Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19.

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.

Involvement of Peptidoglycan Receptor Proteins in Mediating the Growth-Promoting Effects of Bacillus pumilus TUAT1 in Arabidopsis thaliana.

Bacillus pumilus TUAT1 acts as plant growth-promoting rhizobacteria for various plants like rice and Arabidopsis. Under stress conditions, B. pumilus TUAT1 forms spores with a thick peptidoglycan (PGN) cell wall. Previous research showed that spores were significantly more effective than vegetative cells in enhancing plant growth. In Arabidopsis, lysin motif proteins, LYM1, LYM3 and CERK1, are required for recognizing bacterial PGNs to mediate immunity. Here, we examined the involvement of PGN receptor proteins in the plant growth promotion (PGP) effects of B. pumilus TUAT1 using Arabidopsis mutants defective in PGN receptors. Root growth of wild-type (WT), cerk1-1, lym1-1 and lym1-2 mutant plants was significantly increased by TUAT1 inoculation, but this was not the case for lym3-1 and lym3-2 mutant plants. RNA-seq analysis revealed that the expression of a number of defense-related genes was upregulated in lym3 mutant plants. These results suggested that B. pumilus TUAT1 may act to reduce the defense response, which is dependent on a functional LYM3. The expression of the defense-responsive gene, WRKY29, was significantly induced by the elicitor flg-22, in both WT and lym3 mutant plants, while this induction was significantly reduced by treatment with B. pumilus TUAT1 and PGNs in WT, but not in lym3 mutant plants. These findings suggest that the PGNs of B. pumilus TUAT1 may be recognized by the LYM3 receptor protein, suppressing the defense response, which results in plant growth promotion in a trade-off between defense and growth.

Low-temperature Ruby Crystal Growth Via a Supersaturation Process Based on Flux Decomposition.

Crystal growth methods that do not require high temperatures are highly needed for the facile growth of oxide single crystals with melting points of several thousand degrees Celsius. This paper represents the first report of a method for the low-temperature growth of ruby crystals (chromium-doped Al2O3) at 750 °C, which is one-third of the conventionally required temperature (2050 °C). In solution-based crystal growth, the target crystal is grown at a temperature considerably lower than its melting point. However, conventional crystal growth processes involving solvent evaporation and cooling require high temperatures to completely liquefy the material, with previously reported solution growth temperatures of ≈1100 °C. Supersaturation based on the decomposition of crystal-solvent intermediates eliminates the need to completely liquefy the material, enabling low-temperature crystal growth. The combination of computational and experimental investigations helps determine the optimum conditions for low-temperature crystal growth. The proposed method is a novel green process that breaks the conventional frontiers of crystal growth while ensuring eco-friendliness and low energy consumption. In addition, its scope can potentially be expanded to the synthesis of various crystals and direct growth on substrates with low melting points.

Factors associated with improved health-related quality of life due to improvements in physical function and dialysis-related symptoms following intradialytic exercise in outpatients undergoing haemodialysis.

PURPOSE: Exercise therapy is a crucial intervention for improving health-related quality of life (HRQOL) in patients undergoing haemodialysis. However, factors that improve HRQOL by improving physical function and dialysis-related symptoms remain unknown. This study aimed to examine the physical function parameters and dialysis-related symptoms that improve HRQOL following intradialytic exercise. METHODS: This multicentre cohort study included 596 patients who participated in an intradialytic exercise program three times per week for a period of 6 months, which comprised of stretching and resistance training. EuroQol 5 dimensions 5-level (EQ5D-5L), grip strength, isometric knee extension strength, 10-m walking speed, Short Physical Performance Battery (SPPB), and improvement in dialysis-related symptoms were measured at the baseline and post-intervention. A linear mixed model was used to analyse the effects of improved physical function and dialysis-related symptoms on improvements in EQ5D-5L. RESULTS: As a physical function index affecting ΔEQ5D-5L, only SPPB showed a significant increase in ΔEQ5D-5L compared with the non-improved group [difference in ΔEQ5D-5L, 0.05 (0.004 to 0.092) point; p < 0.05]). In addition, dialysis-related symptoms with Improved physical conditions [difference in ΔEQ5D-5L, 0.07 (0.02 to 0.13) point] and an Extended walking distance [difference in ΔEQ5D-5L was 0.07 (0.01 to 0.12) point] significantly influenced ΔEQ5D-5L (p < 0.05, both). CONCLUSIONS: The improvements observed in the SPPB scores and self-percieved physical fitness and ambulation range, attributable to intradialytic exercise, may potentially improve HRQOL.

