Age and period of ventilator use are related to walking independence at the time of discharge in patients with severe COVID-19 pneumonia: a single-center retrospective observational study.

[Purpose] This study aimed to identify the factors and cutoffs associated with walking independence in patients with severe COVID-19 pneumonia. [Participants and Methods] In total, 112 patients with COVID-19 pneumonia (98 males and 14 females) who were hospitalized between March 2020 and August 2021 and underwent physiotherapy during mechanical ventilation were included in the study. Attributes, respiratory function, physical function, and bed-withdrawal status were compared between two groups of patients, who were classified according to their ability to walk independently at discharge. The independent variables were reduced to four components by principal component analysis. Logistic regression analysis was performed with walking independence at discharge as the dependent variable. Receiver operating characteristic curves for the extracted factors were drawn, and cutoff values were calculated. [Results] At discharge, 76 patients were able to walk independently, while 36 were not. The logistic regression analysis was adjusted according to age and mechanical ventilation time. Cutoffs were an age of 56 years and a ventilation period of 7.5 days. [Conclusion] In cases of patients with severe COVID-19 pneumonia who required ventilators, age and mechanical ventilation time were associated with ambulatory independence at discharge, indicating the importance of reducing the ventilation period by providing respiratory physiotherapy, including expectoration, positioning, and weaning.

Targeting all transforming growth factor-ß isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-ß (TGF-ß) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-ß comprises three isoforms, TGF-ß1, -ß2, and -ß3, and transduces intracellular signals via TGF-ß type I receptor (TßRI) and TGF-ß type II receptor (TßRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TßRII (TßRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-ß ligands, but several lines of evidence indicate that TßRII-Fc more effectively traps TGF-ß1 and TGF-ß3 than TGF-ß2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-ß receptor containing both TßRI and TßRII (TßRI-TßRII-Fc) and found that TßRI-TßRII-Fc trapped all TGF-ß isoforms, leading to inhibition of both the TGF-ß signal and TGF-ß-induced EMT of oral cancer cells, whereas TßRII-Fc failed to trap TGF-ß2. Furthermore, we found that TßRI-TßRII-Fc suppresses tumor growth and angiogenesis more effectively than TßRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-ß expression. These results suggest that TßRI-TßRII-Fc may be a promising tool for targeting all TGF-ß isoforms in the TME.

Hyperechoic and Low Morphological Changes in the Prefemoral Fat Pad in Individuals with Knee Osteoarthritis Based on Ultrasonographic Findings.

BACKGROUND: To clarify the changes in the echo intensity (EI) in the prefemoral fat pad (PFP) and identify the relationship between the PFP and clinical features of knee osteoarthritis (OA). METHODS: Twenty-six women with knee OA (mean age: 76 years) and 17 healthy women (mean age: 73 years) were enrolled. The Kellgren and Lawrence grading scale was used for the radiographic evaluation of knee OA. The EI of the PFP was measured as grayscale values. The change ratio of the anteroposterior PFP length during quadriceps contraction was measured. Knee range of motion and pain (100-mm visual analog scale) were evaluated. RESULTS: The EI was significantly higher in the OA group than in the healthy group (P < 0.001). The change ratio of the PFP in the OA group was significantly lower than that in the healthy group (P < 0.001). The ranges of knee flexion and extension were correlated with the EI of the PFP (both P < 0.01) and the change ratio of the PFP (both P < 0.01). There was no significant correlation observed with knee pain. CONCLUSION: Hyperechoic changes and a decreased change ratio of the PFP were observed in the patients with knee OA. High EI and decreased morphological PFP changes were associated with decreased ranges of motion.

The association between systemic inflammation and the time spent in posture and movement during daytime in patients with chronic obstructive pulmonary disease and lower weight.

[Purpose] The effect of physical activity on systemic inflammation remains unclear and might be negative in patients with chronic obstructive pulmonary disease (COPD) and lower weight. We investigated the amount of physical activity as the time spent in posture and movement and its association with systemic inflammation. [Participants and Methods] In this retrospective cross-sectional pilot study, we evaluated 11 patients with COPD (age, 73 ± 7 years; body mass index, 18.9 ± 2.9 kg/m2). A recently developed triaxial accelerometer was used to measure the time spent in posture and movement. We also evaluated body composition, physiological indexes, and serum levels of inflammatory cytokines. Single correlation coefficients were calculated as the association between physical activity and other outcomes. [Results] The walking time was 36 ± 32 min/d, and the standing time was 151 ± 118 min/d. The time spent walking significantly correlated with the fat-free mass index (r=0.73) and interleukin (IL)-8 level (r=0.76). The time spent standing significantly correlated with the C-reactive protein (r=0.80) and IL-6 levels (r=0.74). [Conclusion] These data indicate that increased physical activity is associated with higher systematic inflammation. We should consider that the systemic inflammation may have been affected by the increased physical activity of the patients with COPD and lower weight in this study.

