Publications by authors named "Takeshi Nakamura"

356 Publications

Differences in subtrochanteric and diaphyseal atypical femoral fractures in a super-aging prefectural area: YamaCAFe Study.

J Bone Miner Metab 2021 Apr 5. Epub 2021 Apr 5.

Faculty of Orthopaedic surgery, Yamagata University, Yamagata, Japan.

Introduction: Atypical femoral fractures (AFFs) have been correlated with long-term use of bisphosphonates (BPs), glucocorticoids (GCs), and femoral geometry. We investigated the incidence and characteristics of subtrochanteric (ST) and diaphyseal (DP) AFFs in all institutes in a super-aging prefectural area.

Materials And Methods: We performed a blinded analysis of radiographic data in 87 patients with 98 AFFs in all institutes in Yamagata prefectural area from 2009 to 2014. Among the 98 AFFs, 57 AFFs comprising 11 ST fractures in 9 patients and 46 DP fractures in 41 patients with adequate medical records and X-rays were surveyed for time to bone healing and geometry.

Results: Of the 87 patients, 67 received BPs/denosumab (77%) and 10 received GCs (11%). Surgery was performed in 94 AFFs. Among 4 AFFs with conservative therapy, 3 required additional surgery. In univariate regression analyses for ST group versus DP group, male-to-female ratio was 2/7 versus 1/40, mean age at fracture was 58.2 (37-75) versus 78 (60-89) years, rheumatic diseases affected 55.5% (5/9) versus 4.9% (2/41), femoral lateral bowing angle was 1.7 (0-6) versus 11.8 (0.8-24)°, GC usage was 67% (6/9) versus 4.9% (2/41), and bone healing time was 12.1 (6-20) versus 8.1 (3-38) months (p < 0.05). In multivariate analyses, higher male-to-female ratio, younger age, greater proportion affected by rheumatic diseases, and higher GC usage remained significant (p < 0.05).

Conclusions: The incidence of AFFs in our prefectural area was 1.43 cases/100,000 persons/year. This study suggests that the onset of ST AFFs have greater correlation with the worse bone quality, vice versa, the onset of DP AFFs correlated with the bone geometry. The developmental mechanisms of AFFs may differ significantly between ST and DP fractures.
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http://dx.doi.org/10.1007/s00774-021-01215-4DOI Listing
April 2021

Infective endocarditis due to Streptococcus agalactiae in the puerperal period.

J Obstet Gynaecol Res 2021 Mar 23. Epub 2021 Mar 23.

Department of Obstetrics and Gynecology, Showa University Northern Yokohama Hospital, Yokohama-shi, Kanagawa, Japan.

Streptococcus agalactiae, also known as group B Streptococcus, is a species of bacteria occasionally detected in the vagina and/or rectum of pregnant women. This report describes the case of a 33-year-old woman who developed infective endocarditis on puerperal day 17, owing to group B Streptococcus, and required lifesaving surgery. The patient was rushed to our hospital with chief complaints of fever and fatigue. After hospitalization, antibiotics were administered; however, the symptoms did not improve. Following a detailed examination, vegetation was found in the heart, suggestive of infective endocarditis. Surgical removal of the vegetation improved the patient's condition. The development of group B Streptococcus infection and infective endocarditis in a pregnant woman with no risk factors is rare. This case confirms that this patient's life was saved by a timely diagnosis and appropriate therapeutic intervention.
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http://dx.doi.org/10.1111/jog.14757DOI Listing
March 2021

The use of micro-computed tomography to determine the accuracy of electronic working length with two apex locators.

J Oral Sci 2021 Mar 18;63(2):167-169. Epub 2021 Mar 18.

Department of Endodontics, Nihon University School of Dentistry.

Purpose: This study evaluated the precision of electronic working length by microcomputed tomography using two electronic apex locators (EALs).

Methods: Twenty single-rooted permanent teeth without caries or restorations were selected as the subject teeth. The positions of the minor apical constriction (AC) and major apical foramen (AF) were measured by electronic root canal length, and microcomputed tomography was performed with the file inserted and fixed in the root canal. All teeth were measured individually and independently by two operators. The Mann-Whitney U-test was used to statistically test the AC and AF values using two EALs; P < 0.05 was defined as statistically significant.

Results: This was 65.0% within 1.5 mm in the case of two EALs on AC. This was more than 90.0% within 1.0 mm in the case of two EALs on AF. Comparison of the differences between the respective AC and AF of the measurements obtained using the two EALs revealed no significant difference.

Conclusion: The two EALs are devices that can greatly improve the accuracy of WL control.
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http://dx.doi.org/10.2334/josnusd.20-0466DOI Listing
March 2021

Post-intensive care syndrome as a predictor of mortality in patients with critical illness: A cohort study.

PLoS One 2021 10;16(3):e0244564. Epub 2021 Mar 10.

Department of Cardiovascular Medicine, School of Medicine, Kitasato University, Sagamihara, Japan.

Introduction: The post-intensive care syndrome (PICS) encompasses multiple, diverse conditions, such as physical disability, cognitive impairment, and depression. We sought to evaluate whether conditions within PICS have similar associations with mortality among survivors of critical illness.

Materials And Methods: In this retrospective cohort study, we identified 248 critically ill patients with intensive care unit stay ≥72 hours, who underwent PICS evaluation. Patients with disability in activities of daily living, cognitive impairment, or depression before hospitalization were excluded. We defined PICS using established measures of physical disability (usual gait speed), cognitive impairment (Mini-Cog test), and depression (Patient Health Questionnaire-2) at hospital discharge. The endpoint was all-cause mortality.