Predicting residual pressure gradients after balloon angioplasty in patients with femoropopliteal artery lesions.

In endovascular therapy (EVT) for femoropopliteal artery (FPA) lesions, studies examining the relationship between lesion morphology and hemodynamic status are limited. The purpose of this study was to investigate FPA lesion characteristics, including imaging findings and their cutoff values that can predict hemodynamic significance after balloon angioplasty. This single-center retrospective study enrolled 50 de novo FPA lesions from 43 patients treated under intravascular ultrasound (IVUS) usage between June 2022 and March 2023. As a physiological parameter, the pressure gradient was measured, and the cutoff value of the residual pressure gradient (RPG) was defined as a systolic pressure > 10 mmHg through the lesions after balloon angioplasty. The pressure gradients were measured using a 0.014-inch wire-guided, rapid exchange-type microcatheter, Navvus II (Acist, Eden Prairie, Minnesota, USA). Predictive risk factors for RPG were analyzed using the random forest (RF) method. The relationship between the variables, RPG, and the cutoff points of each predictor was assessed using the partial dependence plot (PDP) method. RPG was observed in 20% of the lesions after balloon angioplasty. The RF model revealed that the percent diameter stenosis (%DS) and minimum lumen area (MLA) on IVUS assessment were strong predictive factors for RPG after balloon angioplasty. The PDP model revealed that a higher %DS (cutoff 30%) and smaller MLA (cutoff 10 mm2) could predict RPG after balloon angioplasty. Conventional lesion parameters such as %DS and MLA can predict hemodynamic significance during EVT for FPA lesions.

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

Comparison of transposition and interposition methods in microvascular decompression for hemifacial spasm: an analysis of 109 cases performed by a single surgeon in a single-center retrospective study.

BACKGROUND: Microvascular decompression (MVD), the standard surgical approach for hemifacial spasm (HFS), can be divided into the interposition and transposition methods. Although the risk of HFS recurrence following interposition has been reported, there is limited data comparing long-term outcomes between both methods performed by a single surgeon. This study aimed to investigate the efficacy of MVD techniques on HFS by comparing surgical outcomes performed by a single surgeon in a single-center setting. METHODS: A total of 109 patients who underwent MVD were analyzed and divided into the transposition (86 patients) and interposition (23 patients) groups. Postoperative outcomes at 1 month and 1 year were assessed and compared, including rates of spasm relief, complications, and recurrence. RESULTS: Outcome assessment revealed higher rates of early spasm relief in the interposition group (66.3% vs. 100%, transposition vs. interposition, respectively, p = 0.0004), although spasm relief at 1-year postoperatively was comparable between the two groups (84.9% vs. 95.7%, transposition vs. interposition, respectively, p = 0.2929). No significant differences were observed in complication and recurrence rates. Kaplan-Meier analysis demonstrated no significant differences in the duration of spasm resolution by MVD method (p = 0.4347, log-rank test). CONCLUSION: This study shows that both the transposition (Surgicel® and fibrin glue) and interposition (sponge) methods were excellent surgical techniques. The interposition method may achieve earlier spasm resolution compared to the transposition method.

Radiographic and clinical comparisons between loose-fit and press-fit stems in monopolar radial head arthroplasty for comminuted radial head fractures.

