allium cepa) as a representative species and (12)C- and (13)C-based mass spectrometry (MS) and tandem mass spectrometry (MS/MS) analyses by liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FTICR-MS). Use of the ultrahigh quality data from FTICR-MS enabled simplifying the previous methods to determine specific elemental compositions. MS analysis with a resolution of >250,000 full width at half-maximum and a mass accuracy of <1 ppm can distinguish S-containing monoisotopic ions from other ions on the basis of the natural abundance of (32)S and (34)S and the mass differences among the S isotopes. Comprehensive peak picking using the theoretical mass difference (1.99579 Da) between (32)S-containing monoisotopic ions and their (34)S-substituted counterparts led to the assignment of 67 S-containing monoisotopic ions from the (12)C-based MS spectra, which contained 4693 chromatographic ions. The unambiguous elemental composition of 22 ions was identified through comparative analysis of the (12)C- and (13)C-based MS spectra. Finally, of these, six ions were found to be derived from S-alk(en)ylcysteine sulfoxides and glutathione derivatives. This S-atom-driven approach afforded an efficient chemical assignment of S-containing metabolites, suggesting its potential application for screening not only S but also other heteroatom-containing metabolites in MS-based metabolomics.

Discovery of novel tricyclic compounds as squalene synthase inhibitors.

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

BACKGROUND: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. OBJECTIVE: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. RESULTS: A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). CONCLUSIONS: Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.

Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.

To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.

Simultaneous characterization of quaternary alkaloids, 8-oxoprotoberberine alkaloids, and a steroid compound in Coscinium fenestratum by liquid chromatography hybrid ion trap time-of-flight mass spectrometry.

Simultaneous characterization of quaternary alkaloids, 8-oxoprotoberberine alkaloids, and a steroid compound in Coscinium fenestratum was successfully performed by liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LC/IT-TOF MS). A total of 32 compounds, including 2 benzylisoquinoline alkaloids, 3 aporphine alkaloids, 12 quaternary protoberberine alkaloids, 10 8-oxoprotoberberine alkaloids, 3 tetrahydroprotoberberine alkaloids, and a steroid compound were simultaneously separated and characterized by matching the empirical molecular formulae with those published in literature and the multi-stage mass spectrometry (MS(n)) data obtained using structural information from IT, accurate mass measurement obtained from TOF MS, and HPLC separation. A total of 20 compounds, including 4 novel natural products were identified or tentatively identified for the first time from Coscinium fenestratum. In the positive-ion mode, 8-oxoprotoberberines produced [M+H](+) and [M+Na](+); the fragmentation of 8-oxodihydroprotoberberines produced [M+H-*CH(3)](+*), [M+H-*CH(3)-*CH(3)](+), and [M+H-*CH(3)-*CH(3)-CO](+), while 8-oxotetrahydroprotoberberines generated [M+H-*CH(3)](+*), [M+H-*CH(3)-*CH(3)](+), [M+H-*CH(3)-*H](+), and iminium ions from the cleavage of the protoberberine skeleton. The method can be applied for the analysis of 8-oxoberberine and other alkaloids in Coptis japonica, Phellodendron amurense, and other herbal medicines.

The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load.

Residents of Okinawa, the southernmost prefecture of Japan, are known for their long average life expectancy, high numbers of centenarians, and accompanying low risk of age-associated diseases. Much of the longevity advantage in Okinawa is thought to be related to a healthy lifestyle, particularly the traditional diet, which is low in calories yet nutritionally dense, especially with regard to phytonutrients in the form of antioxidants and flavonoids. Research suggests that diets associated with a reduced risk of chronic diseases are similar to the traditional Okinawan diet, that is, vegetable and fruit heavy (therefore phytonutrient and antioxidant rich) but reduced in meat, refined grains, saturated fat, sugar, salt, and full-fat dairy products. Many of the characteristics of the diet in Okinawa are shared with other healthy dietary patterns, such as the traditional Mediterranean diet or the modern DASH (Dietary Approaches to Stop Hypertension) diet. Features such as the low levels of saturated fat, high antioxidant intake, and low glycemic load in these diets are likely contributing to a decreased risk for cardiovascular disease, some cancers, and other chronic diseases through multiple mechanisms, including reduced oxidative stress. A comparison of the nutrient profiles of the three dietary patterns shows that the traditional Okinawan diet is the lowest in fat intake, particularly in terms of saturated fat, and highest in carbohydrate intake, in keeping with the very high intake of antioxidant-rich yet calorie-poor orange-yellow root vegetables, such as sweet potatoes, and green leafy vegetables. Deeper analyses of the individual components of the Okinawan diet reveal that many of the traditional foods, herbs, or spices consumed on a regular basis could be labeled "functional foods" and, indeed, are currently being explored for their potential health-enhancing properties.

[Association between childhood oral allergy syndrome and sensitization against four major pollens (Japanese cedar, orchard grass, short ragweed, alder)].

BACKGROUND/AIM: Although OAS (oral allergy syndrome) during childhood is believed to be rare, it seems to be increasing these days. METHODS, SUBJECTS: We here report 16 cases of childhood OAS, which were diagnosed, in our division. In addition to these reports, we investigated the rate of sensitization against four major pollens (Japanese cedar, orchard grass, short ragweed, alder) among 1067 pediatric patients with allergic diseases (median age: 4 years old) in our division. The sensitization was examined by IgE CAPRAST and above class 2 was judged as positive sensitization. RESULTS: OAS in childhood differs from that in adulthood in some ways. One is that childhood OAS does not always accompany with pollinosis. The most frequent allergen in our study was kiwi fruits followed by tomato, orange and melon among these patients. The sensitization rate against alder was equivalent as that against orchard grass and short ragweed, but less than that against Japanese cedar. CONCLUSION: Childhood OAS may have different mechanisms from adulthood OAS which almost always accompanies with pollinosis or latex allergy.