Results: Patients had a median age of 69 years and Acute Physiology and Chronic Health Evaluation (APACHE) II score of 16. One hundred thirty-two patients were classified as having PICS, and 19 patients died. 81/248 (34%) patients had physical disability, 42/248 (19%) had cognitive impairment, and 44/248 (23%) had depression. After adjusting for covariates on multivariable Cox regression analyses, PICS was significantly associated with all-cause mortality (hazard ratio [HR] 3.78, 95% confidence interval [CI] 1.02 - 13.95; P = 0.046). However, the association between PICS and all-cause mortality was related to physical disability and cognitive impairment (P = 0.001 and P = 0.027, respectively), while depression was not (P = 0.623).

Conclusion: While PICS as a syndrome has been useful in gaining attention to the sequelae of critical illness, its relationship with long-term mortality is driven largely by physical disability and cognitive impairment and not depression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244564PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946187PMC
March 2021

Recurrent Infective Endocarditis Following Transcatheter Edge-to-Edge Mitral Valve Repair with MitraClip System.

Korean Circ J 2021 Mar;51(3):283-285

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.4070/kcj.2020.0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925964PMC
March 2021

Efficacy of prototype endodontic obturators for novel root canal obturation techniques using a resin-based sealer in various powder-liquid ratios.

J Oral Sci 2021 Mar 17;63(2):157-162. Epub 2021 Feb 17.

Department of Endodontics, Nihon University School of Dentistry.

Purpose: This study aimed to examine novel techniques using prototype endodontic obturators to obturate a resin-based sealer.

Methods: Powder-liquid ratios of MetaSEAL Soft were changed to obtain suitable root canal sealing, and the physical properties for various powder-liquid ratios were analyzed according to ISO-6876. Tensile bond strength was also examined. Prototype endodontic obturators with a combination of thread numbers and pitch angles were analyzed for sealing ability after MetaSEAL Soft was obturated in simulated root canals.

Results: Powder-liquid ratios of 1.0:1, 1.1:1, 1.2:1, and 1.3:1 showed suitable physical properties; however, flow for 1.4:1 was below a standard value. Tensile bond strength increased gradually when the powder-liquid ratio changed from 1.0:1 to 1.3:1, and 1.3:1 and 1.4:1 showed the highest and lowest bond strengths, respectively. Sealing ability increased when pitch angles of the obturators were 5°, 8°, and 11°; 11° showed the best results. Similarly, sealing ability increased when the thread number was 12, 17, and 22 pitches; 22 showed the best results.

Conclusion: These findings suggest that the prototype endodontic obturator can be useful for obturating MetaSEAL Soft, and a powder-liquid ratio of 1.3:1 MetaSEAL Soft may be the most suitable for achieving excellent sealing.
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http://dx.doi.org/10.2334/josnusd.20-0543DOI Listing
March 2021

Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?

ORL J Otorhinolaryngol Relat Spec 2021 Feb 15:1-7. Epub 2021 Feb 15.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Miyazaki, Miyazaki, Japan.

We describe a dominant Japanese patient with progressive conductive hearing loss who was diagnosed with NOG-related symphalangism spectrum disorder (NOG-SSD), a spectrum of congenital stapes fixation syndromes caused by NOG mutations. Based on the clinical features, including proximal symphalangism, conductive hearing loss, hyper-opia, and short, broad middle, and distal phalanges of the thumbs, his family was diagnosed with stapes ankylosis with broad thumbs and toes syndrome (SABTT). Genetic analysis revealed a heterozygous substitution in the NOG gene, c.645C>A, p.C215* in affected family individuals. He had normal hearing on auditory brainstem response (ABR) testing at ages 9 months and 1 and 2 years. He was followed up to evaluate the hearing level because of his family history of hearing loss caused by SABTT. Follow-up pure tone average testing revealed the development of progressive conductive hearing loss. Stapes surgery was performed, and his post-operative hearing threshold improved to normal in both ears. According to hearing test results, the stapes ankylosis in our SABTT patient seemed to be incomplete at birth and progressive in early childhood. The ABR results in our patient indicated the possibility that newborn hearing screening may not detect conductive hearing loss in patients with NOG-SSD. Hence, children with a family history and/or known congenital joint abnormality should undergo periodic hearing tests due to possible progressive hearing loss. Because of high success rates of stapes surgeries in cases of SABTT, early surgical interventions would help minimise the negative effect of hearing loss during school age. Identification of the nature of conductive hearing loss due to progressive stapes ankylosis allows for better genetic counselling and proper intervention in NOG-SSD patients.
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http://dx.doi.org/10.1159/000512668DOI Listing
February 2021

Genetic Creutzfeldt-Jakob disease-M232R with the cooccurrence of multiple prion strains, M1 + M2C + M2T: Report of an autopsy case.

Neuropathology 2021 Feb 14. Epub 2021 Feb 14.

Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan.

Genetic Creutzfeldt-Jakob disease (gCJD) with a methionine to arginine substitution at codon 232 of the prion protein gene (gCJD-M232R) is rare and has only been reported in Japan. We report an autopsy case of gCJD-M232R showing alleles of codon 129 that were homozygous for methionine and the presence of multiple strains of the protease-resistant, abnormal isoform of prion protein (PrP ), M1 + M2C + M2T. The patient, a 54-year-old Japanese man, died after a clinical course of 21 months characterized by slowly progressive dementia and sleep disturbance. At autopsy, the neuropil of the cerebral neocortex showed a widespread and severe spongiform change. Grape-like clusters of large confluent vacuoles were admixed with fine vacuoles. Neuronal loss was moderate, but reactive astrocytosis was mild. The dorsomedial nucleus of the thalamus and the inferior olivary nucleus showed moderate and severe neuronal loss, respectively. Many amyloid plaques were present in the cerebellar molecular layer. PrP deposition pattern was predominantly the synaptic type in the cerebrum and corresponded to the plaques in the cerebellum. Perivacuolar deposition was also seen. Western blot analysis of PrP revealed the predominance of type 2. Moreover, by employing Western blot analysis in combination with the protein misfolding cyclic amplification (PMCA) method, which selectively amplifies the minor M2T prion strain, we demonstrated the presence of M2T, in addition to M1 and M2C strains, in the brain of the patient. PMCA was a powerful method for demonstrating the presence of the M2T strain, although the amount is often small and the transmission is difficult.
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http://dx.doi.org/10.1111/neup.12722DOI Listing
February 2021

Prognostic value of cardio-hepatic-skeletal muscle syndrome in patients with heart failure.