PURPOSE: Few clinical studies have compared the operative outcomes between loose- and press-fit stems in radial head arthroplasty (RHA). We aimed to evaluate the radiographic and clinical results of the two radial head implant concepts. METHODS: In this retrospective multicenter study, 32 patients (24 women and 8 men) with a mean age of 63.1 years who underwent RHA for comminuted radial head fractures were reviewed between 2005 and 2021. Seventeen patients underwent RHA with a loose-fit stem (L-group), whereas the remaining fifteen patients underwent RHA with a press-fit stem (P-group). The mean follow-up period was 40.1 ± 9.9 months, with the minimum follow-up duration of 12 months. The radiographic findings were evaluated for periprosthetic osteolysis; furthermore, clinical outcomes were analyzed to measure the range of motion of the elbow. The rate of reoperations and prosthesis removal were also reviewed. RESULTS: The general characteristics of the patients were similar in the two groups. The rate of periprosthetic osteolysis was 17.6% in the L-group, whereas it was 53.3% in the P-group. The mean elbow flexions were 128° and 133° in the L- and P-groups, respectively. The mean elbow extensions were -12° and -9° in the L- and P-groups, respectively. The rate of reoperation was 23.5% in the L-group and 15.2% in the P-group. One patient in the L-group had the prosthesis removed because of surgical site infection, whereas one patient in the P-group had the prosthesis removed owing to painful loosening. CONCLUSIONS: No significant differences in the clinical outcomes and reoperation rate were observed between the two radial head implant concepts in this study. However, osteolysis occurred more frequently in the P-group. Although patients with periprosthetic osteolysis are currently asymptomatic, they should be carefully followed up for the symptoms in the long term.

Genetic analysis of chlorophyll synthesis and degradation regulated by BALANCE of CHLOROPHYLL METABOLISM.

Chlorophyll (Chl) serves a number of essential functions, capturing and converting light energy as a component of photosystem supercomplexes. Chl degradation during leaf senescence is also required for adequate degeneration of chloroplasts and salvaging of nutrients from senescent leaves. In this study, we performed genetic analysis to determine the functions of BALANCE of CHLOROPHYLL METABOLISM1 (BCM1) and BCM2, which control Chl levels by regulating synthesis and degradation, and STAY-GREEN (SGR)1 (also known as NON-YELLOWING1 [NYE1]) and SGR2, which encode Mg-dechelatase and catalyze Chl a degradation in Arabidopsis (Arabidopsis thaliana). Analysis of bcm1 bcm2 revealed that both BCM1 and BCM2 are involved in the regulation of Chl levels in presenescent leaves and Chl degradation in senescing leaves. Analysis of bcm1 bcm2 nye1 nye2 suggested that BCMs repress Chl-degrading activity in both presenescent and senescing leaves by regulating SGR activity. Furthermore, transactivation analysis and chromatin immunoprecipitation (ChIP) assay revealed that GOLDEN2-LIKE1 (GLK1), a central transcription factor regulating the expression of genes encoding photosystem-related proteins, such as light-harvesting Chl a/b-binding proteins (LHCPs), directly regulates the transcription of BCM1. LHCPs are stabilized by Chl binding, suggesting that GLKs control the amount of LHCP through transcriptional and post-translational regulation via BCM-mediated Chl-level regulation. Meanwhile, we generated a mutant of the BCM ortholog in lettuce (Lactuca sativa) by genome editing and found that it showed an early yellowing phenotype, but only a slight reduction in Chl in presenescent leaves. Thus, this study revealed a conserved but slightly diversified regulation of Chl and LHCP levels via the GLK-BCM pathway in eudicots.

Long-term effects of primary aldosteronism treatment on patients with primary aldosteronism and chronic kidney disease.

OBJECTIVE: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood. DESIGN AND PATIENTS: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD　defined as eGFR < 60 ml/min/1.73 m2 . RESULTS: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was -20.1 ± 8.2 ml/min/1.73 m2 . Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was -9.2 ± 5.9 ml/min/1.73 m2 . Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities. CONCLUSIONS: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury.