Promotive effect of Shoyu polysaccharides from soy sauce on iron absorption in animals and humans.

Soy sauce (Shoyu) is a traditional fermented seasoning of Japan and is available throughout the world. We investigated the effect of Shoyu polysaccharides (SPS) prepared from soy sauce on iron absorption in vitro and in vivo. First, by measuring the iron-binding capacity of SPS, it was found that SPS stabilized the solubility of ferrous iron at neutral pH's by forming a complex, Fe-SPS. Second, in experiments with animals, it was found that SPS enhanced the absorption and/or pooling of iron in organs when anemic rats were fed iron-supplemented diets. Third, in a 4-week randomized, double-blind, placebo-controlled parallel group study, healthy women were treated with 600 mg of SPS (n = 22) or placebo (n = 23) each day. After the 4 weeks, serum levels of iron, hematocrit, and hemoglobin were significantly higher (P < 0.05) in the SPS-treated than in the placebo-treated group. In conclusion, SPS of soy sauce enhanced iron absorption, and soy sauce is a potentially promising seasoning for the treatment of anemia through food.

A novel human Cl(-) channel family related to Drosophila flightless locus.

Large conductance chloride (maxi-Cl(-)) currents have been recorded in some cells, but there is still little information on the molecular nature of the channel underlying this conductance. We report here that tweety, a gene located in Drosophila flightless, has a structure similar to those of known channels and that human homologues of tweety (hTTYH1-3) are novel maxi-Cl(-) channels. hTTYH3 mRNA was found to be distributed in excitable tissues. The whole cell current of hTTYH3 was large enough to be discriminated from the control but emerged only after treatment with ionomycin. Analysis of pore mutants suggested that positively charged amino acids contributed to anion selectivity. Like a maxi-Cl(-) channel in situ, the hTTYH3 single channel showed 26-picosiemen linear current voltage, complex kinetics, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid sensitivity, subconductance, and the permeability order of I(-) > Br(-) > Cl(-). Similarly, hTTYH2 encoded an ionomycin-induced maxi-Cl(-) channel, but TTYH1 encoded a Ca(2+)-independent and swelling-activated maxi-Cl(-) channel. Therefore, the hTTYH family encoded maxi-Cl(-) channels of mammals. Further studies on the hTTYH family should lead to the elucidation of physiological and pathophysiological roles of novel Cl(-) channel molecules.

Recognition of far-field electrograms during entrainment mapping of ventricular tachycardia.

OBJECTIVES: The goal of this study was to assess entrainment for distinguishing far-field potentials (FFP) due to depolarization of tissue at a distance from the mapping catheter from the local potential (LP) due to depolarization of tissue at the catheter electrode during mapping of ventricular tachycardia (VT). BACKGROUND: Electrograms with multiple peaks commonly complicate mapping and identification of catheter ablation targets in infarcts. METHODS: Retrospective analysis of catheter mapping data from eight patients with prior infarction was performed to evaluate multipotential electrograms at sites where pacing entrained VT. Potentials that were visible and not altered during pacing were defined as FFP. Potentials obscured by the pacing stimulus were designated possible LPs. The criteria for FFP were then assessed in a second cohort of five patients. RESULTS: At 32 of 39 (82%) sites with multiple potentials, entrainment identified one of the potentials as an FFP. Radiofrequency ablation, assessed at 15 sites, reduced the amplitude of LPs by 62%, without significant effect on FFP amplitude. At 56% of sites with multiple potentials, measuring the postpacing interval to an FFP would lead to erroneous classification of the site location relative to the reentry circuit. In prospective evaluation, double potentials were identified at 77 sites in infarcts; entrainment demonstrated an FFP at 66 (86%) sites. CONCLUSIONS: Far-field potentials are common during mapping in infarcts. Many can be distinguished from local potentials by entrainment, improving the accuracy of mapping.

Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy.

BACKGROUND: Intensive care unit (ICU) psychosis is still a relatively frequent complication after esophageal surgery. We investigated the correlation between ICU psychosis and serum melatonin concentration during the period after esophagectomy. METHODS: The study group comprised 41 patients who underwent esophagectomy for treatment of esophageal cancer between 1999 and 2001. The cohort included 36 men and 5 women, aged 36 to 78 years. After surgery, blood samples were collected 4 times a day for 4 days. Serum levels of melatonin were determined with a melatonin radioimmunoassay kit. The regularity of the melatonin circadian rhythm pattern, as defined by the frequency of occurrence of the peak level of melatonin secretion, was determined (the pattern was described as irregular at less than 3 times in the measurement period). RESULTS: Of the 41 patients who met the inclusion criteria, 11 (26.8%) had ICU psychosis develop. These patients were older than those patients in whom ICU psychosis did not develop (P =.01). No significant differences were seen in the duration of surgery, volume of blood loss, term in the ICU, term of intubation, tumor location, disturbances of organ function, and postoperative complications between patients in whom ICU psychosis developed, and those patients in whom it did not. Patients with ICU psychosis tended to have abnormally low serum levels of melatonin. Of the 41 patients studied, 9 (22%) had an irregular pattern of melatonin circadian rhythm. A significant correlation was seen between ICU psychosis and an irregular melatonin circadian rhythm (P =.0001). CONCLUSION: Irregular patterns of melatonin circadian rhythm may be associated with ICU psychosis. Supplementation with melatonin, or acceleration of melatonin secretion, may protect patients from development of ICU psychosis and may promote recovery to a normal mental state.