Sci Rep 2021 Feb 12;11(1):3715. Epub 2021 Feb 12.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Although heart failure (HF) and liver dysfunction often coexist because of complex cardiohepatic interactions, the association between liver dysfunction and physical dysfunction, and between coexistence of both and prognosis in HF patients remains unclear. We reviewed 895 patients with HF (mean age, 69.4 ± 14.2 years) who underwent liver function test using model for end-stage liver disease excluding international normalized ratio (MELD-XI) score and physical function test (grip strength, leg strength, gait speed, and 6-min walking distance [6MWD]). In the multiple regression analysis, MELD-XI score was independently associated with lower grip strength, leg strength, gait speed, and 6MWD (all P < 0.001). One hundred thirty deaths occurred over a median follow-up period of 1.67 years (interquartile range: 0.62-3.04). For all-cause mortality, patients with high MELD-XI scores and reduced physical functions were found to have a significantly higher mortality risk even after adjusting for several covariates (grip strength, hazard ratio [HR]: 3.80, P < 0.001; leg strength, HR: 4.65, P < 0.001; gait speed, HR: 2.49, P = 0.001, and 6MWD, HR: 5.48, P < 0.001). Liver dysfunction was correlated with reduced physical function. Moreover, the coexistence of lower physical function and liver dysfunction considerably affected prognosis in patients with HF.
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http://dx.doi.org/10.1038/s41598-020-80641-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880995PMC
February 2021

Characteristics of patients who developed glucose intolerance in the early period after partial pancreatectomy.

Diabetol Int 2021 Jan 28;12(1):140-144. Epub 2020 May 28.

Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan.

Background: New-onset diabetes mellitus (DM) often develops after partial pancreatectomy. Little is known regarding how soon patients develop glucose intolerance after partial pancreatectomy. We investigated the incidence of and factors contributing to the development of glucose intolerance during hospitalization after partial pancreatectomy.

Patients And Methods: We retrospectively analyzed the cases of 38 patients with normal glucose tolerance pre-surgery who underwent a partial pancreatectomy (pancreaticoduodenectomy,  = 23; distal pancreatectomy,  = 15). The patients' glucose tolerance and insulin secretory/sensitivity values were determined by a normal meal tolerance test (NMTT) within 2 months post-surgery during their hospitalization.

Results: The post-surgery NMTT values revealed that 11 (28.9%) patients developed new-onset impaired glucose tolerance (the IGT group); the other 27 (71.1%) patients maintained normal glucose tolerance (the NGT group). The pre-operative hemoglobin A1c (HbA1c) levels were significantly higher in the IGT group (5.84%) versus the NGT group (5.58%,  = 0.034). There were no significant between-group differences in age, sex ratio, body mass index, the ratio of operative procedure (either pancreaticoduodenectomy or distal pancreatectomy), or post-operative insulin secretory values including the fasting/postprandial C-peptide index. The IGT group showed significantly higher insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) versus the NGT group (1.52 ± 0.67 vs. 0.65 ± 0.42,  < 0.001).

Conclusion: After undergoing a partial pancreatectomy, approximately 30% of the patients developed glucose intolerance during the hospitalized period. Our findings indicate that pre-operative HbA1c and post-operative HOMA-IR values can be associated with developing glucose intolerance just after partial pancreatectomy.
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http://dx.doi.org/10.1007/s13340-020-00440-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790964PMC
January 2021

Prognostic value of cardiac I-metaiodobenzylguanidine imaging for predicting cardiac events after transcatheter aortic valve replacement.

ESC Heart Fail 2021 Apr 5;8(2):1106-1116. Epub 2021 Jan 5.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Aims: In patients with aortic valve stenosis (AS), cardiac sympathetic nervous (CSN) dysfunction and its improvement after transcatheter aortic valve replacement (TAVR) have been reported. The prognostic impact of CSN function remains unclear. This study investigated the prognostic value of cardiac I-metaiodobenzylguanidine (MIBG) imaging for predicting cardiac events after TAVR.

Methods And Results: This single-centre prospective observational study enrolled patients with AS between July 2017 and May 2019. MIBG scintigraphy was performed before and soon after TAVR to evaluate the late heart-mediastinum ratio (L-H/M). Patients were classified into three pairs of groups based on the baseline and post-TAVR L-H/M (≥2.0 or <2.0) and on the presence of TAVR-related improvement in L-H/M. The study endpoint was the occurrence of major adverse cardiac events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction, and hospitalization due to heart failure. Among the 187 consecutive patients who underwent TAVR, 107 (27 men; median age: 86 years) were evaluated. Over a median follow-up of 366 days, 15 (14.0%) patients had MACE. The incidence of MACE was significantly low in patients with L-H/M improvement and/or high post-TAVR L-H/M (≥2.0). Baseline L-H/M and frailty were associated with poor response of L-H/M to TAVR treatment. TAVR-related improvement in L-H/M had significant effects on MACE, with an adjusted hazard ratio of 0.233 (95% confidence interval, 0.064-0.856; P = 0.028).

