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Some of the authors of the present research group have previously reported mass spectrometric detection of [PdAu9(PPh3)8(CN)]2+ (PdAu9CN) by atmospheric pressure plasma (APP) irradiation of [MAu8(PPh3)8]2+ (PdAu8) in methanol and proposed based on density functional theory (DFT) calculations that PdAu9CN is constructed by inserting a CNAu or NCAu unit into the Au-PPh3 bond of PdAu8 [Emori et al., J. Chem. Phys. 155, 124312 (2021)]. In this follow-up study, we revisited the structure of PdAu9CN by high-resolution ion mobility spectrometry on an isolated sample of PdAu9CN with the help of dispersion-corrected DFT calculation. In contradiction to the previous proposal, we conclude that isomers in which an AuCN unit is directly bonded to the central Pd atom of PdAu8 are better candidates. This assignment was supported by Fourier transform infrared and ultraviolet-visible spectroscopies of isolated PdAu9CN. The simultaneous formation of [Au(PPh3)2]+ and PdAu9CN suggests that the AuCN species are formed by APP irradiation at the expense of a portion of PdAu8. These results indicate that APP may offer a unique method for transforming metal clusters into novel ones by generating in situ active species that were not originally added to the solution.
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TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians because of its rarity and severity. Since the initial proposal of the TAFRO syndrome as a distinct disease entity in 2010, two independent diagnostic criteria have been developed. Although these are different in the concept of whether TAFRO syndrome is a subtype of idiopathic multicentric Castleman disease or not, they are similar except for the magnitude of lymph node histopathology. Because there have been no specific biomarkers, numerous diseases must be ruled out before the diagnosis of TAFRO syndrome is made. The standard of care has not been fully established, but interleukin-6 blockade therapy with siltuximab or tocilizumab and anti-inflammatory therapy with high-dose corticosteroids are the most commonly applied for the treatment of TAFRO syndrome. The other immune suppressive agents or combination cytotoxic chemotherapies are considered for patients who do not respond to the initial treatment. Whereas glowing awareness of this disease improves the clinical outcomes of patients with TAFRO syndrome, further worldwide collaborations are warranted.
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The charging behavior of molecular Au clusters protected by alkanethiolate (SCnH2n+1=SCn) is, under electrochemical conditions, significantly affected by the penetration of solvents and electrolytes into the SCn layer. In this study, we estimated the charging energy EC(n) associated with [PtAu24(SCn)18]-+e-â[PtAu24(SCn)18]2- (n=4, 8, 12, and 16) in vacuum using mass-selected gas-phase anion photoelectron spectroscopy of [PtAu24(SCn)18]z (z=-1 and -2). The EC(n) values of PtAu24(SCn)18 in vacuum are significantly larger than those in solution and decrease with n in contrast to the behavior reported for Au25(SCn)18 in solution. The effective relative permittivity (ϵm*) of the SCn layer in vacuum is estimated to be 2.3-2.0 based on the double-concentric-capacitor model. Much smaller ϵm* values in vacuum than those in solution are explained by the absence of solvent/electrolyte penetration into the monolayer. The gradual decrease of ϵm* with n is ascribed to the appearance of an exposed surface region due to the bundle formation of long alkyl chains.
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AIM: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Quimioterapia Combinada , Taxa de Filtração Glomerular , Receptor do Peptídeo Semelhante ao Glucagon 1 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Pessoa de Meia-Idade , Idoso , Nefropatias Diabéticas/epidemiologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Progressão da Doença , Albuminúria/epidemiologia , Hipoglicemiantes/uso terapêutico , Resultado do Tratamento , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
A prototypical thiolate (RS)-protected gold cluster [Au25(SR)18]- has high stability due to specific geometric and electronic structures: an icosahedral (Ih) Au13 core with a closed electronic shell containing eight electrons is completely protected by six units of Au2(SR)3. Nevertheless, collisional excitation of [Au25(SR)18]- in a vacuum induces the sequential release of Au4(SR)4 to form [Au21(SR)14]- and [Au17(SR)10]- both containing eight electrons. To answer a naive question of whether these fragments bear an Ih Au13(8e) core, the geometrical structures of [Au21(SC3H7)14]- and [Au17(SC3H7)10]- in the gas phase were examined by the combination of anion photoelectron spectroscopy and density functional theory (DFT) calculation of simplified models of [Au21(SCH3)14]- and [Au17(SCH3)10]-. We concluded that [Au21(SC3H7)14]- retains a slightly distorted Ih Au13(8e) core, while [Au17(SC3H7)10]- has an amorphous Au13 core composed of triangular Au3, tetrahedral Au4, and prolate Au7 units. DFT calculations on putative species [Au19(SCH3)12]- and [Au18(SCH3)11]- suggested that the Ih Au13(8e) core undergoes dramatic structural deformation due to mechanical stress from µ2 ligation of only one RS.
