Search

6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for aromatic L-amino acid hydroxylases, including tyrosine hydroxylase (TH), alkylglycerol monooxygenase, and three types of nitric oxide (NO) synthases (NOS). Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene-disrupted (Spr

Background Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. Methods Adult C57BL/6J mice of both sexes were subjected to potassium chloride–induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg–1 · h–1, dexmedetomidine at 1 µg · kg–1 · h–1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. Results Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. Conclusions Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The purpose of this study was to examine the survival benefits of a workflow in which an interventional radiology (IR) team participates in a primary trauma survey on patients with hemodynamically unstable trauma.A retrospective observational study was conducted between 2012 and 2019 at a single institution. Patients who underwent an IR procedure as the initial hemostasis were assigned to the hemodynamically stable group (HSG) or hemodynamically unstable group (HUG). The primary and secondary outcomes were survival at hospital discharge compared with the probability of survival (Ps) and the time course.A total of 160 patients (100 men, 60 women; median age, 57.5 years [interquartile range (IQR): 31.5-72 years]) with an injury severity score of 24 (IQR: 13.75-34) were included. A total of 125 patients were included in the HSG group and 35 patients in the HUG group. The observational survival rate was significantly greater than the Ps rate by 4.9% (95% confidence interval [CI]: 1.6-8.4%; P = 0.005) in HSG and by 24.6% in HUG (95% CI: 16.9-32.3%; P0.001). The observational survival rate was significantly greater than Ps in HUG than in HSG (P0.001). The median time to initiate IR procedures and the median procedure time in HUG were 54 min [IQR: 45-66 min] and 48 min [IQR: 30-85 min], respectively; both were significantly shorter than those in the HSG.A trauma workflow utilizing an IR team in a primary survey is associated with improved survival of patients with hemodynamically unstable trauma when compared with Ps with a shorter time course.

Catecholamine signaling is known to influence bone tissue as reuptake of norepinephrine released from sympathetic nerves into bone cells declines with age leading to osteoporosis. Further, β-adrenoceptor-blockers like propranolol provoke osteoprotective effects in osteoporotic patients. However, besides systemic adrenal and sympathetic catecholamine production, it is also known that myeloid cells can synthesize catecholamines, especially under inflammatory conditions. To investigate the effects of catecholamines produced by CD11b+ myeloid cells on bone turnover and regeneration, a mouse line with specific knockout of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in CD11b+ myeloid cells (THflox/flox/CD11b-Cre+, referred to as THCD11b-Cre) was generated. For bone phenotyping, male mice were sacrificed at eight and twelve weeks of age and harvested bones were subjected to bone length measurement, micro-computed tomography, fluorescence-activated cell sorting of the bone marrow, gene expression analysis, histology and immunohistochemistry. Support for an age-dependent influence of myeloid cell-derived catecholamines on bone homeostasis is provided by the fact that twelve-week-old, but not eight-week-old THCD11b-Cre mice, developed an osteopenic phenotype and showed increased numbers of neutrophils and T lymphocytes in the bone marrow, while CCL2, IL-6, IL-4 and IL-10 mRNA expression was reduced in sorted myeloid bone marrow cells. To investigate the influence of myeloid cell-derived catecholamines on fracture healing, mice received a diaphyseal femur osteotomy. Three days post-fracture, immunohistochemistry revealed an increased number of macrophages, neutrophils and cytotoxic T lymphocytes in the fracture hematoma of THCD11b-Cre mice. Micro-computed tomography on day 21 showed a decreased tissue mineral density, a reduced bone volume and less trabeculae in the fracture callus indicating delayed fracture healing, probably due to the increased presence of inflammatory cells in THCD11b-Cre mice. This indicates a crucial role of myeloid cell-derived catecholamines in immune cell-bone cell crosstalk and during fracture healing.

Vancomycin (VCM) is a standard treatment for bacterial meningitis. However, little is known about the transferability of VCM to cerebrospinal fluid (CSF), thus evidence of the transferability of VCM to CSF during bacterial meningitis is needed. In this study, we evaluated the concentration of VCM in the plasma and CSF of postoperative neurosurgical patients with bacterial meningitis and evaluated the factors that affect the transferability of VCM to CSF. The concentrations of VCM in plasma (trough) and CSF were determined in eight patients (four males and four females) with bacterial meningitis who were treated with VCM using HPLC. The ratio of the VCM concentrations in CSF/plasma was also calculated by estimating the blood VCM concentration at the same time as the VCM concentration in CSF was measured. The results showed that the VCM concentration in CSF was 0.9-12.7 µg/mL and the CSF/plasma VCM concentration ratio was 0.02-0.62. We examined the effect of drainage on the transferability of VCM to CSF, which showed that the VCM concentration in CSF and the CSF/plasma VCM concentration ratio were significantly higher in patients not undergoing drainage than in patients who were undergoing drainage. The CSF protein and glucose concentrations, which are diagnostic indicators of meningitis, were positively correlated with the VCM concentration in CSF and the CSF/plasma VCM concentration ratio. Thus, VCM transferability to CSF may be affected by changes in the status of the blood-brain barrier and blood-cerebrospinal fluid barrier due to drainage or meningitis.

