[Sarcoidosis diagnosed by a tiny esophageal lesion:a case report].

A woman in her 60s was referred to the Department of Gastroenterology with anemia. She had a recurrent transient loss of consciousness 11 years ago, and she was examinated at the cardiology and neurology departments, but the cause was not identified. Epileptic seizures were suspected. Sodium valproate medication was started, and the patient's condition progressed with no recurrence. Esophagogastroduodenoscopy showed a tiny submucosal tumor-like lesion with mild depression in a 21cm thoracic esophagus. Biopsy revealed epithelioid granulomas with multinucleated giant cells in the subepithelial stroma. Computed tomography (CT), positron emission tomography-computed tomography (PET-CT), and magnetic resonance imaging (MRI) showed multiple lesions in the hilar lymph nodes, spleen, and heart that are typical of sarcoidosis. These findings led to the diagnosis of esophageal lesion associated with sarcoidosis. The patient had no subjective symptoms;however, treatment with prednisolone 30mg was started because cardiac sarcoidosis is a risk of death. Gastrointestinal tract involvement in sarcoidosis is rare;esophageal sarcoidosis is particularly rare, and there are few reports on superficial lesions. Here, we report a case of sarcoidosis that was diagnosed from a tiny esophageal lesion.

Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds.

This letter describes synthesis and evaluation of two series of dual mGlu2/mGlu3 positive allosteric modulators with moderate mGlu3 potency and robust mGlu2 potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu3-mediated signaling in central neurons by co-application of a selective mGlu2 NAM to isolate mGlu3-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca2+ signaling in PFC pyramidal cells with either the dual mGlu2/mGlu3 PAM 16e or 23d demonstrated effects mediated selectively via mGlu3.

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity.

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 µg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Pitching form determines probabilistic structure of errors in pitch location.

According to recent motor control studies, it is important to know probabilistic structure of his/her own motor errors to choose an optimal motor plan (i.e., where you aim at) to maximise the expected gain. In this study, we questioned if pitching form determines the probabilistic structure of pitching errors in baseball pitchers. Eighteen collegiate baseball pitchers with various pitching forms including right- and left-handed overarm, sidearm and underarm throwers threw 100 pitches aiming at a target located 90 cm above the ground. Two dimensional distribution of pitch location was fitted by using bivariate normal distribution and 95% confidence ellipse was calculated. In order to quantify the pitching form, the direction of the throwing arm trajectory in frontal plane was calculated. The direction of the long axis was dependent on each participant's pitching form (e.g., right overarm pitchers pitched along a right-up-left-down ellipse and left overarm pitchers pitched along a left-up-right-down ellipse). This was confirmed by circular correlation analysis (P = 0.98). These results suggest that different mechanisms, potentially errors in pitching mechanics and errors in ball release timing, might contribute to errors along the long axis and those along the short axis.

Breathing intolerance index in healthy infants.

BACKGROUND: The breathing intolerance index (BITI) is used to justify ventilator use in adult patients with pulmonary or chest wall disease. BITI in ventilated patients is mostly ≥0.15. The mean BITI of healthy adults in the upright sitting position and the supine position is 0.050 ± 0.009 and 0.057 ± 0.016, respectively. The aim of this study was to establish a normal BITI in infants. METHODS: Thirty healthy infants were examined in the supine position. BITI was defined as BITI = (Ti/Ttot) × (TV/VC), where Ti is inspiratory time, Ttot is total breath cycle duration, TV is tidal volume, and VC is vital capacity. TV and Ti/Ttot were obtained from tidal breathing at rest and VC was obtained spirometrically. BITI was calculated using customized software. RESULTS: The mean ± SD BITI of 30 healthy infants in the supine position was 0.120 ± 0.013. The BITI of infants was significantly higher than that of adults. CONCLUSIONS: BITI was measured in healthy infants. Further evaluation is needed to determine the significance and usefulness of BITI.

[A case of Stage IV gastric cancer was successfully treated with multi combination chemotherapy with S-1].