Ultrasonographic Morphological Changes in the Prefemoral Fat Pad Associated with Knee Osteoarthritis.

BACKGROUND: In normal knees, quadriceps contraction changes the shape of the prefemoral fat pad (PFP). However, in persons with knee osteoarthritis (OA), the functional or morphological changes of the PFP are unclear. This study aimed to clarify the morphological changes in the PFP in individuals with knee OA through ultrasonography. MATERIALS AND METHODS: Participants were divided into the OA (36 knees; mean age, 74 years), elderly (31 knees; mean age, 70 years), and young (26 knees; mean age, 21 years) groups. The anteroposterior (AP) length of the PFP before and during isometric quadriceps contraction at 0°, 30°, 60°, and 90° knee flexion was measured ultrasonographically. The difference between the maximum and minimum length values, change in length, was also measured. These parameters were compared among the three groups. In the OA group, correlations between the parameters and clinical features (knee pain; visual analog scale, knee range of motion [ROM], Kellgren and Lawrence (K/L) grade, and intercondylar distance) were examined by Spearman and Pearson's correlation coefficient tests. RESULTS: The AP lengths of the PFP before contraction were significantly lower in the OA group than in elderly group and young group at 30° (6.9 ± 2.5 vs. 12.0 ± 3.6 or 11.1 ± 2.7 mm, respectively; in order P = 0.014, P = 0.006) and 60° (6.5 ± 2.0 vs. 9.7 ± 2.5 or 9.1 ± 2.7 mm, respectively; both P < 0.001). The AP lengths of the PFP during contraction were significantly lower in the OA group than in elderly group and young group at 0° (6.7 ± 2.3 vs. 8.8 ± 3.7 or 9.1 ± 1.6 mm, respectively; both P < 0.001), 30° (7.9 ± 2.6 vs. 12.9 ± 3.7 or 13.0 ± 2.6 mm, respectively; both P < 0.001), and 60° (7.1 ± 2.5 vs. 13.5 ± 2.6 or 13.6 ± 3.0 mm, respectively; both P < 0.001). The change in length before maximum isometric quadriceps contraction was significantly lower in the knee OA group than in both elderly and young groups (3.3 ± 1.9 vs. 8.4 ± 2.5 or 6.8 ± 3.0 mm, respectively; both P < 0.001). The change in length during contraction was also significantly lower in the knee OA group than in both the elderly and young groups (3.9 ± 2.3 vs. 8.7 ± 2.3 or 8.9 ± 2.0 mm, respectively; both P < 0.001). In the OA group, change in length during contraction was significantly associated with knee pain (r = -0.476, P = 0.007), knee ROM (r = 0.388, P = 0.019), and Kellgren and Lawrence grade (r = -0.357, P = 0.045). CONCLUSIONS: In knee OA, movement of PFP was decreased more than healthy participants. In the knee OA group, the decrease of the morphological change of the PFP showed the relationship between VAS score, knee extension ROM, intercondylar distance (ICD), and K/L grade. An evaluation to the PFP may be required in individuals with knee OA.

Contractile capability of the diaphragm assessed by ultrasonography predicts nocturnal oxygen saturation in COPD.