Conclusions: TAVR-related improvement in L-H/M was an independent predictor of cardiac events, 1 year after TAVR. Cardiac MIBG imaging is useful for predicting cardiac events after TAVR.
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http://dx.doi.org/10.1002/ehf2.13123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006649PMC
April 2021

Strong Antiferromagnetic Interaction in a Gadolinium(III) Complex with Methoxy-TEMPO Radical: A Relation between the Coupling and the Gd-O-N Angle.

Inorg Chem 2021 Jan 31;60(2):535-539. Epub 2020 Dec 31.

Department of Engineering Science, The University of Electro-Communications, Chofu, Tokyo 182-8585, Japan.

A new compound [Gd(hfac)(MeOTEMPO)(MeOH)] (MeOTEMPO = 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl) was prepared. From the X-ray crystal structure analysis, the Gd-O-N angle is 170.9(3)°. The magnetic study clarified the Gd-radical interaction with 2/ = -26.6(3) K (in the = -2· convention), which corresponds to one of the strongest antiferromagnetic couplings in the Gd-nitroxide systems. Wider Gd-O-N angles seem to favor stronger antiferromagnetic couplings.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02568DOI Listing
January 2021

Optical coherence tomography analysis of late lumen enlargement after paclitaxel-coated balloon angioplasty for de-novo coronary artery disease.

Catheter Cardiovasc Interv 2020 Dec 28. Epub 2020 Dec 28.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Paclitaxel-coated balloon angioplasty for de-novo coronary artery lesions causes late lumen enlargement (LLE), however, the mechanisms and predictors of LLE have not been elucidated.

Methods And Results: We retrospectively analyzed 91 consecutive patients with 95 de-novo coronary lesions, who underwent paclitaxel-coated balloon angioplasty without stenting from August 2018 to July 2019 as well as follow-up coronary angiography and optical coherence tomography (OCT). The mean follow-up duration was 8.2 ± 2.9 months. The target lesion revascularization rate was 7.3%. OCT demonstrated LLE in 50.5% of lesions. The lesions with LLE had a higher incidence of vessel enlargement (76.6 vs. 29.2%, p < .01), regression of plaque or dissection flap (55.3 vs. 10.4%, p < 0.01; 40.4 vs. 14.6%, p < .01, respectively), and reattachment and healing of dissection flaps (74.5 vs. 27.1%, p < .01) compared with those without LLE. Preprocedure thick-cap fibroatheroma plaques and postprocedure deep dissection reaching the tunica media were positive predictors of LLE (hazard ratio, HR 3.74 [1.93-7.25], p < .001; HR 2.04 [1.02-4.05], p < .05, respectively).

Conclusions: OCT analysis after paclitaxel-coated balloon treatment of de-novo coronary artery lesions revealed that the mechanism of LLE was associated with vessel enlargement, healing of dissection flaps, and regression of plaque or dissection flap. Preprocedure thick-cap fibroatheroma plaques and postprocedure deep dissection reaching the tunica media on OCT were predictors of LLE.
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http://dx.doi.org/10.1002/ccd.29435DOI Listing
December 2020

Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy.

Commun Biol 2020 Dec 7;3(1):742. Epub 2020 Dec 7.

Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.

While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4Foxp3 regulatory T (T) cells abrogates the protective effect of SLIT against allergic disorders. Furthermore, sublingual antigenic application primarily induces antigen-specific CD4Foxp3 T cells in draining ManLNs, in which it is severely impaired in the absence of cDCs. In ManLNs, migratory CD11b cDCs are superior to other conventional dendritic cell subsets for the generation of antigen-specific CD4Foxp3 T cells, which is reflected by their dominancy in the tolerogenic features to favor this program. Thus, ManLNs are privileged sites in triggering mucosal tolerance mediating protect effect of SLIT on allergic disorders that requires a tolerogenesis of migratory CD11b conventional dendritic cells.
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http://dx.doi.org/10.1038/s42003-020-01466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721894PMC
December 2020

Prolonged Elevation of Tricuspid Regurgitation Pressure Gradient After Exercise in Patients With Exercise-induced Pulmonary Hypertension.

Am J Cardiol 2021 03 3;142:124-129. Epub 2020 Dec 3.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

It is necessary to measure the peak tricuspid regurgitation pressure gradient (TRPG) that is recorded at maximum exercise intensity when diagnosing exercise-induced pulmonary hypertension (ePH) on exercise stress echocardiography (ESE). However, it is difficult to measure maximum TRPG during the treadmill exercise. If ePH induced TRPG elevation continues during recovery period after exercise termination, this elevation will serve as a practical diagnostic standard. We aimed to assess whether the elevation of postexercise peak TRPG prolong soon after finishing exercise in patients with ePH. Seventy-four patients underwent symptom-limited ESE by using a semirecumbent bicycle ergometer. ePH was defined as peak TRPG > 50 mm Hg at maximum exercise. We measured peak TRPG during exercise and until 5 minutes afterward. Thirty-five patients were diagnosed with ePH; their median TRPG was 57 mm Hg [interquartile range: 52-62 mm Hg] at maximum exercise. Peak TRPG in patients with ePH was > 40 mm Hg until 2 minutes after exercise. The cut-off values of peak TRPG to detect ePH were 43 mm Hg just after exercise and 41 mm Hg at 1 minute afterward (areas under the curve: 0.98, 0.92, respectively; both p < 0.001). In conclusion, elevated peak TRPG persisted for at least 2 minutes after finishing exercise, and this time frame will therefore provide a new window for diagnosing ePH by ESE.
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http://dx.doi.org/10.1016/j.amjcard.2020.11.037DOI Listing
March 2021

Acute coronary syndrome with large thrombus successfully managed with no-stenting revascularization based on intravascular imaging in a patient with hyperhomocysteinemia: a case report.