Factors associated with dropout from an intradialytic exercise program among patients undergoing maintenance hemodialysis.

BACKGROUND: Continuation of an intradialytic exercise program is necessary to improve and maintain physical function in patients undergoing hemodialysis. Factors associated with dropout must be identified to ensure program continuation. This study aimed to investigate the dropout rates from an intradialytic exercise program at 6 and 12 months in patients undergoing hemodialysis and to identify dropout predictors. METHODS: This was a multicenter, retrospective observational study. Overall, 980 patients were enrolled in this study. Grip strength, 10-m walking speed, physical function, demographics and blood sampling data were measured at baseline, and dropouts were observed. Patients were classified as either continued or dropped out of the program at 6 and 12 months. The dropout rate was calculated for each time point. Multivariate logistic regression analysis was performed to identify the predictors of dropout. RESULTS: The dropout rate was 26.4% (n = 259) after 6 months, 24.1% (n = 172) between 6 and 12 months, and 44.3% (n = 424) overall at 1 year. Significant predictors of dropout after 6 months were slower 10-m walking speed, older age and high C-reactive protein level. Predictors of dropout after 12 months were slower 10-m walking speed and lower standardized dialysis volume. CONCLUSIONS: Walking capacity, age, inflammation and hemodialysis volume were determinants of dropout from the exercise program. Our findings provide new and important insights into the potential risk factors for dropout from long-term intradialytic exercise programs in patients undergoing hemodialysis.

Reduced antibody response to SARS-CoV-2 in COVID-19 patients with newly diagnosed diabetes: a retrospective observational study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has dramatically impacted global health, and patients with type 2 diabetes have been identified as a high-risk group for COVID-19 infection and the development of severe disease. In response, this study aimed to evaluate whether patients with type 2 diabetes infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could develop antibody responses in the same manner as patients without diabetes, and whether there is a difference in antibody response to SARS-CoV-2 between patients with diabetes diagnosed prior to hospitalization, and those with newly diagnosed diabetes. METHODS: SARS-CoV-2-specific immunoglobulin G (IgG) levels were quantified using two iFlash 3000 Chemiluminescence Immunoassay analyzer kits (Shenzhen YHLO Biotech Co., Ltd.) to detect IgG antibodies specific for nucleocapsid protein (IgG-N), and specific for the S1 subunit of the spike protein (IgG-S1). In 124 hospitalized patients with COVID-19, 40 patients with type 2 diabetes were matched to 40 patients without diabetes using propensity score matching (PSM). RESULTS: There was no difference in IgG-N and IgG-S1 levels between the patients with diabetes and those without. Of patients with diabetes, 31 patients had known diabetes and nine patients had newly diagnosed diabetes. The median levels of IgG-N at 7-13 days in patients with newly diagnosed diabetes were significantly lower than those in patients with known diabetes (IgG-N; 10.9 vs. 31.0 AU/mL, p = 0.031, IgG-S1; 7.5 vs. 24.4 AU/mL, p = 0.023). CONCLUSIONS: Even after adjusting for covariates using PSM, COVID-19 patients with type 2 diabetes had comparable antibody responses to patients without diabetes. Patients with newly diagnosed diabetes had lower IgG-N and IgG-S1 production in the second week of the disease compared with those with previously known diabetes.

Serum chemokine CC-motif ligand 17 is a predictive marker of severe COVID-19 in haemodialysis patients: A retrospective observational study.

