Comparison of anti-anginal effect of cilnidipine with those of nicardipine and nifedipine in the vasopressin-induced angina model of rats.

We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex-mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca2+ channel inhibition by cilnidipine might have suppressed the parasympathetic nerve activity in vivo like those reported in the sympathetic nerve. Thus, cilnidipine may become a useful strategy for inhibiting coronary vasospasm-induced anginal attack.

[A case of atypical Tolosa-Hunt syndrome with a contrast enhanced lesion of the oculomotor and trigeminal nerves on MRI].

A 30-year-old woman was admitted to our hospital because of intractable orbital pain and ptosis on the left side. On admission, she had left oculomotor, ophthalmic and maxillary nerves palsy. MRI revealed a contrast enhanced lesion of the left oculomotor and trigeminal nerves through the covernous sinus and orbita. We diagnosed her condition as Tolosa-Hunt syndrome. The orbital pain was resolved within 48-hours by the pulse therapy with intra-venous methylpredonisolone. The cranial nerve palsy was gradually improved, but never reached complete remission. The left oculomotor and trigeminal nerves also remained enhanced on MRI until 200 days from the onset. Although there have been few reports to demonstrate the contrast enhancement of cranial nerves in Tolosa-Hunt syndrome, these MRI findings may be a specific indicator of the pathological process.

Early effect of tacrolimus in improving excitation-contraction coupling in myasthenia gravis.

OBJECTIVES: Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation. METHODS: In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation-contraction (E-C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4 weeks of tacrolimus (3 mg day(-1)) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1-4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase. RESULTS: Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1-2 weeks of tacrolimus treatment as well as in eight patients assessed after 3-4 weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after short-term tacrolimus treatment. CONCLUSIONS: Tacrolimus induces ECCT shortening accompanying clinical improvement despite no improvement in % decrement within 2 weeks. SIGNIFICANCE: This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E-C coupling in MG.

Contribution of anti-ryanodine receptor antibody to impairment of excitation-contraction coupling in myasthenia gravis.

OBJECTIVE: The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling and anti-ryanodine receptor (RyR) antibody in patients with myasthenia gravis (MG). METHODS: Masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated as the latency difference between CMAP and MRP. For each patient, we selected a representative data set when there was no abnormal decrement in response to repetitive nerve stimulation. The 26 data sets were divided into an anti-RyR-positive group (n=12) and an anti-RyR-negative group (n=14). RESULTS: Masseteric ECCT was significantly longer (p=0.017) in anti-RyR-positive group (median, mean, range; 3.6, 3.8, 3.0-5.9 ms) than in anti-RyR-negative group (3.1, 3.1, 2.7-4.0) although there were no significant differences in masseteric CMAP amplitude and % decrement between the two groups. The bite force was significantly lower in anti-RyR-positive group than in normal controls. CONCLUSIONS: Presence of anti-RyR antibodies is associated with significantly prolonged masseteric ECCT compared to absence of the antibodies in MG. SIGNIFICANCE: Anti-RyR antibody contributes to E-C coupling impairment in the masseter muscle in patients with MG.

Relationship between dysphagia and depressive states in patients with Parkinson's disease.

Aspiration pneumonia related to dysphagia is known to be the leading cause of death in patients with Parkinson's disease (PD). We investigated the relationship between depressive states and dysphagia in patients with PD. A hundred and twenty-seven PD patients gave their informed consent and were enrolled in this study. We used the Beck Depression Inventory (BDI) questionnaire to determine the participants' depressive states, and also used a questionnaire to assess participants' state of dysphagia. Participants were divided into four groups according to their BDI score. We compared the PD patients with Swallowing Disturbances Questionnaire (SDQ) scores of more than or equal to 11 with the SDQ scores of less than 11 regarding depressive categories. A logistic regression analysis was conducted to calculate odds ratios (ORs) and their 95% confidence intervals (95%CI) adjusting for age, sex, disease duration, wearing-off phenomenon and severity of movement disorder. OR (95%CI) of depressive categories, in which the trivial class was set as a reference group, were 3.28 (0.93-11.55), 13.44 (3.10-58.16), 30.35 (5.65-162.97) in the mild class, the moderate class and the severe class, respectively. This study suggests that there may be a strong relationship between depressive states and dysphagia in patients with PD.

Correlation between the degree of left subclavian artery stenosis and the left vertebral artery waveform by pulse Doppler ultrasonography.

BACKGROUND: Development of retrograde blood flow may be observed in the vertebral artery and is associated with progressive ipsilateral proximal subclavian or innominate artery stenosis. The subclavian steal phenomenon is more prevalent in the left subclavian artery (LSA). The purpose of this study was to analyze the correlation between the degree of LSA stenosis and pulse Doppler waveforms of the left vertebral artery (LVA). METHODS: A retrospective analysis of LVA waveforms was performed in 22 cases with LSA proximal stenosis before the origin of the LVA in conventional angiograms. The degree of LSA stenosis was classified into 5 groups (<50, 50-59, 60-69, 70-89, 90-100%). Pulse Doppler waveforms of the LVA were also classified into 5 subtypes depending on the depth of the mid-systolic notch representing retrograde blood flow (normal, mid-systolic notch, retrograde flow smaller than antegrade flow, retrograde flow larger than antegrade flow, retrograde flow without antegrade flow). RESULTS: A statistically significant correlation (R(2) = 0.646, p < 0.0001) was found between the degree of LSA stenosis and the LVA waveform. CONCLUSIONS: The pattern analysis of LVA pulse Doppler waveforms seems to be useful in determining the degree of LSA stenosis.