BACKGROUND AND OBJECTIVE: Diaphragm function might be useful to predict nocturnal oxygen desaturation in COPD. Ultrasonography has been widely used for the assessment of the diaphragm. We aimed to investigate the relationship between the contractile capability of the diaphragm assessed by ultrasonography and the nocturnal percutaneous arterial oxygen saturation (NSpO2 ) in COPD. METHODS: Twenty-eight male patients with COPD (age, 73 ± 7 years; forced expiratory volume in 1 s (FEV1 ), 54.2 ± 17.0% predicted) were included. The thickness of the diaphragm (Tdi) was assessed by ultrasonography. We calculated the change ratio of Tdi at the end of maximal inspiration and expiration (%ΔTdi). The mean value of NSpO2 (NSpO2mean ), the percentage of total sleep time (TST) with desaturation above 4% (DA4%) and the percentage of TST with saturation below 90% (SB90%) were measured by overnight oximetry. Daytime arterial oxygen pressure (PaO2 ) and maximal inspiratory mouth pressure (PImax ) were also measured. RESULTS: All participants had mild or no daytime hypoxaemia (PaO2 , 77.3 ± 8.6 mm Hg). The NSpO2mean , DA4% and SB90% were significantly correlated with %ΔTdi, PaO2 , %PImax of the predicted value and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. The %ΔTdi and PaO2 were predictors of NSpO2 mean by multiple regression analysis. CONCLUSION: This study suggested a close relationship between the NSpO2 and the contractile capability of the diaphragm assessed by ultrasonography in COPD. The %ΔTdi combined with PaO2 might predict NSpO2 in COPD patients with mild or no daytime hypoxaemia.

Estrous cycle stage-dependent manner of type I interferon-stimulated genes induction in the bovine endometrium.

Interferon tau (IFN-τ) is a ruminant-specific type I IFN secreted by a conceptus before its attachment to the uterus. IFN-τ induces the expression of IFN-stimulated genes (ISGs) via the type I IFN receptor (IFNAR), which is composed of IFNAR1 and IFNAR2 subunits in the endometrium. However, expression patterns of IFNARs during the estrous cycle have not been reported. We hypothesized that the response to a type I IFN changes along with IFNARs and the IFN-regulatory factors (IRFs) driving transcription of IFN signal-related genes and modulating a type I IFN signal during the estrous cycle. We investigated the estrous cycle stage-dependent type I IFN induction of ISGs and expression patterns of IFN signal-related genes in bovine endometrial tissues. Endometrial tissue pieces collected from bovine uteri at each estrous stage (early, mid, and late) were cultured with or without recombinant bovine IFN-α or concentrated pregnant uterine flushing (PUF) on day 18 after confirming the presence of a conceptus. IFN-α and PUF each significantly increased the expression of ISGs in endometrial tissues. The induction levels of the typical ISGs (MX1-a and ISG15) were significantly higher at the mid stage and correlated with high expression of IRFs at the mid stage. The immunostaining of IFNARs showed strong fluorescence intensities in luminal and glandular epithelia at the early and mid stages. Collectively, these results suggest that the endometrium exhibits estrous cycle stage-dependent responsiveness to type I IFN that may be associated with the expression of IFNARs and IRFs for pregnancy recognition.

Ruptured breast implant removal because of patient anxiety in the absence of breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has been regarded as a long-term problem after silicone breast implantations. We report a case in which BIA-ALCL and breast cancer were not detected preoperatively, with subsequent removal of a ruptured breast implant. A 52-year-old woman had silicone breast implants on both sides for breast augmentation 15 years ago. Right axillary lymphadenopathy and intracapsular ruptures were noted by magnetic resonance imaging. Right axillary lymph node biopsy was performed at our department of breast surgery. Flow cytometry for BIA-ALCL was also performed using the exudate around the implant. The results were negative for breast cancer and BIA-ALCL. However, taking into consideration exacerbation of breast implant rupture and the patient's anxiety about BIA-ALCL, ruptured bilateral implants were removed by total capsulectomy. The postoperative course was uneventful 1 year after the operation, and her anxiety was dispelled despite her breast deformity. Appropriate explantation and periodic examination may be required to prevent excessive anxiety.