J Med Case Rep 2020 Nov 9;14(1):214. Epub 2020 Nov 9.

Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: Hyperhomocysteinemia is caused by genetic and environmental factors, which can result in systemic arteriosclerosis and arteriovenous thrombosis including acute coronary syndrome. Thrombus burden in patients with acute coronary syndrome and hyperhomocysteinemia might involve the culprit lesion as compared with those without any coagulopathy. The primary percutaneous coronary intervention with stent implantation had been established as the treatment strategy for patients with acute coronary syndrome. However, in patients with acute coronary syndrome with high thrombus burden or uncontrolled coagulopathy, stent implantation might lead to slow-flow phenomenon or stent thrombosis. Therefore, the treatment strategy in these patients was not established.

Case Presentation: A 49-year-old Japanese man with history of splenic infarction of unknown cause had continued anticoagulant therapy since its diagnosis, but stopped taking the medication several months ago. He presented with sudden-onset chest dorsalgia. Contrast computed tomography showed a small pulmonary embolism and his troponin I level was elevated on initial laboratory test. Coronary angiography revealed a contrast defect caused by a large thrombus from the proximal to mid portion of the left anterior descending artery. Near-infrared spectroscopy-intravascular ultrasonography showed a large amount of thrombus without lipid plaque. Therefore, revascularization was performed using a thrombus-aspiration catheter and intracoronary thrombolysis. In addition, , hyperhomocysteinemia and a deep vein thrombosis occurred. He was diagnosed with acute coronary syndrome complicated with pulmonary embolism and deep vein thrombosis simultaneously induced by hyperhomocysteinemia. After 1 week of antithrombotic therapy, near-infrared spectroscopy-intravascular ultrasonography and optical coherence tomography revealed a decreased thrombus and no significant residual organic stenosis in the left anterior descending artery. He continued conservative therapy with antithrombotic medications including aspirin and warfarin and had no cardiovascular events after discharge. Follow-up coronary angiography and optical coherence tomography at 9 months revealed complete disappearance of the thrombus and no severe stenosis.

Conclusions: Hyperhomocysteinemia should be considered as a cause of arterial vein thrombosis of unknown cause. The antithrombotic therapy and percutaneous revascularization without stenting based on intravascular imaging might be a safe and effective treatment option in patients with acute coronary syndrome complicated with hyperhomocysteinemia.
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http://dx.doi.org/10.1186/s13256-020-02531-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650176PMC
November 2020

TC10, a Rho family GTPase, is required for efficient axon regeneration in a neuron-autonomous manner.

J Neurochem 2020 Nov 6. Epub 2020 Nov 6.

Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan.

Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock-out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild-type and TC10 knock-out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron-intrinsic.
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http://dx.doi.org/10.1111/jnc.15235DOI Listing
November 2020

Increased serum levels of brain-derived neurotrophic factor following wheelchair half marathon race in individuals with spinal cord injury.

J Spinal Cord Med 2020 Oct 15:1-6. Epub 2020 Oct 15.

Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan.

Brain-derived neurotrophic factor (BDNF) has beneficial effects on metabolism as well as the peripheral and central nervous systems. The aim of this study was to assess the response of serum BDNF concentration ([BDNF]s) to wheelchair half marathon race in individuals with spinal cord injury (SCI). Prospective observational study. The 34th Oita International Wheelchair Marathon Race in Japan. Nine cervical SCIs (CSCI) and 8 thoracic and lumber SCIs (LSCI) male athletes. Wheelchair half-Marathon Race. [BDNF]s, plasma concentrations of adrenaline ([Ad]p), noradrenaline ([Nor]p), and cortisol ([Cor]p), hematocrit, and platelet count were measured the day before, immediately after, and an hour after the race. [BDNF]s increased significantly immediately after the race in both groups (CSCI; P = 0.0055, LSCI; P = 0.0312) but returned to the baseline levels at one hour after the race. However, [BDNF]s immediately and one hour after the race were significantly higher in LSCI than in CSCI (immediately after the race; P = 0.0037, 1 h after the race; P = 0.0206). Hematocrit and platelet count remained unchanged throughout the study. In LSCI, [Ad]p, [Nor]p and [Cor]p increased significantly immediately after and one hour after the race, compared with the baseline values (P < 0.05). On the other hand, these variables remained unchanged throughout the study in the CSCI. [BDNF] increased significantly from the baseline in both LCSI and CSCI but was higher in LSCI than in CSCI immediately after and one hour after the race.
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http://dx.doi.org/10.1080/10790268.2020.1816402DOI Listing
October 2020

Favorable changes of left ventricular function in the circumferential direction following transcatheter atrial septal defect closure: a strain imaging study.

Int J Cardiovasc Imaging 2021 Mar 12;37(3):903-912. Epub 2020 Oct 12.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto, 602-8566, Japan.