Stage IV gastric cancer has poor prognosis, and median survival time (MST) is reported to range from 6 to 13 months. We report a case of long-term survival in a Stage IV gastric cancer patient who was successfully treated with multi combination chemotherapy with S-1. A 73-year-old woman presenting with gastric cancer with pyloric stenosis and peritoneal dissemination at the sigmoid colon underwent distal gastrectomy with D2 lymphadenectomy and sigmoidectomy. She received adjuvant chemotherapy with S-1 and CDDP after surgery. During the twelfth administration of S-1 and CDDP, she developed an anaphylactic reaction against CDDP; therefore, only S-1 was administered for the next 6 courses. Thirty one months postgastrectomy, a left ovarian metastasis (about 4 cm) was detected by computed tomography. Two courses of S-1 and CPT-11 were administered; however, the ovarian metastasis grew to twice its initial size. She underwent hysterectomy and bilateral ovariectomy. The pathological diagnosis was metastatic tumors in the uterus and ovary(Krukenberg tumor). After the second surgery, S-1 and docetaxel therapy was initiated. A metastasis (S2, 5mm diameter) appeared in the right lung around 65 months after the gastrectomy. The patient received a total of 28 courses, up until 69 months post-gastrectomy. At present, she hopes to finish the chemotherapy and is consulting a palliative care facility. At 80 months post-gastrectomy, she has no symptoms because the lung metastasis exhibits slow growth (15 mm diameter), and is maintaining her quality of life (QOL).

Product of heart rate and first heart sound amplitude as an index of myocardial metabolic stress during graded exercise.

BACKGROUND: The double product (DP) breakpoint of heart rate (HR) and systolic blood pressure has been identified as coincident with anaerobic threshold (AT), but there are no simple methods for measuring cardiac metabolic stress (CMS) during an exercise test. It was hypothesized that the DP of HR and the amplitude of the first heart sound (AHS1) (DP-AHS1) would reflect CMS, and thus, the breakpoint in the DP-AHS1 (DPBP-AHS1) could be an alternative method for determining AT. METHODS AND RESULTS: Subjects (age range, 18-73 years) were recruited to perform a graded exercise test on a cycle ergometer with continuous monitoring of DP-AHS1, with left ventricular pressure (LVP; experiment 1, Ex1), plasma catecholamine and blood lactate (experiment 2, Ex2) and gas exchange (experiment 3, Ex3). Ex1: in all subjects there was a strong correlation between AHS1 and LVdP/dtmax (r=0.94-0.98), and between the DP-AHS1 and the triple product of HR, LVdP/dtmax, and max LVP (r=0.98-0.99). Ex2: DP-AHS1 was strongly correlated with adrenaline (r=0.97-1.00) and lactate (r=0.96-1.00) levels in all subjects. Ex3: there was a strong correlation between DPBP-AHS1, AT and maximum oxygen consumption. CONCLUSIONS: The present simple measure of DP-AHS1 can reflect plasma adrenaline and lactate levels during graded exercise testing. Further, DPBP-AHS1 is a surrogate marker of AT and a good index of functional aerobic capacity.

Seven new monoterpenoid indole alkaloids from Gelsemium elegans.

Seven new indole alkaloids were isolated from the roots of Gelsemium elegans Benth. and their structures were determined by spectroscopic analysis and chemical transformation from known alkaloids. Kounaminal (1) is a new koumine-type alkaloid that contains an unusual aminal moiety. Humantenoxenine (2) and 15-hydroxyhumantenoxenine (3) are humantenine-type alkaloids that contain a novel ß-amino-α,ß-unsaturated ketone residue. The other four novel alkaloids are two gelsedilam-related and two gelsenicine-related alkaloids.

Weight distribution influences the time required to lift the leg even under normal standing condition.

The purpose of the present study is to demonstrate whether the time taken to initiate a lift-one-leg task from a quiet standing position is determined by the initial weight distribution (WD), irrespective of whether the initial posture is controlled spontaneously or by using visual feedback. Seven healthy young subjects performed a lift-one-leg task in response to visual stimulation provided by an LED. The experiment included the normal (N) condition in which the participants stand on both legs symmetrically, as subjectively estimated, and the three feedback (FL, FC and FR) conditions in which the participants regulate the WD at -20% (left-weighted by 6:4), 0% (center-weighted by 5:5) and 20% (right-weighted by 4:6), respectively, through the use of visual feedback. In the N condition, the inter-trial variation of WD was larger than that of the FC condition, which was enough to significantly correlate with the time required to lift the leg. The slope, intercept, and standard error of estimation of the regression equation between the WD and the duration of anticipatory postural adjustment were consistent between conditions. The quantification of the effect of WD on anticipatory postural adjustment indicated that the time taken to lift the leg was delayed by 2.81ms as the center of mass shifted toward the lifting leg by 1mm. Our results demonstrate that asymmetric loading is a simple biomechanical factor that determines the time needed to initiate a subsequent lift-one-leg task.