Objective physical activity level is associated with rectus femoris muscle echo-intensity in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Skeletal muscle dysfunction is one of the major extrapulmonary complications of chronic obstructive pulmonary disease (COPD). Some studies have reported a relationship between physical activity (PA) level and skeletal muscle quality assessed by echo-intensity (EI) in healthy individuals but not in patients with COPD. OBJECTIVES: The aim of this study is to investigate the relationships between PA level and both skeletal muscle EI and skeletal muscle mass in patients with COPD. METHODS: We employed a cross-sectional design. Forty male outpatients with stable COPD were enrolled. Using B-mode ultrasonography, we measured the rectus femoris muscle cross-sectional area (RF-CSA) and EI (RF-EI). The RF-CSA and RF-EI were measured on frozen images using an electronic caliper and 8-bit gray-scale analysis, respectively. The objective PA level was determined by monitoring daily step counts and moderate-to-vigorous physical activity time (MVPA) with an activity monitor. A general regression model was used to assess the relationships between PA level and both RF-CSA and RF-EI. Age and body mass index (BMI) were adopted as confounding variables. RESULTS: Twenty-five outpatients with stable COPD (age, 70 ± 7 years old; forced expiratory volume in 1 s, 55.0 ± 24.9% of predicted values) were finally enrolled in the present study. Even after adjusting for age and BMI, the daily step counts and MVPA were significantly associated with RF-EI, and knee extensor force was associated with RF-CSA. CONCLUSION: The present study showed that PA level was associated with RF-EI in patients with COPD. In addition, RF-CSA was associated with knee extensor force. When assessing skeletal muscle using ultrasonography in patients with COPD, we should also assess EI.

Prediction of Low-intensity Physical Activity in Stable Patients with Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To develop an equation of the predicted amount of low-intensity physical activity (LPA) by analyzing clinical parameters in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this cross-sectional study, we analyzed the assessments of clinical parameters evaluated every 6 months from the start of pulmonary rehabilitation in 53 outpatients with stable COPD (age 77 ± 6 yrs; 46 men; body mass index 21.8 ± 4.1 kg/m2; forced expiratory volume in one second 63.0 ± 26.4% pred). An uniaxial accelerometer was used to measure the number of steps and the time spent in LPA of 1.8-2.3 metabolic equivalents during 14 consecutive days. We also evaluated body composition, respiratory function, skeletal muscle strength, inspiratory muscle strength, exercise capacity, and gait speed. Factors associated with the time spent in LPA were examined by multivariate regression analysis. Internal validity between the predicted amount of LPA obtained by the equation and the measured amount was examined by regression analysis. RESULTS: Multivariate regression analysis revealed that gait speed (ß = 0.369, p = 0.007) and maximum inspiratory mouth pressure (PImax) (ß = 0.329, p = 0.016) were significant influence factors on LPA (R2 = 0.354, p <0.001). The stepwise regression analysis showed a moderate correlation between the measured amount and predicted amount of LPA calculated by the regression equation (r = 0.609, p <0.001; LPA = 31.909 × gait speed + 0.202 × PImax - 20.553). CONCLUSION: Gait speed and PImax were extracted as influence factors on LPA, suggesting that the regression equation could predict the amount of LPA.

The localization of phototropin to the plasma membrane defines a cold-sensing compartment in Marchantia polymorpha.

Plant cells perceive cold temperatures and initiate cellular responses to protect themselves against cold stress, but which cellular compartment mediates cold sensing has been unknown. Chloroplasts change their position in response to cold to optimize photosynthesis in plants in a process triggered by the blue-light photoreceptor phototropin (phot), which thus acts as a cold-sensing molecule. However, phot in plant cells is present in multiple cellular compartments, including the plasma membrane (PM), cytosol, Golgi apparatus, and chloroplast periphery, making it unclear where phot perceives cold and activates this cold-avoidance response. Here, we produced genetically encoded and modified variants of phot that localize only to the cytosol or the PM and determined that only PM-associated phot-induced cold avoidance in the liverwort Marchantia polymorpha. These results indicate that the phot localized to the PM constitutes a cellular compartment for cold sensing in plants.

Culture-based preservation of Marchantia polymorpha gemmalings and thalli without encapsulation, drying, or freezing.

Ongoing research has generated many important lines of the model liverwort Marchantia polymorpha, including mutants and transgenic lines. To maintain these lines, researchers typically spend a lot of time and effort periodically replanting thalli (e.g., every month). To avoid this routine maintenance, researchers have developed methods for cryopreservation of dried and frozen gemmae. In this study, we developed a culture-based method for preserving gemmalings and thalli without encapsulation, drying, or freezing. The method requires only tissue culture on agar medium supplemented with sucrose in the dark at regular temperature (22°C). These culture conditions severely inhibit growth of gemmalings and thalli; however, these tissues remained alive after more than 1 year of storage. Survival rate of tissues using this method was 100% in all tests. This method thus enables preservation of gemmaling and thallus cultures on medium under regular temperature conditions, thereby relieving researchers of labor-intensive routine maintenance.

Functionally relevant threshold of inspiratory muscle strength in patients with chronic obstructive pulmonary disease.