Correlation of bite force with excitation-contraction coupling time of the masseter in myasthenia gravis.

OBJECTIVE: The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling of masseter and the bite force in patients with myasthenia gravis (MG). METHODS: In 20 patients with MG, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRP) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT, and bite force were performed before and after corticosteroid therapy alone or in various combinations with FK506, cyclosporin A, intravenous immunoglobulin and immunoabsorption. RESULTS: Percent amplitude decrement in RNS and ECCT decreased significantly accompanying an increase in bite force after treatment. Simple regression analysis demonstrated a linear correlation among % decrement, ECCT and bite force. However, ECCT shortening accompanying bite force recovery without reduction in % decrement was observed in 4 patients. CONCLUSIONS: Masseteric E-C coupling is impaired in some MG patients, and functional recovery of E-C coupling contributes at least in part to the increase in bite force after treatment. SIGNIFICANCE: Impaired E-C coupling contributes to muscle weakness in patients with MG.

Usefulness of a blood flow analyzing program 3DSRT to detect occipital hypoperfusion in dementia with Lewy bodies.

In the latest criteria for the clinical diagnosis of dementia with Lewy bodies (DLB), supportive features include generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity. In this study, we investigated the usefulness of a cerebral blood flow (CBF) quantification program '3DSRT' in detecting occipital hypoperfusion in DLB. Twenty two patients with probable DLB, 38 patients with probable Alzheimer's disease (AD) and 16 normal controls underwent brain perfusion SPECT. Compared with AD, DLB patients had a bilateral lower CBF in the posterior cerebral segments. The correlation of clinical symptoms and brain blood perfusion was examined by dividing the subjects into subgroups. DLB patients with Parkinsonism, when compared to non-Parkinsonism subgroup, had a lower CBF throughout the cerebrum with statistical significance in the posterior cerebral segments. The quantitative analysis of brain perfusion SPECT by 3DSRT could be a useful supportive measurement in the diagnosis of DLB.

Quantitative analysis of brain perfusion SPECT in Alzheimer's disease using a fully automated regional cerebral blood flow quantification software, 3DSRT.

PURPOSE: The clinical symptoms of Alzheimer's disease (AD) show great diversity depending on the clinical stage. We investigated the correlation of regional cerebral blood flow (rCBF) changes and the clinical severity of AD patients. METHODS: Thirty-nine AD patients and 16 normal subjects participated in this study. AD patients were divided into three subgroups by clinical severity. Quantitative brain perfusion SPECT analyses were performed using a rCBF quantification software, 3DSRT. RESULTS: In mild AD, significant decreases of rCBF were detected in the bilateral parietal, angular gyrus, pericallosal, thalamus, right temporal and left hippocampal regions. Moderate AD patients showed significantly lower blood flow than those with mild AD only to the right hippocampus. Analysis of the severe AD group revealed a nearly diffuse decrease of rCBF throughout the cerebral cortex except for part of the frontal lobe compared with moderate patients. CONCLUSIONS: These results were consistent with previous findings demonstrated by qualitative analysis of CBF. The decreased thalamic blood flow was noteworthy as this finding has rarely been reported. In consideration of the structure and function of the Papez circuit, which connects the medial temporal lobe and thalamus, a remote metabolic effect might be the cause of lower rCBF in the thalamus.

GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT-I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT-I mRNA as well as GM3 in 40 tumor tissues surgically removed from non-small cell lung cancer patients. Adenocarcinoma tissues expressed SAT-I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT-I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT-I mRNA and epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR-TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC(50) values for gefitinib and AG1478 decreased dramatically with increasing SAT-I mRNA levels (R(2) = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR-TK inhibitors, the SAT-I gene was introduced stably into a GM3-negative clone of murine 3LL lung cancer cells to produce GM3-reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3-reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT-I mRNA in lung biopsy samples from non-small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR-TK inhibitors.

Effect of cigarette smoking on gastric emptying of solids in Japanese smokers: a crossover study using the 13C-octanoic acid breath test.