Background: Dynamic balance is essential for pitching motion because pitching kinematics requires whole body coordination. The Star Excursion Balance Test (SEBT) and the Y balance test (YBT) evaluate dynamic balance quantitatively. There are some reports that investigated the relationship between SEBT/YBT and pain in upper and lower extremities, but there is no study among high school baseball pitchers. Hypothesis: Dynamic balance deficiency is associated with shoulder pain among high school baseball pitchers. Study Design: Cross-sectional study. Level of Evidence: Level 4. Methods: A total of 259 male high school pitchers who participated in the preseason medical checkups were included in the study. YBT was used to measure their dynamic balance. The participants completed a questionnaire which asked if they were currently experiencing shoulder pain. Results: Twenty-two pitchers had shoulder pain during the preseason medical checkups. In the YBT, the posterolateral balance while standing with the axis leg as well as the posteromedial and posterolateral balance while standing with the step leg were significantly lower in the pain group than in the nonpain group ( P = 0.05, 0.04, and 0.001, respectively). A logistic regression analysis showed that posterolateral balance when standing with the step leg was an independent risk factor for current shoulder pain ( P = 0.04, odds ratio 0.942, 95% CI 0.892-0.996). Conclusion: The dynamic balance of high school baseball pitchers with shoulder pain was lower than that of participants without shoulder pain. In particular, posterolateral direction with the step leg standing was significantly related to shoulder pain. Clinical Relevance: Among high school baseball pitchers, decreased dynamic balance was related to current shoulder pain. YBT maybe recommended in preseason medical checkups for high school baseball pitchers.

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury., The brain is sensitive to oxygen deprivation. Here, the authors show in experimental animals that sensitivity to hypoxia is inversely related to the level of sulfide:quinone oxidoreductast (SQOR) and the capacity to catabolize sulfide in the brain.

Background Infection is a major cause of mortality in patients with systemic lupus erythematosus (SLE). Therefore, minimizing the risk of infection is an important clinical goal to improve the long-term prognosis of SLE patients. Treatment with ≥7.5 mg prednisolone (PSL) or equivalent has been reported to increase the risk of infections. However, it remains unclear whether Methods This prospective cohort study included patients from the Japanese multicenter registry of patients with SLE (defined as ≥4 American College of Rheumatology 1997 revised criteria) over 20 years of age. The PSL dose was categorized as PSL 0–2.5, 2.6–5.0, 5.1–7.5, and 7.6–15.0 mg. The primary outcome was infection requiring hospitalization. We conducted a multivariable analysis using time-dependent Cox regression analysis to assess the hazard ratio of infection occurrence compared with a dose of 0–2.5 mg PSL or equivalent in the other three PSL dose groups. Based on previous reports and clinical importance, the covariates selected were age, sex, and concurrent use of immunosuppressants with GC. In addition, two sensitivity analyses were conducted. Results The mean age of the 509 SLE patients was 46.7 years; 89.0% were female, and 77.2% used multiple immunosuppressants concomitantly. During the observation period, 52 infections requiring hospitalization occurred. The incidence of infection with a PSL dose of 5.0–7.5 mg was significantly higher than that in the PSL 0–2.5 mg group (adjusted hazard ratio: 6.80, 95% confidence interval: 2.17–21.27). The results of the two sensitivity analyses were similar. Conclusions Our results suggested that the use of 5.0–7.5 mg PSL or equivalent could pose an infection risk in SLE patients. This finding indicates that PSL dose should be reduced to as low as possible in SLE patients to avoid infection.

Nitric oxide (NO) exerts its biological effects primarily via activation of guanylate cyclase (GC) and production of cyclic guanosine monophosphate. Inhaled NO improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CPR). However, mechanisms of the protective effects of breathing NO after cardiac arrest are incompletely understood.To elucidate the mechanisms of beneficial effects of inhaled NO on outcomes after cardiac arrest.Adult male C57BL/6J wild-type (WT) mice, GC-1 knockout mice, and chimeric WT mice with WT or GC-1 knockout bone marrow were subjected to 8 min of potassium-induced cardiac arrest to determine the role of GC-1 in bone marrow-derived cells. Mice breathed air or 40 parts per million NO for 23 h starting at 1 h after CPR.Breathing NO after CPR prevented hypercoagulability, cerebral microvascular occlusion, an increase in circulating polymorphonuclear neutrophils and neutrophil-to-lymphocyte ratio, and right ventricular dysfunction in WT mice, but not in GC-1 knockout mice, after cardiac arrest. The lack of GC-1 in bone marrow-derived cells diminished the beneficial effects of NO breathing after CPR.GC-dependent signaling in bone marrow-derived cells is essential for the beneficial effects of inhaled NO after cardiac arrest and CPR.

Objective This study aimed to assess the prevalence and actual treatment conditions for hypertension and dyslipidaemia complicated with systemic lupus erythematosus (SLE). Methods This was a cross-sectional study. We established the lupus registry of nationwide institutions (LUNA), a multi-centre cohort of SLE patients in Japan. From February 2016 to July 2018, 597 SLE patients were registered in the LUNA. We evaluated the incidence of hypertension and dyslipidaemia and analysed the risk factors for hypertension and dyslipidaemia by logistic regression analysis. Results Overall, 597 patients were enrolled in the study. The median age was 44 years, and 88.0% of the patients were female. Among all the patients, 92.9% used prednisolone. The prevalence of hypertension and dyslipidaemia was 43.9% and 54.7%, respectively. Among the patients receiving medication for hypertension, 24.7% exhibited insufficient control (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg), and among those receiving medication for hyperlipidaemia, 48.1% showed insufficient control (low-density lipoprotein cholesterol >140 mg/dL or triglyceride >150 mg/dL). The risk factors for hypertension were age, body mass index (BMI), disease duration, past maximum dose of prednisolone, and renal involvement, whereas those for dyslipidaemia were age and BMI. Conclusion About half of the patients had hypertension or dyslipidaemia, and a considerable number of cases were poorly controlled despite medication. Our data suggest that physicians should treat SLE activity as well as its complications, especially the common risk factors for atherosclerosis.

