Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels

The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.     

Interleukin‐8‐producing primary cardiac undifferentiated sarcoma in a child with sustained fever

We report the case of a 12‐year‐old boy with primary undifferentiated sarcoma of the left atrium. He had sustained fever during the clinical course and multiple lung and brain metastases. Chemotherapy and irradiation were ineffective; he died 41 days after hospitalization. On retrospective analysis, interleukin‐8 (IL‐8) was elevated; this was supported by immunohistochemistry and gene expression analysis of tumor samples. IL‐8 continued to increase with tumor progression accompanied by elevated neutrophil count and C‐reactive protein. IL‐8 is involved in malignant tumor proliferation, migration, and angiogenesis and may have been related to the clinical condition and prognosis in the present case.     

Liver with hypoechoic nodular pattern as a risk factor for hepatocellular carcinoma

Ultrasonography should be used for screening of hepatocellular carcinoma, but there are few reports on the relationship between liver ultrasonographic findings and the development of hepatocellular carcinoma (HCC). Using prospective follow-up studies, we examined the role of liver with a hypoechoic nodular pattern as a high-risk factor in HCC. The study was performed by follow-up on 593 patients with chronic liver disease recorded at our hospital. The ultrasonographic pattern of the liver parenchyma was classified either as a small or large hypoechoic nodular pattern or as a nonnodular pattern. Patients were followed up from the time of initial ultrasonographic examination (1985–1987) until January 1, 1991. During the follow-up period (average, 4.2 years, range, 0.3–6.0 years), 62 patients were found to have HCC (12%). Patients whose livers showed small or large hypoechoic nodular pattern had a significantly higher risk of HCC than did patients whose livers showed a nonnodular pattern (rate ratios were 14.0 and 20.0, respectively, adjusted for age, sex, hepatitis virus markers, ICG R15, α-fetoprotein concentration, and ultrasonographic pattern of the liver). Liver showing a hypoechoic nodular pattern is a major risk factor in HCC.     

Life‐threatening hemorrhage from the corona mortis after laparoscopic inguinal hernia repair: Report of a case

Along with the increased use of other laparoscopic procedures, laparoscopic inguinal hernia repair has become widely used because of its minimally invasive nature. Here, we report a case of 66‐year‐old man who underwent transabdominal preperitoneal laparoscopic hernioplasty and developed hemorrhagic shock on postoperative day 1. CT showed postoperative venous hemorrhage from the retropubic space. Successful hemostasis of the massive hemorrhage was achieved laparoscopically. The origin of the hemorrhage was assumed to be the corona mortis vein, which was slightly injured during the operation. Despite the rarity of this complication, surgeons must be aware of the need to carefully dissect and fix the mesh in the retropubic space to avoid injuring the corona mortis. Laparoscopic hemostasis may be an effective alternative to the open approach.     

Autochthonous Dengue Fever,Tokyo, Japan, 2014

After 70 years with no confirmed autochthonous cases of dengue fever in Japan, 19 cases were reported during August–September 2014. Dengue virus serotype 1 was detected in 18 patients. Phylogenetic analysis of the envelope protein genome sequence from 3 patients revealed 100% identity with the strain from the first patient (2014) in Japan.     

Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury,Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient''s underlying diseases or therapeutic pharmacological backgrounds.     

A Targeted Biopsy during Menstruation for the Definitive Diagnosis of Rectovaginal Endometriosis: A Report of Two Cases

We herein report the definitive diagnosis of rectovaginal endometriosis in two cases. Case 1 involved a 46-year-old woman with abdominal pain and hematochezia. The diagnosis after the first and second examinations using lower gastrointestinal (GI) endoscopy was unclear. Differential diagnoses included mucosa-associated lymphoid tissue and colorectal cancer. The third lower GI endoscopy with a targeted biopsy, performed during menstruation, confirmed rectovaginal endometriosis. Case 2 involved a 38-year-old woman with hematochezia. Lower GI endoscopy during menstruation revealed rectovaginal endometriosis. When rectovaginal or bowel endometriosis is suspected, lower GI endoscopy and a targeted biopsy during menstruation can prevent unnecessary surgery.     