BACKGROUND: Maintenance haemodialysis (HD) patients are at higher risk for severe coronavirus disease 2019 (COVID-19). Because of a limited number of facilities that can provide inpatient treatment for COVID-19 and HD, it is important to identify HD patients who are at high risk for severe COVID-19. For mild to moderate COVID-19 patients, chemokine CC-motif ligand 17 (CCL17) was reported to be a predictive marker for severe COVID-19; however, the validity of CCL17 among HD patients is unknown. METHODS: This retrospective observational study enrolled 107 HD patients with mild or moderate COVID-19 at hospitalization (mean age 70.1 ± 15.1 years; 71.0% male). Receiver operating characteristic and logistic regression analyses were used to examine the predictive validity of indices for severe COVID-19. RESULTS: During hospitalization, 32 patients developed severe COVID-19. Serum CCL17 collected at admission exhibited a higher area under the curve value (0.818) compared with that of other indicators including lactate dehydrogenase and C-reactive protein for the prediction of severe COVID-19. The optimal cut-off value for CCL17 was 150.5 pg/mL. A multi-variate logistic analysis revealed that CCL17 (above 150.5 pg/mL) was significantly associated with severe COVID-19 (Odds ratio, 0.063; 95% Confidence interval [CI], 0.017-0.227; p < .001) even after adjustment for covariates. The addition of the CCL17 to a model consisting of vaccination status, albumin, blood urea nitrogen, C-reacting protein and lactate dehydrogenase significantly improved classification performance for severe COVID-19 using the net reclassification (1.16, 95% CI: 0.82-1.50, p < .001) and integrated discrimination (0.18, 95% CI: 0.09-0.26, p < .001) improvement. CONCLUSION: CCL17 levels in HD patients with mild or moderate COVID-19 predict risk of developing severe COVID-19.

Influence of Malnutrition on the Improvement of Physical Function by Intradialytic Resistance Exercise in Patients Undergoing Hemodialysis.

OBJECTIVE: Intradialytic exercise improves physical function. However, malnutrition may be an essential factor affecting the effectiveness of exercise to improve physical function. Few studies of the relationship between malnutrition and the effectiveness of intradialytic exercise to improve physical function exist. Therefore, this study investigated malnutrition at the beginning of intradialytic exercise and how it affects the subsequent improvement in physical function. METHODS: Patients who performed intradialytic exercise for 12 months were enrolled in this study. A Geriatric Nutritional Risk Index of 91.2 was defined as malnutrition. Patients were assigned to 2 groups using propensity score matching to adjust for confounding factors. Physical function outcomes were handgrip strength, isometric knee extension strength, short physical performance battery, and 10-m walking speed; these were compared at baseline, 3 months, 6 months, and 12 months. The 2 groups were further divided into another 2 groups as per whether the nutritional status had improved after 12 months; therefore, a total of 4 groups were analyzed. RESULTS: After matching, the data of 154 patients in each group were analyzed. During the intragroup comparison, isometric knee extension strength, short physical performance battery, and 10-m walking speed improved significantly in both groups after intradialytic exercise was started compared with before intradialytic exercise was started. However, there was no significant improvement in handgrip strength in the malnutrition group. There were no significant differences in any of the physical function measurements or changes from the baseline values among the 4 groups divided as per subsequent recovery of the nutritional status. CONCLUSION: Malnutrition may not impact the effectiveness of intradialytic exercise to improve lower-leg physical function. Its effect on the improvement of handgrip strength requires further investigation.

The Role of Thermogenic Fat Tissue in Energy Consumption.

Mammalian adipose tissues are broadly divided into white adipose tissue (WAT) and thermogenic fat tissue (brown adipose tissue and beige adipose tissue). Uncoupling protein 1 (UCP1) is the central protein in thermogenesis, and cells that exhibit induced UCP1 expression and appear scattered throughout WAT are called beige adipocytes, and their induction in WAT is referred to as "beiging". Beige adipocytes can differentiate from preadipocytes or convert from mature adipocytes. UCP1 was thought to contribute to non-shivering thermogenesis; however, recent studies demonstrated the presence of UCP1-independent thermogenic mechanisms. There is evidence that thermogenic fat tissue contributes to systemic energy expenditure even in human beings. This review discusses the roles that thermogenic fat tissue plays in energy consumption and offers insight into the possibility and challenges associated with its application in the treatment of obesity and type 2 diabetes.