OBJECTIVES: We aimed to identify the inspiratory muscle strength thresholds below which exercise capacity is compromised in men with chronic obstructive pulmonary disease (COPD). METHODS: We measured the maximum static inspiratory mouth pressure (PImax) and the percentage of predicted values (%PImax) in 113 patients with COPD. Six-minute walk distance (6-MWD) was measured as an indicator of functional exercise capacity, and a 6-MWD of <350 m was defined as functional exercise intolerance. Thresholds were determined as values with high specificity (>0.90) and maximal sensitivity. Statistical significance was set at P < 0.01. RESULTS: The data of 96 patients (74 ± 6 years old; forced expiratory volume in 1-s [FEV1], 56.5 ± 26.2% predicted) were analyzed; three women and 14 participants with missing data were excluded. Multivariate logistic regression models identified significant associations of PImax (odds ratio at 99% confidence interval [CI]: 0.95 [0.92-0.98]) and %PImax (odds ratio at 99% CI: 0.97 [0.95-0.99]) with 6-MWD, after adjustments for height and FEV1. C-statistics showed that the area under the curves (99% CI) of PImax and %PImax were comparable (0.87 [0.77-0.96] and 0.83 [0.72-0.94]). The thresholds of PImax and %PImax were 45.1 cmH2O and 66%; PImax and %PImax also had moderate positive likelihood ratios of 4.44 and 5.00. CONCLUSIONS: Thresholds of inspiratory muscle strength in men with COPD could help clinicians evaluate whether their patient's inspiratory muscle strength is inadequate to achieve a 6-MWD of ≥350 m, and identify patients who should be targeted for inspiratory muscle training.

Estimation of minimal clinically important difference for quadriceps and inspiratory muscle strength in older outpatients with chronic obstructive pulmonary disease: a prospective cohort study.

OBJECTIVE: To estimate the minimal clinically important difference (MCID) of quadriceps and inspiratory muscle strength after a home-based pulmonary rehabilitation program (PRP) in chronic obstructive pulmonary disease (COPD). METHOD: Eighty-five COPD patients were included. Quadriceps maximal voluntary contraction (QMVC) was measured. We measured maximal inspiratory mouth pressure (PImax), the 6-minute walk distance (6MWD), the chronic respiratory questionnaire (CRQ) and the modified Medical Research Council dyspnoea score (mMRC). All measurements were conducted at baseline and at the end of the PRP. The MCID was calculated using anchor-based (using 6MWD, CRQ, and mMRC as possible anchor variables) and distribution-based (half standard deviation and 1.96 standard error of measurement) approaches. Changes in the five variables were compared in patients with and without changes in QMVC or PImax >MCID for each variable. RESULTS: Sixty-nine COPD patients (age 75±6 years) were analysed. QMVC improved by 2.4 (95%CI 1.1-3.7) kgf, PImax by 5.8 (2.7-8.8) cmH2O, 6MWD by 21 (11-32) meters and CRQ by 3.9 (1.6-6.3) points. The MCID of QMVC and PImax was 3.3-7.5 kgf and 17.2-17.6 cmH2O, respectively. The MCID of QMVC (3.3 kgf) could differentiate individuals with significant improvement in 6MWD and PImax from those without. CONCLUSION: The MCID of QMVC (3.3 kgf) can identify a meaningful change in quadriceps muscle strength after a PRP. The MCID of PImax (17.2 cmH2O) should be used with careful consideration, because the value is estimated using distributionbased method.

Functionally Relevant Threshold of Quadriceps Muscle Strength in Patients with Chronic Obstructive Pulmonary Disease.

OBJECTIVES: We aimed to identify the quadriceps muscle strength (QMS) thresholds below which exercise capacity is compromised in men with chronic obstructive pulmonary disease (COPD). METHODS: We measured the quadriceps isometric maximum voluntary contraction (QMVC) and calculated the QMVC values normalized to weight (QMVC-BW), height squared (QMVC-H2), and body mass index (QMVC-BMI) in 113 patients with COPD. The functional exercise capacity was evaluated using the 6-minute walk distance (6MWD), and 6MWD <350 m was defined as functional exercise intolerance. Thresholds were determined for QMVC and its normalized values to achieve high specificity (>0.90) with maximal sensitivity. P-values <0.01 were considered statistically significant. RESULTS: Data from 99 male patients (age, 74 ± 6 years; percentages of predicted forced expiratory volume in 1-s, 56.9 ± 26.4%) were analyzed; 3 women and 11 participants with the missing data were excluded. Multivariate logistic regression models identified significant associations of QMVC and QMVC-H2 with 6MWD, after adjustment for age and dyspnea. C-statistics showed that the area under the curves of all QMVC parameters were comparable. The thresholds of QMVC and QMVC-H2 for predicting compromised exercise capacity were 26.2 kg and 9.6 kg/m2, respectively. CONCLUSIONS: QMS thresholds in men with COPD could help clinicians evaluate whether QMS is insufficient to achieve 6MWD ≥350 m and thereby identify patients who should be specifically targeted for muscle strengthening training during their pulmonary rehabilitation program.