To clarify the impact on left ventricular (LV) function of percutaneous atrial septal defect (ASD) closure in adult patients. Echocardiograms of 46 patients (52 ± 18 years) who underwent ASD closure with a significant left-to-right shunt obtained before and 1 month after the procedure were retrospectively analyzed. Functional parameters were obtained by 2-dimensional speckle-tracking imaging. Global longitudinal strain and strain rate at early diastole (SRe) was calculated from the three standard apical views, while circumferential and radial parameters were calculated from basal, middle, and apical LV short-axis views. Along with a diminished right ventricular (RV) volume, the LV volume and ejection fraction increased (end-diastolic volume: 61 ± 12 to 76 ± 15 mL, p < 0.001; and 63% ± 4 to 64% ± 4% p = 0.03; respectively). Both global strain and SRe was augmented only in the circumferential direction (- 16.2% ± 2.9% to - 19.8% ± 2.8%; and 1.07 ± 0.29 to 1.34 ± 0.28 s, both p < 0.001). Augmentation of circumferential SRe correlated with both the changes in and the pre-procedural value of diastolic LV eccentricity index (r = - 0.57, p < 0.001; and r = 0.37, p = 0.01; respectively), a morphological parameter of RV volume overload. Following ASD closure in adults, both LV systolic and diastolic function could favorably change in the circumferential direction, and the degree of diastolic functional change is associated with RV volume overload, i.e., severity of ventricular interdependence.
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http://dx.doi.org/10.1007/s10554-020-02064-4DOI Listing
March 2021

Two effective cases of additional pedal artery angioplasty for severe lower limb ischemia following acute thrombotic artery occlusion with hypercoagulable state diseases.

CVIR Endovasc 2020 Sep 28;3(1):71. Epub 2020 Sep 28.

Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: Acute limb ischemia (ALI) and critical limb ischemia (CLI) following ALI are life-threatening diseases. The rare potential causes of ALI include hypercoagulable state diseases, such as antiphospholipid syndrome (APS) and essential thrombocythemia (ET). Hypercoagulability often make revascularization for arterial occlusion, especially associated with infrapopliteal lesions, difficult. This is because the vessels have poor run-off, and elevated peripheral vascular resistance associated with microcirculation failure, due to a high thrombus burden. There is no established treatment for this issue.

Case Presentation: A 45 years-old and a 56 years-old male suffered from thrombotic arterial occlusion as a first manifestation of APS and ET, respectively. Combination therapy with aggressive anti-thrombotic therapy and revascularization, such as endovascular therapy and surgical thrombectomy based on the angiosome concept, was performed. However, the high thrombus burden caused a poor pedal outflow, and significant limb ischemia remained. Additional pedal artery angioplasty was performed to improve residual limb ischemia in each case and provided sufficient blood flow to the foot.

Conclusion: The pedal artery angioplasty for thrombotic pedal artery occlusion cases, associated with hypercoagulable state diseases, seems to be a treatment option for relieving residual limb ischemia.
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http://dx.doi.org/10.1186/s42155-020-00166-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520864PMC
September 2020

The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy.

Intern Med 2021 Feb 19;60(3):423-429. Epub 2020 Sep 19.

Department of Pharmacy, University of Miyazaki Hospital, Japan.

We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy.
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http://dx.doi.org/10.2169/internalmedicine.5317-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925267PMC
February 2021

Stabilization of borate by hot isostatic pressing after co-precipitation with hydroxyapatite using MAP.

Chemosphere 2020 Sep 27;254:126860. Epub 2020 Apr 27.

Department of Earth Resource Engineering, Kyushu University, Fukuoka, 819-0395, Japan.

Boric acid is one of the most mobile inorganic contaminant species in nature due to its pK of 9.23. Co-precipitation of borate with hydroxyapatite (HAp: Ca(PO)OH) facilitates the simultaneous removal of borate with co-existing oxoanions in natural waters. The cost of phosphate is an impediment to industrialize the co-precipitation of borate with HAp for treatment of geothermal waters. In the present work, an inexpensive industrial by-product of magnesium ammonium phosphate (MAP) derived from sewage sludge, was examined as a phosphate source. MAP includes 89% pure magnesium ammonium phosphate, resulting in better performance than the pure chemical form of NHHPO, because Mg and Al (trace elements in MAP product) play roles in enhancing the removal rate of borate and lowering the equilibrium borate concentration. These ions have a good affinity with phosphate to nucleate crystal seeds independently of powdery Ca sources. To reduce the bulky volume of solid residues, hot isostatic pressing (HIP) was applied. There is structural water in HAp; therefore, the greatest volume reduction was achieved with 78.3 ± 2.0% (n = 3). Additionally, a synergic effect to suppress the released borate, greater than the sequential combination of calcination and cold isostatic pressing was accomplished in the toxicity contents leaching procedure (TCLP) test. This is not due to larger crystal sizes alone, but it is derived from boron stabilization in HAp at an atomic level by the synergic effect of heating and pressing simultaneously.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126860DOI Listing
September 2020

Knowledge, perception, and level of confidence regarding COVID-19 care among healthcare workers involved in cardiovascular medicine: a web-based cross-sectional survey in Japan.

J Cardiol 2021 03 8;77(3):239-244. Epub 2020 Aug 8.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

Background: The pandemic of coronavirus disease 2019 (COVID-19) has a significant impact on daily practice in cardiovascular medicine. The preparedness of healthcare workers (HCWs) can affect the spread of infection and the maintenance of the healthcare system. This study aimed to investigate the knowledge, perception, and level of confidence regarding COVID-19 care among HCWs involved in cardiovascular medicine.

Methods: A cross-sectional, web-based study about COVID-19 was performed between April 22 and May 7, 2020, among 311 HCWs in cardiovascular departments. The demographic information, COVID-19-related knowledge, and perception and level of confidence toward COVID-19 care were assessed.

Results: The median age of the participants was 38 years, and 215 (69.8%) were male. There were 134 (43.1%) physicians and 177 (56.9%) non-physician HCWs. The HCWs, especially non-physician HCWs, had insufficient knowledge about infection-prevention measures for COVID-19, such as how to isolate patients with COVID-19, how to use personal protective equipment, and how to prevent infection during aerosol-generating procedures. Most HCWs showed a low level of confidence toward COVID-19 care, and such poor confidence was associated with the lack of knowledge on optimal infection-prevention measures.