Comparison of clinical outcomes, including the wound healing rate, between inframalleolar bypass to the pedal artery and that to the pedal branch artery in the modern endovascular era.

OBJECTIVE: Inframalleolar (IM) bypass has been reported to demonstrate acceptable patency and limb salvage in patients with chronic limb-threatening ischemia. However, wound healing after IM bypass and comparisons between pedal artery (PA) bypass and pedal branch artery (PBA) bypass are lacking. METHODS: We reviewed prospectively collected data from 208 consecutive patients after IM bypass performed over a period of 6 years. Patients were divided into two groups based on the distal anastomotic artery: the PA group (dorsal pedis artery or common plantar artery) and the PBA group (medial tarsal, lateral tarsal, medial plantar, and lateral plantar artery). The primary outcome was wound healing, and secondary outcomes included loss of patency and limb and life prognosis. RESULTS: Of the 208 patients, 174 (74%) had PA bypass, whereas 34 (16%) had PBA bypass. Patients in the PBA group were significantly younger than those in the PA group (69 ± 7 vs 73 ± 9; P = .03). Although early (30-day) graft failure was more common in the PBA group, late clinical outcomes, including the wound healing rate (79% in the PA group and 84% in the PBA group; P = .74), were similar between the two groups. The Global Limb Anatomic Staging System IM grade (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.58-0.93; P = .006); wound, ischemia, and foot infection wound grade (HR, 0.67; 95% CI, 0.51-0.89; P < .01); and wound, ischemia, and foot infection foot infection grade (HR, 0.79; 95% CI, 0.65-0.96; P = .02) were independent predictors of wound healing. CONCLUSIONS: The current study revealed that wound healing in patients after PBA bypass was acceptable and comparable with that after PA bypass. In the modern era, including a high prevalence of infrapopliteal angioplasty, our results could provide useful information to clinicians in actual clinical settings. Moreover, PBA bypass may be an alternative revascularization procedure to avoid major amputation when the PA is occluded, such as in the global vascular guideline IM P2 grade. Prospective multicenter larger studies are warranted to confirm the findings of this study and to compare PBA bypass and IM endovascular treatment in patients with anatomical no-option chronic limb-threatening ischemia.

Wheat α-gliadin and high-molecular-weight glutenin subunit accumulate in different storage compartments of transgenic soybean seed.

Wheat seed storage proteins (prolamins) are important for the grain quality because they provide a characteristic texture to wheat flour products. In wheat endosperm cells, prolamins are transported from the Endoplasmic reticulum to Protein storage vacuoles through two distinct pathways-a conventional pathway passing through the Golgi apparatus and an unconventional Golgi-bypassing pathway during which prolamins accumulate in the ER lumen, forming Protein bodies. Unfortunately, transport studies conducted previously achieved limited success because of the seed-specificity of the latter pathway and the multigene architecture of prolamins. To overcome this difficulty, we expressed either of the two families of wheat prolamins, namely α-gliadin or High-molecular-weight subunit of glutenin, in soybean seed, which naturally lacks prolamin-like proteins. SDS-PAGE analysis indicated the successful expression of recombinant wheat prolamins in transgenic soybean seeds. Their accumulation states were quite different-α-gliadin accumulated with partial fragmentation whereas the HMW-glutenin subunit formed disulfide-crosslinked polymers without fragmentation. Immunoelectron microscopy of seed sections revealed that α-gliadin was transported to PSVs whereas HMW-glutenin was deposited in novel ER-derived compartments distinct from PSVs. Observation of a developmental stage of seed cells showed the involvement of post-Golgi Prevacuolar compartments in the transport of α-gliadin. In a similar stage of cells, deposits of HMW-glutenin surrounded by membranes studded with ribosomes were observed confirming the accumulation of this prolamin as ER-derived PBs. Subcellular fractionation analysis supported the electron microscopy observations. Our results should help in better understanding of molecular events during the transport of prolamins in wheat.