Antibody responses in Japanese volunteers after immunization with yellow fever vaccine

To monitor the development of specific and cross-reactive antibody response in twenty Japanese volunteers after vaccination with live yellow fever vaccine. Serum samples were collected on various days after vaccination and examined for hemagglutination inhibition (HI) antibodies against yellow fever virus (YFV), Japanese encephalitis virus (JEV) and dengue virus (DV), neutralizing antibodies against YFV and JEV, and IgM antibodies against YFV. None of the volunteers had been previously immunized with this vaccine. Fifteen of 20 had pre-vaccinated with JEV 7 to 40 years before. Ten of the 20 had neutralizing antibodies against JEV before immunization. None of the 20 had detectable antibodies against YFV or DV before vaccination. On day 10th after the vaccination, neutralizing antibodies to YFV were detected in 6 of 19 volunteers and IgM antibodies against YFV were detected in 7 of 19. On day 14th, HI, neutralizing, and IgM antibodies against YFV were detected in all the tested sera. Neutralizing antibodies against JEV were developed in 2 volunteers and HI antibodies against JEV were increased in 3 of 6 volunteers respectively. On day 29th, cross-reactive HI antibodies for JEV and DV were detected in all the tested sera. The results indicate that YF vaccine induces YFV-specific antibodies in all the tested volunteers and that it also induces HI antibodies cross-reactive for JEV and DV. The YF vaccine has a strong immunogenicity because it is a live vaccine, and induces antibody against YFV predominantly. The international certificate of yellow fever vaccination becomes valid 10 days after vaccination. On day 14th after vaccination, we detected neutralizing antibodies against YFV from all tested volunteers, however, only 6 of 19 volunteers had detectable neutralizing antibody on the 10th day after vaccination. Therefore, the vaccine may not be perfectly effective on day 10th after the vaccination.     

Guanabenz Combination Therapy Inhibits Sympathetic Nerve Activity and Regresses Left Ventricular Hypertrophy

The cardiovascular and sympatholytic effects of combination therapy with guanabenz were examined in 26 patients (48 ± 13 years old [mean ± SD]) with stage 2 and 3 hypertension. Included in the study were patients under treatment with conventional antihypertensive drugs whose systolic and diastolic blood pressure was above 140 and 90 mmHg, respectively. Blood pressure, heart rate, and sympathetic parameters such as plasma concentration of norepinephrine and muscle sympathetic nerve activity at rest as well as during ambulatory conditions, 24-hour urinary excretion of norepinephrine, and low frequency (LF: 0.04–0.15 Hz)/high frequency (HF: 0.15–0.4 Hz) power ratio as a marker of cardiac sympathetic activity during 24 hours were examined before and after guanabenz (4–8 mg/d) combination therapy with first-line antihypertensive drugs such as diuretics. Left ventricular mass index (LVMI) was also calculated by conventional echocardiography. After 32 weeks of guanabenz combination therapy, systolic and diastolic blood pressure, heart rate, plasma and urinary excretion of norepinephrine, muscle sympathetic nerve activity, and LF/HF power ratio were significantly decreased, while neither LF nor HF power was changed. LVMI was also significantly decreased (270 ± 81 vs. 236 ± 83 g/m², p < 0.005). These results indicate that guanabenz combination therapy inhibits sympathetic nerve activity under resting conditions as well as during ambulatory conditions and may accelerate regression of left ventricular hypertrophy in patients with moderate to severe hypertension.     

Acute myocardial infarction associated with myocardial bridging in a young adult

A 28-year-old man was admitted because of chest pain. Emergency coronary angiography showed a massive thrombus in the proximal segment and another occlusive thrombus in the distal segment of the left anterior descending artery. He was treated with thrombolytic therapy. Repeat coronary angiography showed disappearance of the thrombi in the proximal and distal segments and obvious myocardial bridging in the mid segment. Intravascular ultrasound revealed an atherosclerotic plaque in the segment immediately proximal to the myocardial bridging, but did not reveal any plaque within or distal to the site. He was discharged 12 days later.