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

C188-9, a specific inhibitor of STAT3 signaling, prevents thermal burn-induced skeletal muscle wasting in mice

Burn injury is the leading cause of death and disability worldwide and places a tremendous economic burden on society. Systemic inflammatory responses induced by thermal burn injury can cause muscle wasting, a severe involuntary loss of skeletal muscle that adversely affects the survival and functional outcomes of these patients. Currently, no pharmacological interventions are available for the treatment of thermal burn-induced skeletal muscle wasting. Elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), are important hallmarks of severe burn injury. The levels of signal transducer and activator of transcription 3 (STAT3)—a downstream component of IL-6 inflammatory signaling—are elevated with muscle wasting in various pro-catabolic conditions, and STAT3 has been implicated in the regulation of skeletal muscle atrophy. Here, we tested the effects of the STAT3-specific signaling inhibitor C188-9 on thermal burn injury-induced skeletal muscle wasting in vivo and on C2C12 myotube atrophy in vitro after the administration of plasma from burn model mice. In mice, thermal burn injury severity dependently increased IL-6 in the plasma and tibialis anterior muscles and activated the STAT3 (increased ratio of phospho-STAT3/STAT3) and ubiquitin-proteasome proteolytic pathways (increased Atrogin-1/MAFbx and MuRF1). These effects resulted in skeletal muscle atrophy and reduced grip strength. In murine C2C12 myotubes, plasma from burn mice activated the same inflammatory and proteolytic pathways, leading to myotube atrophy. In mice with burn injury, the intraperitoneal injection of C188-9 (50 mg/kg) reduced activation of the STAT3 and ubiquitin-proteasome proteolytic pathways, reversed skeletal muscle atrophy, and increased grip strength. Similarly, pretreatment of murine C2C12 myotubes with C188-9 (10 µM) reduced activation of the same inflammatory and proteolytic pathways, and ameliorated myotube atrophy induced by plasma taken from burn model mice. Collectively, these results indicate that pharmacological inhibition of STAT3 signaling may be a novel therapeutic strategy for thermal burn-induced skeletal muscle wasting

A Bacterial Effector Targets Mad2L2, an APC Inhibitor, to Modulate Host Cell Cycling

SummaryThe gut epithelium self-renews every several days, providing an important innate defense system that limits bacterial colonization. Nevertheless, many bacterial pathogens, including Shigella, efficiently colonize the intestinal epithelium. Here, we show that the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2, an anaphase-promoting complex/cyclosome (APC) inhibitor. Cyclin B1 ubiquitination assays revealed that APC undergoes unscheduled activation due to IpaB interaction with the APC inhibitor Mad2L2. Synchronized HeLa cells infected with Shigella failed to accumulate Cyclin B1, Cdc20, and Plk1, causing cell-cycle arrest at the G2/M phase in an IpaB/Mad2L2-dependent manner. IpaB/Mad2L2-dependent cell-cycle arrest by Shigella infection was also demonstrated in rabbit intestinal crypt progenitors, and the IpaB-mediated arrest contributed to efficient colonization of the host cells. These results strongly indicate that Shigella employ special tactics to influence epithelial renewal in order to promote bacterial colonization of intestinal epithelium

Evodiamine Inhibits Insulin-Stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/Diabetic Mice

Evodiamine, an alkaloid extracted from the dried unripe fruit of the tree Evodia rutaecarpa Bentham (Rutaceae), reduces obesity and insulin resistance in obese/diabetic mice; however, the mechanism underlying the effect of evodiamine on insulin resistance is unknown. This study investigated the effect of evodiamine on signal transduction relating to insulin resistance using obese/diabetic KK-Ay mice and an in vitro adipocyte culture. There is a significant decrease in the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (S6K) signaling in white adipose tissue (WAT) in KK-Ay mice treated with evodiamine, in which glucose tolerance is improved. In addition, reduction of insulin receptor substrate 1 (IRS1) serine phosphorylation, an indicator of insulin resistance, was detected in their WAT, suggesting suppression of the negative feedback loop from S6K to IRS1. As well as the stimulation of IRS1 and Akt serine phosphorylation, insulin-stimulated phosphorylation of mTOR and S6K is time-dependent in 3T3-L1 adipocytes, whereas evodiamine does not affect their phosphorylation except for an inhibitory effect on mTOR phosphorylation. Moreover, evodiamine inhibits the insulin-stimulated phosphorylation of mTOR and S6K, leading to down-regulation of IRS1 serine phosphorylation in the adipocytes. Evodiamine also stimulates phosphorylation of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, which may cause down-regulation of mTOR signaling in adipocytes. A similar effect on AMPK, mTOR and IRS1 phosphorylation was found in adipocytes treated with rosiglitazone. These results suggest evodiamine improves glucose tolerance and prevents the progress of insulin resistance associated with obese/diabetic states, at least in part, through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes

Sepsis Induces Physical and Mental Impairments in a Mouse Model of Post-Intensive Care Syndrome

Post-intensive care syndrome (PICS) is a physical, cognitive, and mental impairment observed in intensive care unit (ICU) survivors. Although this is an emerging problem in the ICU, how sepsis induces the characteristic symptoms of PICS remains unclear. To develop a model of PICS, we induced sepsis in male C57/B6 mice via sublethal cecum slurry injection and subsequently treated them using ICU-like interventions. At 1-2 weeks post-sepsis induction, we simultaneously evaluated the abilities of the surviving mice using the following behavioral tests: (1) a grip strength test (GST) and a treadmill test for physical assessment, (2) a novel object recognition test (NORT) for cognitive assessment, and (3) an open field test (OFT) and a marble burying test (MBT) for mental assessment. The surviving mice showed a range of deficits, including muscle weakness with significantly decreased grip strength in the GST; decreased total mileage during the treadmill test; anxiety and decreased activity, with significantly decreased time in the central area, and increased duration of immobility in the OFT; and an increased number of buried marbles in the MBT. Given these physical and mental impairments in the surviving mice, our model has the potential to elucidate mechanistic insights and to discover therapeutic targets and new interventions for PICS

Repetitive abdominal pain in a reproductive‐aged woman

Key Clinical Message We report a young woman with ileocecal endometriosis who presented with repeated abdominal pain. Under hormonal effects, the endometrium may proliferate and cause bleeding in the bowel wall, leading to cyclical abdominal pain. When recurring abdominal pain is observed in reproductive‐aged women, physicians should always be aware of gastrointestinal endometriosis