Background and objectives The effectiveness of local therapy has been reported in non-small-cell lung cancer (NSCLC) patients with oligo-recurrence. However, there is still no clear consensus on the choice of local therapy. We aimed to examine the choice of local therapy in NSCLC patients with lung oligo-recurrence. Methods Among 1760 consecutive NSCLC patients who underwent complete resection between 1990 and 2008, 535 patients developed recurrence. Lung oligo-recurrence was defined as 1-5 metachronous recurrences limited to the lungs only; such recurrence was found in 97 patients. We examined the differences in the prognosis of each therapy for these patients. Results The 5-year postrecurrence survival (PRS) rates in patients who underwent local therapy (n = 54) and those who did not (n = 43) were 55.6% and 31.1%, respectively; it was significantly higher in patients who underwent local therapy (p = 0.004). Among 47 patients who underwent resection or radiation therapy, the 5-year PRS rates were 61.5% and 47.6% (p = 0.258), and the 5-year postrecurrence progression-free survival rates were 30.3% and 24.7% (p = 0.665), respectively, without any significant difference. Conclusions Patients with lung oligo-recurrence should consider local therapy individually, depending on their general condition.

The relationship between ankle joint function and throwing-related injuries has not been demonstrated. We hypothesized that limited ankle joint range of motion (ROM) was related to risk factors for shoulder and elbow injuries in young baseball players. This 12-month prospective cohort study evaluated the age, height, weight, playing position, shoulder, elbow, and ankle function of 228 enrolled baseball players. Shoulder and elbow injuries were tracked during the season. Univariate and multivariate analyses were performed to identify risk factors for shoulder and elbow injuries among participants divided into non-injured and injured groups. Univariate analysis showed that age, height, weight, ROM of elbow flexion in the dominant arm, muscle strength ratio of shoulder abduction, and the likelihood of being a pitcher or a catcher were significantly greater in the injured group than in the non-injured group. ROM of shoulder abduction-external/internal rotation, shoulder total arc on the dominant arm, ankle joint dorsiflexion, and plantar flexion on the back (non-lead) and front (lead) legs were significantly less in the injured group than in the non-injured group. In conclusion, ROM dorsiflexion deficits in the back leg, shoulder abduction-external rotation in the dominant arm, ROM increase in elbow flexion on the dominant side, older age, and being a pitcher were significant independent risk factors for injury.

Background: Right ventricular (RV) dysfunction is common and associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19). In non-COVID-19 acute respiratory distress syndrome, RV dysfunction develops due to pulmonary hypoxic vasoconstriction, inflammation, and alveolar overdistension or atelectasis. Although similar pathogenic mechanisms may induce RV dysfunction in COVID-19, other COVID-19-specific pathology, such as pulmonary endothelialitis, thrombosis, or myocarditis, may also affect RV function. We quantified RV dysfunction by echocardiographic strain analysis and investigated its correlation with disease severity, ventilatory parameters, biomarkers, and imaging findings in critically ill COVID-19 patients. Methods: We determined RV free wall longitudinal strain (FWLS) in 32 patients receiving mechanical ventilation for COVID-19-associated respiratory failure. Demographics, comorbid conditions, ventilatory parameters, medications, and laboratory findings were extracted from the medical record. Chest imaging was assessed to determine the severity of lung disease and the presence of pulmonary embolism. Results: Abnormal FWLS was present in 66% of mechanically ventilated COVID-19 patients and was associated with higher lung compliance (39.6 vs 29.4 mL/cmH2O, P = 0.016), lower airway plateau pressures (21 vs 24 cmH2O, P = 0.043), lower tidal volume ventilation (5.74 vs 6.17 cc/kg, P = 0.031), and reduced left ventricular function. FWLS correlated negatively with age (r = −0.414, P = 0.018) and with serum troponin (r = 0.402, P = 0.034). Patients with abnormal RV strain did not exhibit decreased oxygenation or increased disease severity based on inflammatory markers, vasopressor requirements, or chest imaging findings. Conclusions: RV dysfunction is common among critically ill COVID-19 patients and is not related to abnormal lung mechanics or ventilatory pressures. Instead, patients with abnormal FWLS had more favorable lung compliance. RV dysfunction may be secondary to diffuse intravascular micro- and macro-thrombosis or direct myocardial damage. Trial Registration: National Institutes of Health #NCT04306393. Registered 10 March 2020, https://clinicaltrials.gov/ct2/show/NCT04306393

Introduction Laparoscopic cholecystectomy is a common surgery with a varying difficulty level. Difficult laparoscopic cholecystectomy may be experienced by many surgeons. If difficult procedures are predicted preoperatively, surgeons may be able to plan the surgical approach and treatment accordingly. Studies have reported using blood and clinical imaging data to predict difficult cholecystectomy. However, to our knowledge, no studies have reported using MRI. The purpose of this study was to evaluate the usefulness of MRI as a predictor of difficult laparoscopic cholecystectomy. Methods We retrospectively evaluated 25 patients with cholecystitis or biliary colic who had undergone diffusion-weighted whole-body imaging before laparoscopic cholecystectomy. The apparent diffusion coefficient value of the cystic duct was measured and its relationship with operative time and blood loss was examined to assess the capacity of diffuse-weighted whole-body imaging to predict difficult cholecystectomy. Further, we collected blood data and compared its usefulness as a predictor. Results The apparent diffusion coefficient value of the cystic duct was significantly lower in patients with difficult laparoscopic cholecystectomy than in those with non-difficult procedures (P = .00007). White blood cell count and serum C-reactive protein level were significantly higher in patients with difficult cholecystectomy than in those with non-difficult procedures (P = .035, .030). In the receiver operating characteristic analysis, the apparent diffusion coefficient value was the best predictor. Conclusion Our results suggest that the apparent diffusion coefficient value of the cystic duct is a predictor of difficult laparoscopic cholecystectomy. In the future, it may be useful to study changes in coefficient values over time to determine optimal surgical timing.