Progression of melanoma is suppressed by targeting all transforming growth factor­ß isoforms with an Fc chimeric receptor.

Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor­ß (TGF­ß) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial­mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF­ß isoforms, TGF­ß1, TGF­ß2 and TGF­ß3, all of which engage in pro­tumorigenic activities by activating SMAD signaling pathways. All TGF­ß isoforms activate signaling pathways by binding to their TGF­ß type I (TßRI) and type II (TßRII) receptors. Thus, effective targeting of all TGF­ß isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TßRI and/or TßRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TßRI and TßRII (TßRI­TßRII­Fc) effectively trapped all TGF­ß isoforms. Conversely, TßRII­Fc chimeric receptor, that comprises TßRII only, was able to interact with TGF­ß1 and TGF­ß3 isoforms, but not with TGF­ß2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TßRI­TßRII­Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF­ß isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TßRII­Fc chimeric receptor inhibited the EMT program induced by TGF­ß1 and TGF­ß3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TßRI­TßRII­Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF­ß signals that affect various components of the TME may result in the development of effective anti­melanoma agents.

Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan.

BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

Familial clustering and genetic background of primary biliary cirrhosis in Japan.

BACKGROUND: Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease. AIMS: To elucidate the genetic background of PBC by investigating familial cases of PBC. METHODS: Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases. RESULTS: Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC. CONCLUSIONS: Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment.

Simple swallowing provocation test has limited applicability as a screening tool for detecting aspiration, silent aspiration, or penetration.

A number of tests for evaluating dysphagia without using videofluoroscopic examination of swallowing (VF) or videoendoscopic evaluation of swallowing (VE) have been developed. The simple swallowing provocation test (SSPT) is unique because it is performed while in a supine position and does not require the patient's cooperation. However, whether the SSPT detects aspiration or penetration correctly is unclear because its validity determined by VF or VE has not been evaluated. Therefore, we determined the sensitivity, specificity, and predictive accuracy of SSPT followed by VF in 45 patients. The sensitivities of the first-step and the second-step SSPT for the detection of aspiration, silent aspiration, or penetration were 72-75% and 13-17%, respectively; the specificities of the first-step and the second-step SSPT were 38-44% and 80-89%, respectively; and the predictive accuracies of the first-step and the second-step SSPT were 58-67% and 31-49%, respectively. These data suggest that SSPT has limited applicability as a screening tool for aspiration, silent aspiration, or penetration because of its low sensitivity. This test may be useful for patients who cannot undergo other tests due to cognitive and/or linguistic dysfunction.

CRUNC: a cryopreservation method for unencapsulated gemmae of Marchantia polymorpha.

Genetic modifications such as mutation and transformation are powerful tools to study the function of genes and proteins in the model liverwort Marchantia polymorpha, but maintaining the resulting germplasm requires a practical, reliable method. Cryopreservation methods allow researchers to maintain mutant and transgenic lines of M. polymorpha. To date, two methods have been developed for cryopreservation of M. polymorpha gemmae: in the first method, unencapsulated gemmae are stored in liquid nitrogen at --196 °C, and in the second method, encapsulated gemmae are stored in liquid nitrogen at --196 °C or a deep freezer at -80 °C. In the present study, we developed a simple method named CRUNC (cr yopreservation of un en c apsulated gemmae), which can be used to store unencapsulated, dried gemmae of wild-type and transgenic M. polymorpha lines in liquid nitrogen and in freezers at -80 °C and -20 °C. Using the CRUNC method, we observed a high recovery rate (as high as 100%) and successful long-term (5 months) storage of the gemmae. Therefore, the CRUNC method is practical for maintaining valuable M. polymorpha germplasm.