NMDA receptor signaling induces the chemoresistance of temozolomide via upregulation of MGMT expression in glioblastoma cells.

PURPOSE: The alkylating agent temozolomide (TMZ) has a significant impact on the prognosis of glioblastoma (GBM) patients. Therefore, maximizing TMZ efficacy is important for GBM treatment. Many reports have shown that glutamate signaling promotes GBM progression via glutamate receptors, including N-methyl-D-aspartate receptors (NMDARs). Although NMDARs promote cell migration and invasion of GBM cells, their role in TMZ resistance remains unclear. Therefore, we focused on NMDAR signaling and investigated its effects on TMZ resistance. METHODS: We investigated the effect of NMDAR signaling on O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that induces chemoresistance to TMZ, using quantitative real-time polymerase chain reaction and western blotting in human GBM T98G cells. In addition, we used memantine (MEM), an NMDAR antagonist, to investigate the cytotoxic effect of TMZ/MEM combination and its detailed mechanism. RESULTS: Activation of NMDAR by N-methyl-D-aspartate (NMDA) elevated MGMT expression and suppressed the effect of TMZ in T98G cells. In contrast, knockdown of NMDAR by NMDAR1 shRNA decreased MGMT expression and enhanced the effect of TMZ in T98G cells. The cytotoxic effect of TMZ was enhanced by MEM in T98G cells. Inhibition of NMDAR by MEM decreased MGMT expression and increased DNA alkylation by TMZ. CONCLUSION: NMDAR signaling induced chemoresistance of TMZ via the upregulation of MGMT expression in GBM cells. Furthermore, MEM inhibited TMZ-induced MGMT upregulation and increased the cytotoxic effect of TMZ on MGMT-positive cells. This study demonstrates that the combination of TMZ and MEM could be a new therapeutic strategy for MGMT-positive GBM. Overview of this study. NMDAR signaling controls the expression of MGMT and the cytotoxic effect of TMZ.

Influence of Change of Full-Time Equivalents on Post-prescription Review with Feedback Interventions in an Antimicrobial Stewardship.

Few studies have investigated the influence of more full-time equivalents (FTEs) of infectious disease (ID) pharmacists on the likelihood of a post-prescription review with feedback (PPRF) intervention. This study focused on this in community hospitals before and after the Japanese medical reimbursement system was revised to introduce antimicrobial stewardship (AS) fees. We collected data for two periods: before (April 2017 to March 2018) and after (April 2018 to March 2019) AS fee implementation. The efficacy of the PPRF by the ID pharmacist was assessed based on the usage of broad-spectrum antimicrobials in days of therapy (DOT) per 100 patient-days. Further, we generated the susceptibility rate for antimicrobial-resistant organisms. The number of PPRF drugs was 2336 (2596 cases) before AS fee implementation and 2136 (1912 cases) after implementation. The overall monthly FTE for AS for an ID pharmacist increased from [median (interquartile range; IQR)] 0.34 (0.33-0.36) to 0.63 (0.61-0.63) after AS fee implementation. The DOT of the broad-spectrum antibiotics decreased from 10.46 (9.61-12.48) to 8.68 (8.14-9.18). The DOT of carbapenems and quinolones decreased significantly from 4.11 (3.69-4.41) to 3.07 (2.79-3.22) and 0.96 (0.61-1.14) to 0.37 (0.19-0.46), respectively (p < 0.05). Furthermore, the rate of levofloxacin (LVFX)-susceptible Pseudomonas (P.) aeruginosa improved from 71.5 to 84.8% (p < 0.01). We observed that increasing the FTE of ID pharmacists influences the DOTs of broad-spectrum antibiotics; a higher FTE contributes to fewer DOTs. Further, the susceptibility of P. aeruginosa to meropenem and LVFX increased as the FTE increased.