BACKGROUND: Cigarette smoking is associated with an increased risk of peptic ulcer and gastroesophageal reflux disease. Gastric emptying disorders may play a role in the development of these upper gastrointestinal diseases. Thus, studies examining a link between smoking and gastric emptying disorders have clinical relevance. This study was conducted to investigate the effect of smoking on gastric emptying of solids in Japanese smokers. METHODS: The (13)C-octanoic acid breath test was performed in eight male habitual smokers on two randomized occasions (either sham smoking or actively smoking). The time vs (13)CO(2) excretion rate curve was mathematically fitted to a conventional formula of y (t) = m*k*beta*e(-k*t)*(1 - e(-k*t))(beta-1), and the parameters of k and beta were determined: under the crossover protocol, a larger (smaller) beta indicates slower (faster) emptying in the early phase, and a larger (smaller) k indicates faster (slower) emptying in the later phase. The half (13)CO(2) excretion time (t(1/2b) = -[ln(1 - 2(-1/beta))]/k) and the time of maximal (13)CO(2) excretion rate (t(max) = [lnbeta]/k) were also calculated. Between the two occasions, k, beta, t(1/2b), and t(max) were compared by the Wilcoxon signed-rank test. RESULTS: After smoking, k was significantly increased. No significant differences were found in beta, t(1/2), and t(max) between the two occasions. CONCLUSIONS: The increase in k suggests the acceleration of gastric emptying in the later phase. For the first time, this study has revealed that acute smoking speeds the gastric emptying of solids in Japanese habitual smokers.

Modified 13C-octanoate breath test and impact of sampling points.

In recent years, the C-octanoate breath test has attracted attention as a simple and noninvasive method of assessing gastric emptying of solids. However, practical procedures for test meals, parameters used, and sampling points have not yet been established. Moving toward a more convenient method, here we examined the influences of sampling interval and duration on the C-octanoate breath test performed on 15 healthy subjects using a commercially-available instant cupcake. Breath samples were obtained every 15 minutes within 4 hours, and every 30 minutes in the subsequent 2 hours. Using computer simulation, the time it took for the fitting curve to peak (Tpeak) was calculated in each setting with each interval (15, 30, 60, and 120 minutes) and test duration (3, 4, 5, and 6 hours). When the sampling interval widened over 30 minutes, the difference from the original 6-hour data became larger than 20% of the coefficient of variance. When the sampling duration was shortened to 3 hours, no appropriate fitting curve could be achieved. These results suggest that a sampling duration of 4 hours at 30-minute intervals seems to be suitable for practical use of the test.

MR findings of clear cell sarcoma: two case reports.

We report two patients with clear cell sarcomas arising from tendons in the ankle and knee. In the current cases, calcifications, fluid-fluid levels and the marked hypointense areas are not seen within the masses. In the differential diagnosis of the mass developing in the tendons and aponeuroses, when these signs are absent, the probability of clear cell sarcoma is higher.

Urinary antibody titers to Helicobacter pylori and an impact of clinical characteristics.

This study evaluates the clinical usefulness of titers of antibody to Helicobacter pylori (Hp) in a urine-based enzyme-linked immunosorbent assay (URINELISA; Otsuka Pharmaceutical, Tokushima, Japan) by comparing values of serum antibody to Hp in an already commercialized kit in a population of 250 asymptomatic individuals. Influences of physical and laboratory characteristics on the relationship between serum and urinary titers of antibody to Hp were also estimated using simple and multiple regression analyses. Specific urine gravity, urine pH, proteinuria, and age of the subjects were regarded as significant factors relating to urinary titers of the anti-Hp antibody on simple regression analyses. Both the urinary and serum titers strongly correlated on simple regression analysis (r = 0.782, P < 0.0001). On multiple regression analysis, an additional two factors, specific urine gravity and urine pH, were picked up, and the correlation coefficient was improved (r = 0.795, P < 0.0001). The present results indicate that URINELISA had not only qualitative but quantitative accuracy. However, careful attention should be paid to cases with abnormalities in urinalysis when used quantitatively.

Does Cl-/HCO3- exchange play an important role in reperfusion arrhythmias in rats?

The protective effects of Cl(-)/HCO(3)(-) exchange inhibitors, 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'isothiocyanato-stilbene-2,2'-disulfonic acid (SITS), against reperfusion-induced arrhythmias were investigated in anesthetized rats. Rats were subjected to 5-min occlusion of the left coronary artery followed by 10-min reperfusion. All drugs were intravenously administered 5 min before the onset of occlusion. DIDS (75 mg/kg) reduced the incidence of ventricular fibrillation and mortality to 0%, whereas SITS (75 mg/kg) only decreased these parameters to 60%. DIDS simultaneously decreased the mean blood pressure and heart rate, and prolonged PQ and QRS intervals, whereas SITS produced a weaker effect on these parameters and no change in QRS interval. Mexiletine (5 mg/kg), which had been demonstrated to suppress the arrhythmias and reduce the heart rate and mean blood pressure in this model, was shown to prolong PQ and QRS intervals. Verapamil (0.5 mg/kg) or diltiazem (0.4 mg/kg) suppressed the arrhythmias, simultaneously decreasing the heart rate and mean blood pressure and prolonging PQ interval. The results indicate that the protective effect of DIDS on reperfusion arrhythmias in the anesthetized rats is unlikely to be attributed to the inhibitory action on Cl(-)/HCO(3)(-) exchange, but possibly mediated by its blocking effects on cardiac ion channels, such as Na(+) or Ca(2+) channels.