Conclusions: This survey revealed the lack of knowledge about adequate infection-prevention measures for COVID-19. More attention should be paid to the preparedness of HCWs, and educating and supporting HCWs involved in cardiovascular medicine is an urgent need.
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http://dx.doi.org/10.1016/j.jjcc.2020.07.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414383PMC
March 2021

Prognostic value of pupil area for all-cause mortality in patients with heart failure.

ESC Heart Fail 2020 10 10;7(5):3067-3074. Epub 2020 Aug 10.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Aims: The area of the pupil can be used as an indicator of autonomic function. However, the relation between pupil area and prognosis in heart failure (HF) patients remains unclear. This study was performed to examine whether pupil area can be used as a prognostic indicator in patients with HF.

Methods And Results: This retrospective review was performed in 870 consecutive patients (mean age: 67.0 ± 14.1 years, 37.0% women) hospitalized for acute HF. Pupil area was measured with a pupilometer at least 7 days after hospitalization for HF. The primary endpoint was all-cause mortality, and the secondary endpoint was readmission due to HF. A total of 131 patients died, and 328 patients were readmitted because of HF over a median follow-up of 1.9 (interquartile range: 1.0-3.7 years) years. After adjustment for several pre-existing prognostic factors, including Seattle Heart Failure Score (SHFS), pupil area was shown to be independently associated with all-cause mortality (hazard ratio: 0.72; 95% confidence interval: 0.59-0.88; P = 0.001) and readmission due to HF (hazard ratio: 0.82; 95% confidence interval: 0.73-0.93; P = 0.003). Addition of pupil area to SHFS significantly increased the area under the receiver-operating characteristic curve for all-cause mortality (0.69 vs. 0.72, respectively; P = 0.034).

Conclusions: Pupil area is an independent predictor of all-cause mortality and readmission due to HF and adds prognostic information to SHFS in patients with HF. The results presented here suggest that pupil area may be useful as a prognostic marker in patients with HF.
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http://dx.doi.org/10.1002/ehf2.12933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524244PMC
October 2020

Clinical characteristics, the diagnostic criteria and management recommendation of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) proposed by Japan Otological Society.

Auris Nasus Larynx 2021 Feb 5;48(1):2-14. Epub 2020 Aug 5.

Department of Otolaryngology, Miyazaki University Faculty of Medicine, Miyazaki, Japan.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits. It primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis. Intractable otitis media frequently occurs in patients with GPA, MPA or EGPA, although all patients show similar clinical features, regardless of the type of AAV. Furthermore, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or any other AAV-related lesions at the initial visit; therefore, these patients do not fulfill the ordinary diagnostic criteria for systemic AAV. Thus, we first proposed that this condition could be categorized as "otitis media with AAV (OMAAV)". Subsequently, the Japanese Otological Society (JOS) conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. The survey revealed that OMAAV is a disease that initially occurs in the middle ear and subsequently spreads to other organs such as the lungs and kidneys, with eventual involvement of all body organs. Severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and subarachnoid hemorrhage resulting in death can also occur. In this review, we introduce the clinical features, diagnostic criteria, and treatment strategies recommended by JOS for early diagnosis and treatment of OMAAV.
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http://dx.doi.org/10.1016/j.anl.2020.07.004DOI Listing
February 2021

Sensorineural hearing loss and hypoplastic cochlea in Axenfeld-Rieger syndrome with FOXC1 mutation.

Auris Nasus Larynx 2020 Jul 30. Epub 2020 Jul 30.

Department of Neurology, Osaka Red Cross Hospital, Tennoji-ku, Osaka, 543-8555, Japan.

Objective: Axenfeld-Rieger syndrome (ARS) type 3 is a rare autosomal dominant disease, characterized by anterior segment dysgenesis of the eye, hearing loss, and cardiac defects. ARS type 3 is highly associated with FOXC1 mutations, which induces developmental disorders of neural crest cells. Most studies about ARS patients focused on ophthalmologic findings, but details in their hearing loss have not yet been revealed. In this report, we investigated audiological and otological manifestations in the ARS type 3 patient who had the novel heterozygous FOXC1 mutation leading deletion at the forkhead DNA-binding domain.

Methods And Results: Pure tone audiometry showed bilateral sensorineural hearing loss (SNHL) and audiological examinations confirmed that major dysfunctions existed in the cochlea, rather than the spiral ganglion neurons and the cochlear nerve. CT and MRI revealed the hypoplastic cochlea at both sides. Given that the 6p25 deletion syndrome, lacking one allele of the FOXC1 gene, shows similar, but more severe cochlear malformations than the present case, the FOXC1 mutations might contribute to the hypoplasia and dysfunctions in the cochlea.

Conclusion: To our knowledge, this is the first report demonstrating that the ARS type 3 patient with the FOXC1 mutation has the hypoplasia and dysfunctions in the cochlea, which results in bilateral SNHL.
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http://dx.doi.org/10.1016/j.anl.2020.07.006DOI Listing
July 2020

Rehabilitation Therapy for a COVID-19 Patient Who Received Mechanical Ventilation in Japan.

Am J Phys Med Rehabil 2020 10;99(10):873-875

From the Department of Rehabilitation Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan (TS, MN, TN); Department of Rehabilitation Medicine, Yokohama City University Hospital, Yokohama, Japan (TS, RC, JU); and Department of Emergency Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan (FO, IT).