Background Meningioma is a common intracranial tumor originating from arachnoid cap cells. Meningiomas are generally benign tumors curable by one-time resection. However, some meningiomas regrow and invade into the dura mater, and thus frequently require additional treatment. A useful marker to predict the regrowth of meningioma is desired. This study aimed to clarify the significance of p53 and Ki67 for postoperative recurrence of meningioma. Materials and methods The expression of p53 and Ki67 in 215 intracranial or intraspinal meningiomas was investigated by immunohistochemistry. Results Of the 215 meningiomas, 35 cases (16.3%) were p53-positive and 49 cases (22.8%) were Ki67-positive. Multivariate analysis revealed Ki67 and p53 status as being significantly correlated with recurrence. Positivity for either Ki67- or p53 was significantly associated with poor recurrence-free survival. Conclusion Combined p53 and Ki67 status might represent a useful independent predictive marker for recurrence of meningioma.

The pathogenic mechanism of dementia is still unknown, and the fundamental treatment remains to be established. Thus, there is growing interest in preventing dementia through diet. One of the functional ingredients attracting attention is docosahexaenoic acid. We conducted a 12-month, randomized, double-blind, placebo-controlled clinical trial in healthy elderly Japanese individuals with a Mini-Mental State Examination score of 28 or higher at baseline using a docosahexaenoic acid-enriched milk beverage containing 297 mg docosahexaenoic acid and 137 mg eicosapentaenoic acid. Consumption of a docosahexaenoic acid-enriched milk beverage increased the fatty acid levels of docosahexaenoic acid and eicosapentaenoic acid in erythrocyte membranes, which was the primary outcome of this study. Moreover, intake of this beverage prevented age-related cognitive decline and decreased serum bone resorption marker levels. Our data demonstrate that, even at a low dose, long-term daily intake of docosahexaenoic acid prevents dementia and may show beneficial effect on bone health.

While previous studies have revealed factors affecting the progression of rotator cuff tear (RCT), none have yet described factors affecting its onset. The purpose of this longitudinal observational study was to analyze factors affecting the RCT onset and progression in the general population. The present study included 185 shoulders from 93 participants who completed all the examinations in both 2012 and 2017. Participants received a questionnaire with age, gender, arm dominance, and presence of pain at rest, in motion, and at night. The range of motion (ROM), simple shoulder test (SST) were also examined. Anteroposterior radiograph of the shoulder joint was performed to evaluate the degree of osteoarthritic changes by the Samilson-Prieto (S-P) classification. The degree of RCT was examined by ultrasonography. There were 132 shoulders without RCT and 53 with RCT in 2012. RCT occurred in 21 of 132 shoulders, and the factor affecting the RCT onset was S-P grade 2 osteoarthritic change in 2012 (odds ratio [OR] 10.10). RCT progressed in 22 of 53 shoulders, and the factor affecting RCT progression was the presence of motion pain in 2012 (OR 13.76). These results added new knowledge regarding the natural course of RCT onset and progression.

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.

Background The prognosis of postoperative recurrence in patients with non‐small cell lung cancer (NSCLC) is poor. However, depending on the recurrence patterns and treatment options, some patients can achieve long‐term survival following recurrence. In this study, we investigated the clinicopathological characteristics of NSCLC patients with curable disease who developed postoperative recurrence. Methods This retrospective study enrolled 535 patients who had developed recurrence from among 1760 consecutive patients with NSCLC who underwent curative resection from 1990 to 2008. Post‐recurrence cure was defined as being cancer‐free for at least five years after treatment for recurrence in patients who had undergone radical local treatment or chemotherapy. The clinicopathological characteristics associated with post‐recurrence cure were analyzed. Results Among 535 patients who developed recurrence, 24 (4.5%) achieved post‐recurrence cure. The median post‐recurrence follow‐up duration was 151 (85–275) months for those who achieved post‐recurrence cure. The solitary recurrent lesions and local treatment for the initial recurrence site were significantly more for patients who could be cured after they developed recurrence. All patients with post‐recurrence cure received only radical local treatment for the recurrent lesions. Conclusions Some patients with solitary recurrent NSCLC lesions can be cured with only radical local treatment. Key points Significant findings of the study The post‐recurrence cure patients maintained a cancer‐free status for five years after treatment for recurrence without a second recurrence. All patients with post‐recurrence cure received only radical local treatment for recurrence and had significantly higher number of solitary recurrent lesions. What this study adds Some patients with solitary recurrent NSCLC lesions after resection can be cured with only radical local treatment., Among 535 patients who developed recurrence, 24 (4.5%) patients achieved post‐recurrence cure. The post‐recurrence cure patients who sustained cancer‐free status for five years after treatment for recurrent lesions did not develop second recurrence. All post‐recurrence cure patients received only local treatment, and the solitary recurrent lesions and local treatment at the initial recurrent sites were significantly associated with post‐recurrence cure.

Remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE), a rheumatic disease affecting the elderly, responds well to corticosteroids; however, our RS3PE patients' corticosteroid therapy is longer than expected. Elderly-onset rheumatoid arthritis (EORA) patients are reported to be at a significantly increased risk for steroid-related side effects including cardiovascular diseases (CVDs). To clarify the complications during a 1-year follow-up in corticosteroid-treated RS3PE patients compared to EORA patients. We retrospectively analyzed the records of 47 RS3PE patients (28 men, 19 women, age 78.4 ± 7.5 years) and 46 EORA patients (10 men, 36 women; 77.0 ± 6.8 yrs) to compare the complications over a 1-year follow-up. The RS3PE and EORA groups' average initial PSL doses were 16.5 ± 7.2 mg/day and 7.3 ± 4.6 mg/day, respectively. During the 1-year follow-up after treatment, there was no significant increase in CVDs in both groups. However, infections occurred in nine RS3PE patients, which is a significantly higher incidence compared to the EORA patients with infections (

Objectives To examine whether lithium suppresses orthodontically induced root resorption (OIRR) via two mechanisms (prevention of hyalinization in periodontal tissue and suppression of odontoclasts) and to investigate the changes in the periodontal tissue and alveolar bone, focusing on the appearance of cell death, hyalinization, and odontoclasts. Materials and Methods The maxillary first molars of 10-week-old male Wistar rats were moved mesially by a closed-coil spring for 14 days. Lithium chloride (LiCl; 0.64 mM/kg) or saline (control) was administered intraperitoneally daily. Tooth movements were measured using micro–computed tomography. Appearances of cell death, hyalinization, and odontoclasts were evaluated by histological analysis. Results OIRR observed on day 14 in the control group was suppressed strongly by LiCl administration. Apoptotic cells observed on day 1 in the compression area were gradually diminished on days 2 and 3 and transformed to hyalinization tissue in the control group. LiCl administration remarkably suppressed this cell death and subsequent hyalinization. Also, the appearance of odontoclasts in the compression area observed on day 7 was significantly suppressed by LiCl administration. Accordingly, these degenerative processes to OIRR were suppressed substantially by LiCl treatment. Conclusions Lithium reduces OIRR through the suppression of periodontal ligament cell death, hyalinization, and odontoclast formation.

Background: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Methods: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR −/− ) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. Results: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P =0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P P =0.045). Conclusions: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Objective: To determine whether the positivity of baseline anti-Ro/Sjögren’s syndrome antigen A (SSA) antibodies influences the response to abatacept, we compared therapeutic responses between anti-Ro/SSA antibody-negative and -positive patients with rheumatoid arthritis (RA) using a multicentre RA ultrasonography prospective cohort. Method: We reviewed Japanese patients with RA who started abatacept as the first biological disease-modifying anti-rheumatic drug between June 2013 and April 2018. We assessed 28-joint Disease Activity Score–erythrocyte sedimentation rate (DAS28-ESR) change between baseline and 6 or 12 months after treatment in RA patients treated with abatacept, and European League Against Rheumatism (EULAR) response at 6 and 12 months. The Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated at baseline and at 6 and 12 months. Results: Overall, 51 patients were enrolled and divided into anti-Ro/SSA antibody-negative and -positive groups of 35 and 16, respectively. Median age at baseline was significantly higher in the anti-Ro/SSA antibody-negative group (p = 0.04). The retention rate and percentage of EULAR good responders at 12 months were significantly higher in the anti-Ro/SSA antibody-negative group (both p = 0.02). Anti-Ro/SSA antibody-negative patients exhibited larger decreases in both DAS28-ESR and DAS28-C-reactive protein at 12 months than anti-Ro/SSA antibody-positive patients (p = 0.02 and 0.04, respectively). GLOESS decreased significantly at 6 months in anti-Ro/SSA antibody-negative patients (p = 0.03). Multivariate analyses showed that anti-Ro/SSA antibody positivity was an independent factor associated with change in the DAS28-ESR at 6 months (p Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p

Background Symptomatic intramedullary arachnoid cysts are rarely observed lesions, particularly in the pediatric age group. Treatment includes cyst fenestration or resection of the cyst wall, and recurrence after surgery has never been reported. We report a rare case of a spinal intramedullary arachnoid cyst, which recurred after cyst fenestration and required reoperation after a certain period. Case Description A 4-year-old boy presented to our hospital with tetraparesis and bladder and rectum disorder. A cystic intramedullary lesion in the cervical spinal cord was detected in preoperative imaging. An emergency fenestration of cyst was performed, and his symptoms were resolved immediately. One month after the operation, the symptoms and cyst recurred. The symptoms improved in the natural course without reoperation. However, the cyst increased in size and the symptoms recurred after 27 months from the first relapse and the cyst was removed urgently. The diagnosis was an arachnoid cyst. After the reoperation, the cyst has disappeared and not recurred. Conclusions To the best of our knowledge, this is the first report of recurrence of an intramedullary arachnoid cyst. This case indicates the importance of considering the resection of cyst wall as possible because of the probability of cyst recurrence after fenestration, while careful observation is the option in the short term, especially for children or high-risk cases.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the s-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota., Scientific Reports, 10(1), art.no.9466; 2020

To predict the histologic invasiveness of pure GGNs using the maximum CT value.One hundred eighty patients underwent a resection of pure GGNs. On preoperative CT imaging studies, we selected the axial section that showed the densest component of each GGN. The CT value was measured using a DICOM (Digital Imaging and Communication in Medicine) viewer, excluding portions of vessels and bronchi. The correlation between the CT value and GGN histologic diagnosis was analyzed.The numbers of patients with atypical adenomatous hyperplasia, adenocarcinoma-in-situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) were 9, 108, 56, and 7, respectively. One of the IAC tumors exhibited lymphatic invasion, and there were no cases of vascular invasion. In comparison to preinvasive lesions (atypical adenomatous hyperplasia and AIS), invasive lesions (MIA and IAC) were correlated with a higher maximum CT value (-404 ± 113 Hounsfield units [HU] vs. -216 ± 125 HU, P .01). The cutoff point of maximum CT value was determined at -300 HU using receiver operating characteristic curve analysis, and exhibited sensitivity and specificity of 83% and 88%, respectively. Multivariate analysis revealed that maximum CT value was an independent predictor of histologic invasiveness (odds ratio 39, P .01). The interobserver reliability was satisfactory (intraclass correlation coefficient, 0.738; unweighted kappa-values, 0.722).IAC and MIA accounted for 4% and 31% of the pure GGN lesions, respectively. Higher maximum CT value (≥ -300 HU) was a useful predictor of histologic invasiveness.