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Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: -3.5 ± 9.4 mL/min/1.73 m2/year, post: -0.4 ± 6.3 mL/min/1.73 m2/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: -2.0 ± 10.9 mL/min/1.73 m2/year, post: -1.8 ± 5.4 mL/min/1.73 m2/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits-especially annual eGFR decline-of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.
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BACKGROUND: Stroke often induces gait abnormality, such as buckling knee pattern, compromising walking ability. Previous studies indicated that an adequate trailing limb angle (TLA) is critical for recovering walking ability. OBJECTIVE: We hypothesized that correcting gait abnormality by immobilizing the knee joint using a knee orthosis (KO) would improve walking patterns and increase the TLA, and investigated whether walking training using a KO would increase the TLA in post-stroke patients. METHODS: In a randomized controlled trial, thirty-four participants were assigned to KO (walking training using a KO) and non-KO (without using a KO) groups. Twenty-nine completed the three-week gait training protocol. TLA was measured at baseline and after training. A two-way repeated ANOVA was performed to evaluate TLA increases with training type and time as test factors. A t-test compared TLA changes (ΔTLA) between the two groups. RESULTS: ANOVA showed a main effect for time (Fâ=â64.5, pâ<â0.01) and interaction (Fâ=â15.4, pâ<â0.01). ΔTLA was significantly higher in the KO group (14.6±5.8) than in the non-KO group (5.0±7.0, pâ<â0.001). CONCLUSION: Walking training using a KO may be practical and effective for increasing TLA in post-stroke patients.
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Hemiplegia , Aparelhos Ortopédicos , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Hemiplegia/reabilitação , Hemiplegia/etiologia , Idoso , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/complicações , Transtornos Neurológicos da Marcha/reabilitação , Transtornos Neurológicos da Marcha/etiologia , Caminhada/fisiologia , Articulação do Joelho/fisiopatologia , Adulto , Resultado do Tratamento , Fenômenos BiomecânicosRESUMO
Anion transporters sustain a variety of physiological states in cells. Bestrophins (BSTs) belong to a Cl- and/or HCO3- transporter family conserved in bacteria, animals, algae, and plants. Recently, putative BSTs were found in the green alga Chlamydomonas reinhardtii, where they are upregulated under low CO2 (LC) conditions and play an essential role in the CO2-concentrating mechanism (CCM). The putative BST orthologs are also conserved in diatoms, secondary endosymbiotic algae harboring red-type plastids, but their physiological functions are unknown. Here, we characterized the subcellular localization and expression profile of BSTs in the marine diatoms Phaeodactylum tricornutum (PtBST1 to 4) and Thalassiosira pseudonana (TpBST1 and 2). PtBST1, PtBST2, and PtBST4 were localized at the stroma thylakoid membrane outside of the pyrenoid, and PtBST3 was localized in the pyrenoid. Contrarily, TpBST1 and TpBST2 were both localized in the pyrenoid. These BST proteins accumulated in cells grown in LC but not in 1% CO2 (high CO2 [HC]). To assess the physiological functions, we generated knockout mutants for the PtBST1 gene by genome editing. The lack of PtBST1 decreased photosynthetic affinity for dissolved inorganic carbon to the level comparable with the HC-grown wild type. Furthermore, non-photochemical quenching in LC-grown cells was 1.5 to 2.0 times higher in the mutants than in the wild type. These data suggest that HCO3- transport at the stroma thylakoid membranes by PtBST1 is a critical part of the CO2-evolving machinery of the pyrenoid in the fully induced CCM and that PtBST1 may modulate photoprotection under CO2-limited environments in P. tricornutum.
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Dióxido de Carbono , Diatomáceas , Fotossíntese , Dióxido de Carbono/metabolismo , Diatomáceas/genética , Diatomáceas/metabolismo , Diatomáceas/fisiologia , Fotossíntese/genética , Proteínas de Transporte de Ânions/metabolismo , Proteínas de Transporte de Ânions/genéticaRESUMO
Development of advanced pest control methods that do not rely on insecticides is an important issue for sustainable agriculture. Particularly with regards to micro pests that are not only highly resistant to various insecticides but also because we are running out of options for which insecticide to use against them, resulting in enormous economic damage worldwide. Here we report that the effectiveness of the conventional insect net can be greatly advanced by changing their color to red that helps significantly reduce pesticide use. We demonstrate the red effect using Onion thrips, Thrips tabaci a main vector of Iris Yellow Spot Virus (IYSV) and Tomato Spotted Wilt Virus (TSWV) that cause serious damage to various vegetables. New red nets succeeded in suppressing the invasion rates and damages (white spots on the leaves) in a Welsh onion greenhouse with minimum use of pesticides. We discuss how red nets are compatible with labor-saving, sustainable agriculture and the future potential of "optical pest control" based on insect color vision and its behavioral response.
