Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore

A large number of structurally diverse compounds act as open-channel blockers of NMDA receptors. They may share discrete or overlapping binding sites within the channel. In this study, the effects of mutations in and around the membrane-spanning and pore-forming regions of NMDA receptor subunits were studied with three blockers, MK-801, memantine, and TB-3-4, using recombinant NMDA receptors expressed in Xenopus laevis oocytes. Mutations at the critical asparagine residues in the M2 loop of NR1 and NR2B and at a tryptophan residue in M2 of NR2B reduced block by MK-801, memantine, and TB-3-4. Mutations at residues in the pre-M1, M1, M3, post-M3, and post-M4 regions had differential effects on the three blockers. Many mutations in these regions reduced block by MK-801 and TB-3-4 but had no effect on block by memantine. The differential effects on block by memantine and MK-801 are unlikely to be caused by differences in the size of these blockers. Benzyl rings in MK-801 and TB-3-4 may make hydrophobic interactions with aromatic and hydrophobic amino acid residues in the pore. Some mutations in the pre-M1 and M3 regions generated constitutively open channels, characterized by large holding currents. The effects of the various mutants are discussed in the context of models based on the known structure of the pore of the KcsA potassium channel and on previous studies dealing with solvent accessible residues in NMDA receptor subunits as determined by modification after cysteine mutagenesis.     

The efficacy of herbal medicine (kampo) in reducing the adverse effects of IFN-beta in chronic hepatitis C

The purpose of this study was to determine if the adverse effects of interferon (IFN) in hepatitis C patients could be reduced by treatment with Japanese Oriental (Kampo) medicine. Twelve patients with chronic hepatitis C were treated with a combination of IFN-beta and either Mao-to or Dai-seiryu-to (groups A and B), and 16 patients were treated with IFN-beta alone (group C). Mao-to was administered to eight patients and Dai-seiryu-to was administered to four in groups A and B, respectively. Adverse effects were evaluated by clinical and laboratory examinations. The severity of symptoms was daily self-classified into four categories (1: none, 2: very slight, 3: moderate, and 4: serious), using a questionnaire consisting of 29 items. Scores of symptom such as discomfort and fever in group A, and discomfort, general malaise, paresthesia and arthralgia in group B were significantly lower than those in group C (p < 0.05). In all patients, HCV-RNA was negative at the end of the treatment, and serum alanine aminotransferase (ALT) levels had normalized transiently in all group A and B patients with genotype 1b by 2 weeks after cessation of IFN treatment. This study indicates that Kampo medicines are useful for reducing the adverse effects accompanying IFN treatment in patients with chronic hepatitis C without reducing the antiviral effects.     

A structural model of the relationships among self-efficacy,psychological adjustment,and physical condition in Japanese advanced cancer patients

We made detailed research for relationships among physical condition, self-efficacy and psychological adjustment of patients with advanced cancer in Japan. The sample consisted of 85 (42 males and 43 females) advanced cancer patients. Interviews were conducted with some measurement scales including the Self-efficacy scale for Advanced Cancer (SEAC), and the Hospital Anxiety and Depression Scale (HADS). Karnofsky Performance Status (KPS) and medication status were also recorded from the evaluation by physicians. We used structural equation modeling (SEM) for statistical analysis. The analysis revealed that the model, including three self-efficacy subscales, depression, anxiety, KPS, meal-, liquid-intake, prognosis and three latent variables: 'Self-efficacy', 'Emotional Distress', and 'Physical Condition,' fit the data (chi-square(24)=28.67, p=0.23; GFI=0.93; CFI=0.98; RMSEA=0.05). In this model, self-efficacy accounted for 71% of the variance in emotional distress and physical condition accounted for 8% of the variance in self-efficacy. Overall, our findings suggest clearly that close relationships existed among physical condition, self-efficacy and emotional distress. That is, patients in good physical condition had a high self-efficacy, and patients with high self-efficacy were less emotionally distressed. These results imply that psychological intervention which emphasizes self-efficacy would be effective for advanced cancer patients.     

Correction of nonuniform attenuation and image fusion in SPECT imaging by means of separate X-ray CT