Purpose Acrylamide is known to induce disorders in the central nervous system in humans and experimental animals. The present study investigated effects of exposure to acrylamide on adult neurogenesis, noradrenergic axons and the level of norepinephrine in the brain of male rats. Method Four groups of 12 male Wistar rats each were exposed to acrylamide at 0, 0.2, 2 and 20 mg/kg body weight by gavage for 5 weeks. Six rats of each groups were injected with 5-bromo-2′-deoxy-uridine (BrdU) after five-week exposure to acrylamide to examine proliferative cells in the dentate gyrus using immunostaining. Density of noradrenergic and serotonergic axons in the prefrontal cortex, hippocampus and cortex behind the bregma was quantified. Remaining 6 rats were decapitated after the last exposure and brains were dissected out to measure monoamine level in the hippocampus and prefrontal cortex using high performance liquid chromatography. Result Exposure to acrylamide dose-dependently decreased the density of noradrenergic axons in the prefrontal cortex with a significant change at 20 mg/kg. Norepinephrine level decreased in the hippocampus at 20 mg/kg. Exposure to acrylamide at 20 mg/kg or less did not change the number of BrdU positive cells, but the result should be considered preliminary. Conclusion The results show that oral exposure to acrylamide induces decrease in noradrenergic axons and norepinephrine level in the brain of rats. Given the similar effects are observed in 1-bromopropane-exposed rats, there may be the common mechanism in the toxicity of soft electrophiles to the central nervous system.

To retrospectively analyze the differences in musculoskeletal ultrasound (MSUS) findings to distinguish patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome and patients with elderly-onset rheumatoid arthritis (EORA). We consecutively recruited patients with RS3PE syndrome (n = 7) and EORA (n = 22) who underwent pre-treatment MSUS of both hands. Synovial hypertrophy and vascularity of articular synovitis and those of tenosynovitis of the digital flexor tendons and the carpal extensor tendon were evaluated by gray-scale and power Doppler, respectively on a semi-quantitative scale (0–3). The presence/absence of intra-articular synovial effusion, bone erosion, peritendinitis of the digital extensor tendon, and subcutaneous edema were noted. Compared to the EORA group, mild articular synovitis was observed more extensively, and the frequency of intra-articular synovial effusion was significantly higher in the RS3PE syndrome group. Severe articular synovial hypertrophy was more frequent in the EORA group compared to the RS3PE syndrome group, and bone erosion was observed in some EORA cases. Tenosynovitis of the digital flexor tendon was more frequent and severe in the RS3PE syndrome group compared to the EORA group. Although the frequency and severity of tenosynovitis of the carpal extensor tendon were similar in the two groups, digital extensor tendon peritendinitis was more frequent in the RS3PE syndrome group. To distinguish patients with RS3PE syndrome from those with EORA, it is important to evaluate not only intra-articular lesions but also extra-articular lesions by MSUS.

Objective Pneumonia develops in bedridden patients, even in those receiving oral care, and malnutrition is associated with the development of pneumonia. We examined the effects of nutritional treatment on the prevention of pneumonia. Patients and Methods We retrospectively examined the effects of nutritional treatment on the prevention of pneumonia by analyzing the records of bedridden patients (n=68; mean age: 68.0 years) who stayed in a hospital for 2 years or longer. Results Among the analyzed patients, pneumonia developed in 52 (76%) patients, and the mean frequency of pneumonia was 1.6 times per year during the first year of stay. In a multivariate analysis, the serum albumin level at admission in the pneumonia group was lower than that in the non-pneumonia group. The frequency of pneumonia during the second year of stay was lower than that during the first year of stay. Serum levels of albumin and total protein (TP) at one year after admission were higher than those at admission in all analyzed patients, and in all patients (n=52) and elderly (≥65 years) patients (n=31) in the pneumonia group. The proportions of patients with hypoalbuminemia (

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Colin Reisner,9 Paul Dorinsky8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Großhansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Coagulation factor V (or FV for the purpose of medical safety) is an essential cofactor of coagulation factor X in the common pathway of coagulation; severe FV deficiency leads to a bleeding tendency. Although both congenital and acquired FV deficiencies are widely recognized, FV deficiency also presents as an autoimmune disorder. A nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs) conducted in Japan by our Japanese Collaborative Research Group identified 24 new patients with autoimmune FV deficiency (AiFVD) in the past 5 years. Furthermore, our extensive literature search confirmed that 177 AiFVD cases have been reported in previous articles published from Japan. Patients with AiFVD in Japan were predominantly men, with age similar to those with other AiCFDs. AiFVD was confirmed as a relatively mild type of bleeding diathesis, associated with lower mortality rate than that for AiFVD and other AiCFDs reported in previous studies. Patients with AiFVD had variable FV inhibitor titers and both neutralizing anti-FV autoantibodies and nonneutralizing counterparts. Although spontaneous resolution occurs in some patients, timely initiation of hemostatic and immunosuppressive therapies helps arrest the bleeding and eliminate anti-FV antibodies, resulting in a high cumulative recovery rate. Immunological anti-FV antibody detection is recommended to avoid missing AiFVD cases for the presence of nonneutralizing anti-FV autoantibodies. Further investigation is necessary to clarify the long-term prognosis and optimal management of AiFVD.