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Inseticidas , Tisanópteros , Animais , Doenças das Plantas/prevenção & controle , Insetos Vetores , Insetos/fisiologia , Tisanópteros/fisiologia , Agricultura , Cebolas/fisiologiaRESUMO
Collision-induced dissociation and high-resolution cyclic ion mobility mass spectrometry, along with quantum chemical calculations and trajectory simulations, were used to compare the structures of isolated [MAu24(CîCR)18]2-, M = Ni, Pd, or Pt, and their associated fragment ions. The three different alkynyl ligand-stabilized (CîCR, R = 3,5-(CF3)2C6H3), transition metal-doped, gold cluster dianions showed mutually resolvable collision cross sections (CCS), which were ordered consistently with their molecular structures from X-ray crystallography. All three [MAu24(CîCR)18]2- species fragment by sequential diyne loss to form [MAu24(CîCR)18-n]2-, with n up to 12. The resultant fragment isomer distributions are significantly n- and M-dependent, and hint at a process involving concerted elimination of adjacent ligands. In particular [NiAu24(CîCR)18]2- also fragments to generate alkyne-oligomers, an inference supported by the parallel observation of precursor dianion isomerization as collision energy is increased.
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Noonan syndrome (NS) is a dominantly inherited genetic disorder with mutations in genes encoding components or regulators of the Rat sarcoma virus/mitogen-activated protein kinase pathway. Its diagnosis is based on characteristic features, including typical facial features, a short stature, congenital heart disease, mild developmental delay, and cryptorchidism. Patients with NS sometimes develop autoimmune diseases, such as Hashimoto's thyroiditis and, rarely, systemic lupus erythematosus (SLE). We herein present a 29-year-old Japanese female with NS complicated by SLE and repeated severe hypoglycaemia. The patient was diagnosed with SLE based on thrombocytopenia, nephritis, a positive antinuclear antibody titre (1:640), and a positive anti-dsDNA antibody. The patient was treated with a glucocorticoid, mycophenolate mofetil, and tacrolimus, which attenuated both SLE and hypoglycaemia. Since insulin receptor antibody levels were higher to the upper normal range and decreased after treatment, hypoglycaemia probably appeared to be attributed to type B insulin resistance syndrome. We herein present the first case of SLE in NS complicated by type B insulin resistance syndrome. Although NS is a rare disease, we need to consider the complication of autoimmune diseases, including SLE.
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Hipoglicemia , Lúpus Eritematoso Sistêmico , Síndrome de Noonan , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Feminino , Adulto , Síndrome de Noonan/complicações , Síndrome de Noonan/diagnóstico , Hipoglicemia/etiologia , Hipoglicemia/diagnóstico , Resistência à Insulina , RecidivaRESUMO
Sodium-glucose cotransporter 2 inhibitor (SGLT2-I) shows excellent antihypertensive effects in addition to its hypoglycemic effects. However, whether body mass index (BMI) affects the antihypertensive effect of SGLT2-I remains unknown. We investigated the impact of baseline BMI on the achievement of target blood pressure (BP) with SGLT2-I treatment in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We retrospectively evaluated 447 Japanese patients with T2DM and CKD treated with SGLT2-I for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2-I treatment. Patients were divided into two groups according to a baseline BMI of 29.1 determined by receiver operating characteristic analysis and analyzed in a cohort model with propensity score matching. In each group, 130 patients were compared by propensity score matching. The target BP achievement rate was significantly higher in the BMI < 29.1 group than in the BMI ≥ 29.1 group (34% and 21%, respectively, p = 0.03). The odds ratio for achieving the target BP in the BMI ≥ 29.1 group was 0.50 (95% confidence interval, 0.28-0.90, p = 0.02). The BMI < 29.1 group had significantly lower systolic and diastolic BPs after SGLT2-I treatment than the BMI ≥ 29.1 group. Only the BMI < 29.1 group was showed a significant decrease in the logarithmic albumin-to-creatinine ratio from baseline after SGLT2-I treatment. In patients with T2DM and CKD, baseline BMI was associated with the antihypertensive effects of SGLT2-I. Patients in the lower baseline BMI group were more likely to achieve the target BP after SGLT2-I treatment. Pretreatment BMI affects the antihypertensice effect of SGLT2 inhibirors in patients with T2DM and CKD.