Improvements in image quality and quantitation measurement, and the addition of detailed anatomical structures are important topics for single-photon emission tomography (SPECT). The goal of this study was to develop a practical system enabling both nonuniform attenuation correction and image fusion of SPECT images by means of high-performance X-ray computed tomography (CT). A SPECT system and a helical X-ray CT system were placed next to each other and linked with Ethernet. To avoid positional differences between the SPECT and X-ray CT studies, identical flat patient tables were used for both scans; body distortion was minimized with laser beams from the upper and lateral directions to detect the position of the skin surface. For the raw projection data of SPECT, a scatter correction was performed with the triple energy window method. Image fusion of the X-ray CT and SPECT images was performed automatically by auto-registration of fiducial markers attached to the skin surface. After registration of the X-ray CT and SPECT images, an X-ray CT-derived attenuation map was created with the calibration curve for 99mTc. The SPECT images were then reconstructed with scatter and attenuation correction by means of a maximum likelihood expectation maximization algorithm. This system was evaluated in torso and cylindlical phantoms and in 4 patients referred for myocardial SPECT imaging with Tc-99m tetrofosmin. In the torso phantom study, the SPECT and X-ray CT images overlapped exactly on the computer display. After scatter and attenuation correction, the artifactual activity reduction in the inferior wall of the myocardium improved. Conversely, the incresed activity around the torso surface and the lungs was reduced. In the abdomen, the liver activity, which was originally uniform, had recovered after scatter and attenuation correction processing. The clinical study also showed good overlapping of cardiac and skin surface outlines on the fused SPECT and X-ray CT images. The effectiveness of the scatter and attenuation correction process was similar to that observed in the phantom study. Because the total time required for computer processing was less than 10 minutes, this method of attenuation correction and image fusion for SPECT images is expected to become popular in clinical practice.     

mRNA expression of T-helper 1, T-helper 2 cytokines in autoimmune hepatitis in childhood

Background: In the pathology of autoimmune hepatitis the immunity mechanism of T-helper 1 (Th1) and Th2 cells was recently evaluated. The purpose of the present study was to measure the mRNA levels in peripheral mononuclear cells and serum cytokines obtained from children with autoimmune hepatitis for a better understanding of the mechanism.
Methods: Twenty-five patients with autoimmune hepatitis and seven controls were enrolled. mRNA levels in peripheral mononuclear cells and serum cytokines were measured using real-time polymerase chain reaction and immunoassay.
Results: Serum interferon-γ (IFN-γ) and interleukin-4 (IL-4) were rarely detected. In contrast the IFN-γ/β-actin mRNA levels were high.
Conclusion: Autoimmune hepatitis is a Th1-predominant state, therefore immune modulation therapies that target the control of Th1 cytokines should be used.     

DF3 expression in human gallbladder carcinoma: significance for lymphatic invasion

DF3 (MUC 1) is a member of a family of high molecular weight glycoproteins. Recent studies have demonstrated that DF3 is expressed in tumors of various human organs, and may function as an anti-adhesion molecule that inhibits cell-to-cell adhesion, inducing tumor metastasis. However, expression patterns of DF3 have not yet been established in human gallbladder carcinomas. In this study, we examined DF3 expression in human gallbladder adenocarcinoma and its clinicopathological significance. DF3 immunoreactivity was detected not only in the cancer cells (cytoplasmic type; 50.0%, 27/54) but also in the cancer stroma (stromal type; 46.3%, 25/54). According to TNM classification, 65.0% (26/40) of T2-4 gallbladder cancers showed cytoplasmic DF3, while 7.1% (1/14) of the T1 cancers were cytoplasmic DF3-positive (p<0.001). Stromal DF3 expression was detected in 62.5% (25/40) and none (0/14) of the T2-4 and T1 cancers, respectively (p<0.001). Lymph node metastasis was frequently found in the cytoplasmic DF3- and stromal DF3-positive gallbladder cancers (59.3% and 60.0%, respectively). These observations suggested that DF3 expression plays important roles in cancer cell growth and metastasis of human gallbladder adenocarcinomas.     

The prevalence of vestibular schwannoma among patients treated as sudden sensorineural hearing loss

Objective

To assess the prevalence of vestibular schwannoma (VS) in patients with sudden sensorineural hearing loss (SSNHL).

Prophylactic epidural administration of fentanyl for the suppression of tourniquet pain

Severe dull pain on the side of tourniquet application and marked rises in blood pressure and heart rate associated with that pain are often observed even under adequate regional analgesia. The purpose of this study was to evaluate the effect of epidural fentanyl on the suppression of tourniquet pain during orthopedic surgical procedures. Forty-five patients undergoing orthopedic surgery of the lower extremities with a tourniquet were maintained by continuous epidural anesthesia with 2% lidocaine through an epidural indwelling polyethylene catheter (L3–4). The patients were randomly allocated to the following three groups: epidural fentanyl (100μg) (epidural group,n=15); intravenous fentanyl (100μg) (intravenous group,n=15); control (no fentanyl) (control group,n=15). The epidural or intravenous fentanyl was administered at the time of the second lidocaine injection. The severity of tourniquet pain based on the patient's level of complaint and the total dose of supplemental analgesics requested in the epidural group were significantly lower than those in the control group. Blood pressure during tourniquet application in the epidural group was more stable than in the other two groups. No severe side-effects were observed in any patient. Prophylactic epidural administration of fentanyl might be useful in the suppression of tourniquet pain.