ICU入室時の超音波による筋量測定の有用性についての検討

Background & aims: Muscle mass is an important biomarker of survival from a critical illness; however, there is no widely accepted method for routine assessment of low muscularity at intensive care unit (ICU) admission. We hypothesize that ultrasound-based partial muscle mass assessments can reflect the trunk muscle mass. Therefore, we aimed to investigate whether ultrasound muscle mass measurements could reflect trunk muscle mass and identify patients with low muscularity. Methods: We performed a retrospective analysis of prospectively obtained ultrasound data at ICU admission. We included patients who underwent computed tomography (CT) imaging at the third lumbar vertebra (L3) within 2 days before and 2 days after ICU admission. Primary outcomes included the correlation between the femoral muscle mass measurements using ultrasound and the cross-sectional area (CSA) at L3 obtained by CT. Low muscularity was defined as a skeletal muscle index of 36.0 cm2/m2 for males and 29.0 cm2/m2 for females. Secondary outcomes included the correlation with the ultrasound measurements of the biceps brachii muscle mass and diaphragm thickness. Results: Among 133 patients, 89 underwent CT imaging, which included the L3. The patient mean age was 72 ± 13 years, and 60 patients (67%) were male. The correlation between the femoral muscle ultrasound and CT was p = 0.57 (p < 0.01, n = 89) and p = 0.48 (p < 0.01, n = 89) for quadriceps muscle layer thickness and rectus femoris muscle CSA, and these had the discriminative power to assess low muscularity, with the areas under the curve of 0.84 and 0.76, respectively. The ultrasound measurements of the biceps brachii muscle mass and diaphragm thickness were correlated with CT imaging [p = 0.57 - 0.60 (p < 0.01, n = 52) and p = 0.35 (p < 0.01, n = 79)]. Conclusions: Ultrasound measurements of muscle mass were correlated with CT measurements, and the measurements of femoral muscle mass were useful to assess low muscularity at ICU admission

Chronic inhibition of the norepinephrine transporter in the brain participates in the seizure sensitization to cocaine and local anesthetics

Involvement of chronic inhibition of monoamine transporters (MAT) in the brain concerning the sensitization of cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. Effects of 5 daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. The daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. The daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold with dose-dependent manner between 5 and 20 mg/kg. The daily treatments of citaloplam, a selective serotonin uptake inhibitor, 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and a norepinephrine transporter is an integral component of this sensitization

Inhibition of serotonin transporters by cocaine and meprylcaine

The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice.Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT2A,2C receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions were significantly reduced by 5-HT2A,2B,2C antagonist, LY-53857 and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL-11,939 and ketanserin, and 5-HT2B antagonist SB-204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine- induced convulsions through their direct inhibitory action on central SERT

モノアミントランスポーター慢性的阻害による局所麻酔薬痙攣感作に関する研究

広島大学(Hiroshima University)博士(学術)Sciencedoctora

Early Recognition of Patients with Decreased Methotrexate Clearance Following High-Dose Methotrexate Infusion Therapy

The purpose of this study was to identify the patients with decreased methotrexate (MTX) clearance as early as possible after the start of high-dose methotrexate (HD-MTX) infusion. Fifty-six patients (age: 18~83 years) received a HD-MTX infusion (dosage: 1.9~3.8 g/m2) for 6 h. These patients were retrospectively divided into a low-clearance group and a high-clearance group based on the serum MTX concentration at 48 h (1 μM). Six out of the 56 patients showed decreased MTX clearance. The MTX concentrations in the low-clearance group were significantly higher than those in the high-clearance group even in earlier sampling times than at 48 h. The average MTX concentrations were 330 μM at 6 h, 72 μM at 12 h, and 16 μM at 24 h in the low-clearance group, and those in the high-clearance group were 210 μM, 18 μM, and 1.0 μM, respectively. The estimated elimination half-lives (t1/2) at 6~12 h and 12 ~ 24 h after the start of the infusion were also significantly longer in the low-clearance group (2.8 vs. 1.7 h and 5.0 vs. 2.8 h, respectively). Therefore, we proposed convenient criteria based on the mean + 1 S.D. of the high-clearance group: the concentration > 270 μM at 6 h and > 32 μM at 12 h; the t1/2 value > 2.1 h at 6~12 h. All 6 patients were recognized as belonging to the low-clearance group at an early stage after HD-MTX infusion by using our proposed criteria. These results indicate that patients with decreased MTX clearance could be identified within the first 12 h after the start of HD-MTX infusion. The factors influencing the prolonged elimination of MTX were also investigated. A significant decrease in renal function on day 2 was observed in the low-clearance group. The MTX level at 12 h and the estimated t1/2 values were significantly correlated with BUN, Ser and Clcr on the 2nd day after HD-MTX therapy, suggesting that an alteration in renal function occurs within 12 h of the HD-MTX infusion. The prolonged elimination of MTX could be attributable to this decrease in renal function

Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma

The present study aimed to discern the molecular alterations involved in the progression of EGFR-mutated lung adenocarcinoma (LADC). We previously demonstrated that the micropapillary (mPAP) element is the most important histological factor for assessing malignant grades in LADCs. Therefore, mPAP and other elements were separately collected from three cases of EGFR-mutated LADC using laser capture microdissection and subjected to a comprehensive mRNA expression analysis. We focused on DYRK2 in this study because its level showed a substantial increase in EGFR-mutated LADCs with mPAP. We also immunohistochemically examined 130 tumors for the expression of DYRK2. The results confirmed a strong expression of DYRK2 in EGFR-mutated LADC with mPAP. Fluorescent in situ hybridization (FISH) analyses targeting the DYRK2 locus revealed frequent gene amplification in EGFR-mutated LADC, specifically occurring in the high-grade components, like mPAP. In summary, the results of this study suggest that DYRK2 overexpression through gene amplification is one of the molecular mechanisms responsible for promoting the progression of EGFR-mutated LADC

Relationship between non-TRU lung adenocarcinomas and bronchiolar metaplasia - potential implication in their histogenesis -

Lung adenocarcinomas (ADCs) have been roughly divided into two groups: the terminal respiratory unit (TRU) type and non-TRU type. These ADCs appear to develop through exclusive carcinogenetic pathways because of differences in their cellular morphologies and the profiles of protein expression and genetic alterations. The TRU type develops from atypical adenomatous hyperplasia as a precursor. On the other hand, the histogenesis of the non-TRU type has not yet been defined in detail. We herein investigated histopathological changes in the non-tumor lung tissues of patients with non-TRU-type ADCs in order to define their potential histogenesis. The non-TRU type preferentially occurs in patients with interstitial pneumonia, in whom tumors are located in honeycomb lesions and are associated with bronchiolar metaplasia (BM). Among patients without interstitial pneumonia, non-tumor lung tissues from non-TRU-type ADCs were often affected by multiple BM. In these cases, tumors often were associated with BM. Metaplastic cells adjacent to non-TRU-type ADCs ectopically expressed HNF-4α, a marker for non-TRU-type ADCs. These results suggest that the non-TRU type develops through distinct histogenesis, in which BM is implicated