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Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Índice de Massa Corporal , Pressão Sanguínea , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Anti-Hipertensivos/uso terapêutico , Estudos Retrospectivos , Hipoglicemiantes/farmacologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Glucose/farmacologia , SódioRESUMO
AIMS: Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice. METHODS: We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome. RESULTS: The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] (p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome. CONCLUSION: With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.
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Diabetes Mellitus Tipo 2 , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos Retrospectivos , Glucose , Sódio , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/efeitos adversosRESUMO
Exploring how charge-changing affects the photoluminescence of small organic dyes presents challenges. Here, helium tagging photodissociation (PD) action spectroscopy in the gas phase and dispersed laser-induced fluorescence (DF) spectroscopy in the solid Ne matrix are used to compare the intrinsic photophysical properties of pyronin Y cation [PY]+ and its one electron-reduced neutral radical [PY]⢠at 5 K. Whereas the cation shows efficient visible photoluminescence, no emission from the neutral, in line with theoretical predictions, was detected. B3LYP/aug-cc-pVDZ calculations based on the TD-DFT/FCHT method allow for unambiguous assignment of recorded vibrationally resolved absorption and emission spectra. Surprisingly, our experimental sensitivity was high enough to also observe electronic preresonance Raman (ePR-Raman) spectra of [PY]+, with a significant efficiency factor (EF). These characteristics of the [PY]â¢/[PY]+ pair suggest that appropriately functionalized derivatives may open new perspectives in the area of in vivo bioimagining microscopy and find applications in various sophisticated stimulated-Raman spectroscopies.
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Congenital fitness-disadvantageous mutations are not maintained in the population; they are purged from the population through processes such as purifying selection. However, these mutations could persist in the population as polymorphisms when it is advantageous for the individuals carrying them in adapting to a specific external environment. We tested this hypothesis using the dimorphic land snail Euhadra peliomphala simodae in Japan; these snails have dark or bright coloured shells. The survival rate of dark snails at hatching was lower than that of the bright ones, as observed in the F1 progenies produced through crossing. Dark snails have a congenital fitness-disadvantageous mutation; however, they also have protection against ultraviolet radiation. They have a higher survival rate than the bright snails in a UV environment, as observed using the UV exposure experiments and UV transmittance measurements. This is a good example of a congenitally disadvantageous mutation that is advantageous for adapting to the external environment. These results explain the maintenance of polymorphism and highlight the genotypic and phenotypic diversity in the wild population.
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Polimorfismo Genético , Raios Ultravioleta , Humanos , Animais , Mutação , Genótipo , Caramujos/genéticaRESUMO
Aims: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). Methods: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or aâ ≥â 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. Results: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, Pâ =â 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1â ±â 5.0 vs. -2.8â ±â 5.1â mL/min/1.73 m2, Pâ =â 0.001; and -0.08â ±â 0.61 vs. 0.05â ±â 0.52, Pâ =â 0.03, respectively). Conclusion: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.
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The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.
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Autofagia , Proteínas de Ligação a DNA , Lisossomos , Progranulinas , Humanos , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lisossomos/metabolismo , Progranulinas/genética , Progranulinas/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Inibidores Enzimáticos/farmacologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismoRESUMO
Pulmonary veno-occlusive disease (PVOD) is an extremely rare condition in oncology practice. Although PVOD is clinically similar to pulmonary arterial hypertension, the conditions differ in terms of pathophysiology, management, and prognosis. This report discusses the case of a 47-year-old woman who developed dyspnea and fatigue after high-dose cyclophosphamide chemotherapy and autologous hematopoietic stem cell transplantation for relapsed lymphoma. The patient exhibited tachycardia, tachypnea, and hypotension, but other findings in the physical examination were unremarkable. The imaging studies showed no evidence of pulmonary embolism, but multiple ground-glass opacities and bilateral pleural effusions were observed on chest high-resolution computed tomography scans. In the right heart catheterization study, the mean pulmonary artery pressure and pulmonary vascular resistance were 35 mm Hg and 5.93 Wood units, respectively, with a normal pulmonary capillary wedge pressure of 10 mm Hg. Pulmonary function tests revealed a remarkable reduction in the percentage predicted value of diffusing capacity of the lungs for carbon monoxide to 31%. Lymphoma progression, collagen diseases, infectious diseases such as human immunodeficiency virus or parasitic infections, portal hypertension, and congenital heart disease were carefully excluded as these are also capable of causing pulmonary arterial hypertension. Thereafter, we reached a final diagnosis of PVOD. The patient was treated with supplemental oxygen and a diuretic during 1 month of hospitalization, which relieved her right heart overload symptoms. Herein, we present the patient's clinical course and diagnostic workup because misdiagnosis or inappropriate treatment can lead to unfavorable outcomes in patients with PVOD.