A 65-yr-old man visited a primary care hospital with a continued fever of 38°C for 3 days. As his fever did not improve until 8 days after, he was admitted into another acute care hospital, where his respiratory condition rapidly worsened. Therefore, the patient was transferred to our hospital. On the day of transfer (day 1), he was started on mechanical ventilation. COVID-19 was diagnosed using a polymerase chain reaction assay 6 days after admission (day 6). The rehabilitation therapy was begun on day 6. The initial rehabilitation programs focused on positioning and postural drainage. The patient was extubated on day 19, and he began standing and stepping on the same day. Gait exercises began on day 22, and endurance training was initiated on day 28. The patient was discharged from our hospital on day 34 as he met the physical function milestones. One month after discharge, the Medical Research Council sum score and Barthel Index had each improved; therefore, muscle strength and daily activities had returned to normal. It was assumed that mobilization should be performed as soon as possible after the end of sedation during the acute phase of severe COVID-19 infection in patients receiving mechanical ventilation.
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http://dx.doi.org/10.1097/PHM.0000000000001545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406209PMC
October 2020

Quadriceps Strength and Mortality in Older Patients With Heart Failure.

Can J Cardiol 2021 Mar 3;37(3):476-483. Epub 2020 Jul 3.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Background: This study was performed to test the hypothesis that low quadriceps isometric strength (QIS) is associated with greater risk of mortality and has the additive prognostic significance to the severity of heart failure (HF) and gait speed in older patients with HF.

Methods: A retrospective cohort study was performed in 1273 patients ≥ 60 years of age with HF (mean age 75 ± 8 years, 59.1% men); all of whom were evaluated during hospitalization for usual gait speed and maximal QIS. The QIS was expressed relative to body mass (% BM). The endpoint was all-cause mortality.

Results: Over a median follow-up period of 1.59 years (interquartile range, 0.58 to 3.42 years), 224 patients died. The cutoff value based on the Youden index for the QIS discriminating those at high risk of mortality was 36.2% BM for overall, and we defined less than this cutoff point of QIS as low QIS. After adjustment for the HF risk score, the hazard ratio in low QIS was 1.55 for overall (95% confidence interval [CI], 1.17-2.06). The addition of low QIS to the HF risk score and gait speed was associated with significant increases in both net reclassification improvement (NRI, 0.239 for overall; 95% CI, 0.096-0.381) and integrated discrimination improvement (IDI, 0.004 for overall; 95% CI, 0.001-0.009) for all-cause mortality.

Conclusion: Low QIS was strongly associated with poor prognosis and showed complementary prognostic predictive capability to the HF risk score and gait speed in older patients with HF.
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http://dx.doi.org/10.1016/j.cjca.2020.06.019DOI Listing
March 2021

The GLIM criteria for defining malnutrition can predict physical function and prognosis in patients with cardiovascular disease.

Clin Nutr 2021 Jan 6;40(1):146-152. Epub 2020 May 6.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Background & Aims: The Global Leadership Initiative on Malnutrition (GLIM) published a new international standard for defining malnutrition in 2018. The GLIM criteria were compared with the European Society for Clinical Nutrition and Metabolism (ESPEN) criteria in relation to physical function and mortality risk in patients with cardiovascular disease (CVD).

Methods: A total of 921 CVD patients ≥ 20 years old (67.8 ± 13.4 years, 631 men) hospitalised for heart failure, acute coronary syndrome and other conditions were stratified according to the presence or absence of malnutrition according to the GLIM and ESPEN criteria. Physical function was assessed by measuring grip strength, 6-minute walking distance and quadriceps isometric strength before hospital discharge, and the endpoint was all-cause mortality.

Results: During the median follow-up period of 2.3 years (interquartile range, 0.9-3.5 years), 194 deaths occurred in the study population. Malnutrition defined by the GLIM criteria was significantly associated with low physical function. Malnutrition defined by both the GLIM and ESPEN criteria was significantly related to all-cause mortality (P < 0.05).

Conclusions: Malnutrition defined according to the GLIM criteria was a predictor of both low physical function and mortality in patients with CVD.
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http://dx.doi.org/10.1016/j.clnu.2020.04.038DOI Listing
January 2021

The RAS-interacting chaperone UNC119 drives the RASSF6-MDM2-p53 axis and antagonizes RAS-mediated malignant transformation.

J Biol Chem 2020 08 18;295(32):11214-11230. Epub 2020 Jun 18.

Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

The gene encoding the proto-oncogene GTPase RAS is frequently mutated in human cancers. Mutated RAS proteins trigger antiapoptotic and cell-proliferative signals and lead to oncogenesis. However, RAS also induces apoptosis and senescence, which may contribute to the eradication of cells with RAS mutations. We previously reported that Ras association domain family member 6 (RASSF6) binds MDM2 and stabilizes the tumor suppressor p53 and that the active form of KRAS promotes the interaction between RASSF6 and MDM2. We also reported that Unc-119 lipid-binding chaperone (UNC119A), a chaperone of myristoylated proteins, interacts with RASSF6 and regulates RASSF6-mediated apoptosis. In this study, using several human cancer cell lines, quantitative RT-PCR, RNAi-based gene silencing, and immunoprecipitation/-fluorescence and cell biology assays, we report that UNC119A interacts with the active form of KRAS and that the C-terminal modification of KRAS is required for this interaction. We also noted that the hydrophobic pocket of UNC119A, which binds the myristoylated peptides, is not involved in the interaction. We observed that UNC119A promotes the binding of KRAS to RASSF6, enhances the interaction between RASSF6 and MDM2, and induces apoptosis. Conversely, silencing promoted soft-agar colony formation, migration, and invasiveness in KRAS-mutated cancer cells. We conclude that UNC119A promotes KRAS-mediated p53-dependent apoptosis via RASSF6 and may play a tumor-suppressive role in cells with KRAS mutations.
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http://dx.doi.org/10.1074/jbc.RA120.012649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415979PMC
August 2020