Background: This study was designed to investigate whether psychological status is associated with upper-extremity health status in an elderly general population. Methods: Using Quick Disabilities of the Arm, Shoulder, and Hand of the Japanese Society for Surgery of the Hand (QuickDASH-JSSH), we evaluated 200 Japanese elderly people (76 men, 124 women; mean age, 71.6 years, 60-98 years) to assess their upper-extremity-specific health status. Each had completed a self-administered questionnaire including gender and dominant hand items. As an indicator of hand muscle function, we measured their bilateral hand grip. Study participants were assessed for depressive symptoms using the Geriatric Depression Scale Short-Japanese Version (GDS-S-J). Statistical analyses were applied to clarify associations between self-assessed upper-extremity dysfunction and screening results for depressive symptoms in an elderly general population. Results: Those reporting no complaint of an upper extremity were 72 (36 men and 36 women) (36.0%). The GDS-J score was found to have significant positive correlation with age ( r = 0.20, P= 0.0045) and the QuickDASH score ( r = 0.25, P = 0.0004). The GDS-J score was found to have significant negative correlation with dominant grip ( r = −0.15, P = 0.04) and non-dominant grip strength ( r = −0.21, P = 0.004). For all participants, multiple regression analysis revealed the QuickDASH score as associated with the GDS-J score. Conclusion: Self-administered upper-extremity health condition as assessed using QuickDASH is correlated with depressive symptoms in elderly people. Objective pathophysiology and subjective illness behavior must be identified in daily clinical practice. A biopsychosocial approach must be used when advising and treating patients.

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults., Yamada, Motoike, Kojima et al. undertake a GWAS study on 19,722 participants from two Japanese populations for lung function with adjustment for fractional exhaled nitric oxide levels to account for airway inflammation. The authors identify variants of the RNF5/AGER locus and explore their three-dimensional protein interactions to better investigate the association between these variants and lung function.

A 49-year-old Japanese man with a 2-month history of a fever, headache, and bilateral conjunctival hyperemia was admitted. His condition fulfilled the giant cell arteritis classification criteria (new headache, temporal artery tenderness, elevated ESR) and atypical Cogan’s syndrome (CS) with scleritis and sensorineural hearing loss (SNHL). The interleukin (IL)-6 serum level was extremely high. Two weeks after his insufficient response of SNHL and scleritis to oral prednisolone, we administered tocilizumab (TCZ); rapid improvements in scleritis and SNHL occurred. Early IL-6 target therapy can help prevent irreversible CS-induced sensory organ damage., Internal medicine, 61(8), pp1265-1270; 2022

Supplemental digital content is available in the text., Purpose Proprioceptive feedback is crucial for motor control and stabilization of the shoulder joint in everyday life and sports. Shoulder dislocation causes anatomical and proprioceptive feedback damage that contributes to subsequent dislocations. Previous recurrent anterior shoulder instability (RSI) studies did not investigate functional neuroplasticity related to proprioception of the injured shoulder. Thus, we aimed to study the differences in neuroplasticity related to motor control between patients with RSI and healthy individuals, using functional magnetic resonance imaging, and assess the effects of peripheral proprioceptive deficits due to RSI on CNS activity. Methods Using passive shoulder motion and voluntary shoulder muscles contraction tasks, we compared the CNS correlates of proprioceptive activity between patients having RSI (n = 13) and healthy controls (n = 12) to clarify RSI pathophysiology and the effects of RSI-related peripheral proprioceptive deficits on CNS activity. Results Decreased proprioception-related brain activity indicated a deficient passive proprioception in patients with RSI (P < 0.05 family-wise error, cluster level). Proprioceptive afferent-related right cerebellar activity significantly negatively correlated with the extent of shoulder damage (P = 0.001, r = −0.79). Functional magnetic resonance imaging demonstrated abnormal motor control in the CNS during voluntary shoulder muscles contraction. Conclusion Our integrated analysis of peripheral anatomical information and brain activity during motion tasks can be used to investigate other orthopedic diseases.

Clinical isolates of drug-resistant (isoniazid and/or rifampicin-resistant) Mycobacterium tuberculosis were obtained from 254 patients diagnosed with drug-resistant tuberculosis in Japan from April 2015 to March 2017 in National Hospital Organization hospitals. The 254 patients were approximately 32% of all 795 patients who were diagnosed with culture-confirmed drug-resistant tuberculosis from 2015 to 2016 nationwide in Japan. The whole-genome sequences of all the isolates from the 254 patients and the lineages of these isolates were determined, and phylogenetic trees were constructed based on single nucleotide polymorphism concatemers. Of these patients, 202 (79.5%) were born in Japan and 52 (20.5%) were born elsewhere. Of the 254 drug-resistant isolates, 54 (21.3%) were multidrug resistant, being resistant to both isoniazid and rifampicin. The percentages of multidrug-resistant isolates were significantly higher in foreign-born (38.5% [20/52]) than Japanese-born patients (16.8% [34/202]). Of the 54 multidrug-resistant isolates, nine were extensively drug resistant, which were all obtained from Japanese-born patients. Five extensively drug-resistant isolates were obtained from patients with incipient tuberculosis. A significant number of multidrug-resistant M. tuberculosis strains were isolated from foreign-born patients from Asian countries that have a high tuberculosis burden. Foreign-derived isolates affect the nationwide genetic diversity of drug-resistant M. tuberculosis in Japan. Extensively drug-resistant M. tuberculosis isolates were transmitted among the Japanese population. IMPORTANCE The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis. Of the tuberculosis patients in the present study, 5.4% and 1.0% showed resistance to isoniazid and rifampicin, respectively, and 0.7% were multidrug resistant. The objective of this study was to clarify the molecular epidemiological properties of drug-resistant tuberculosis in Japan. Molecular epidemiology provides several clues to inform potential measures to control drug-resistant tuberculosis in Japan.

BACKGROUND The concept of oligo-recurrence in non-small-cell lung cancer (NSCLC) has been suggested to describe the possibility of achieving long-term survival or even cure with local therapy for recurrence despite having recurrent disease. Oligo-recurrence involves a limited number of metachronous recurrences that can be treated with local therapy. However, the number of recurrences that constitutes an oligo-recurrence has varied among studies and remains to be defined. The aim of this study was to elucidate the number of recurrences that constitutes an oligo-recurrence in NSCLC. PATIENTS AND METHODS We retrospectively reviewed 577 patients with NSCLC who had underwent complete resection and developed recurrence between 1990 and 2009, and these patients were evaluated. Patients were categorized according to the number of recurrences, and postrecurrence survival (PRS) was compared between groups. RESULTS Altogether, 270 patients underwent local therapy for all recurrent lesions. In these patients, sex (female), histological type (adenocarcinoma), gene mutation status, recurrence-free interval

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here, we show that expression of the BMP antagonist Grem1 marks committed layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA-seq analysis of differentially expressed transcripts between FACS-sorted Grem1-positive and -negative cells was performed. We also generated Emx1-cre-mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI, and impaired motor balance and fear sensitivity compared with littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex., Summary: The BMP antagonist Grem1 is expressed by committed deep-layer glutamatergic neurons in the embryonic mouse cortex. Grem1 conditional knockout mice display cortical and behavioral abnormalities.

We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. “PD responder” was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that. Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P

Asymptomatic elbow abnormalities are relatively common in young baseball players, but the factors responsible are unclear. To prospectively identify risk factors related to symptom manifestation in asymptomatic elbow abnormalities, we recruited 573 baseball players (age: 7–14 years) at a pre-participation medical/physical examination in the preseason who were right-handed and had asymptomatic medial elbow abnormalities on ultrasound (US). Baseline preseason and postseason participant characteristics were assessed. A “symptomatic” elbow was defined as an elbow with medial elbow joint problems that prevented ball throwing for ≥ 8 days. After exclusions, 82 players were enrolled, of whom 22 (26.8%) developed a symptomatic elbow. In univariate analyses, the external and internal rotation strengths of the dominant shoulder were significantly greater in the symptomatic group than in the asymptomatic group (P = 0.021). Multivariate logistic regression analysis showed that the internal rotation strength of the dominant shoulder was a significant independent risk factor (odds ratio = 1.091, P = 0.027) for developing a symptomatic elbow. In young asymptomatic baseball players with abnormalities in the medial elbow region of the dominant arm on US, stronger preseason internal rotation strength of the dominant shoulder was a significant independent risk factor for the development of a “symptomatic” elbow.

Corticobasal syndrome (CBS) is associated with diverse pathological substrates such as tau, prion protein, transactive response and, rarely, alpha synuclein. We report the case of a54-year-old man, who presented with asymmetric levodopa-poor-responsive parkinsonism, frontal lobe signs and behavioral changes. He was diagnosed with CBS, and postmortem analyses revealed Lewy body disease Braak stage VI without comorbid pathologies. Retrospectively, the clinical course of our patient and previous reports indicate that CBS plus mood changes and autonomic dysfunction, including reduced uptake of metaiodobenzylguanidine, are predictive factors of Lewy body pathology, even if the clinical picture is atypical.

A pitching motion requires whole-body coordination; therefore, poor control of the lower extremities, pelvis and trunk may cause shoulder and elbow injuries. However, few studies have described the relationship between the shoulder joint function and low back injury in high-school baseball pitchers. In this study, 97 high-school baseball pitchers who underwent pre-season medical checkups were enrolled and their shoulder range of motion and strength were measured. The participants completed a self-recorded questionnaire regarding the presence of low back pain and were divided into injured and non-injured groups. The statistical analyses were performed to identify the independent risk factors for low back injury. Low back injury was observed in 13 participants (13.4%). In the injured group, horizontal adduction on the dominant shoulder was significantly less frequent than in the non-injured group. A logistic regression analysis showed that horizontal adduction on the dominant side was a significant independent risk factor for low back injury during the season. It is important to recognize that restriction of the shoulder function not only causes shoulder and elbow injuries but can also risk low back injury.

Kentaro Machida,1,* Tomotaka Kawayama,2,* Masaharu Kinoshita,3,* Masakazu Ichinose,4 Tohru Tsuda,5 Shohei Takata,6 Hiroshi Koto,7 Makoto Yoshida,8 Yoshinori Ashihara,9 Masaru Kawashima,10 Hideaki Suna,10 Hiromasa Inoue1 1Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; 2Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; 3Nagata Hospital, Yanagawa 832-0059, Japan; 4Department of Respiratory Medicine, Tohoku University, Graduate School of Medicine, Sendai 980-8574, Japan; 5Kirigaoka Tsuda Hospital, Kitakyushu 802-0052 Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka-Higashi Medical Center, Koga 811-3195, Japan; 7Division of Respiratory Medicine, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka 815-8588, Japan; 8Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka 811-1394, Japan; 9Division of Respiratory Medicine, Oita Nakamura Hospital, Oita 870-0022, Japan; 10ONO Pharmaceutical Co. Ltd., Osaka 541-8564, Japan*These authors contributed equally to this workCorrespondence: Hiromasa InoueDepartment of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, JapanTel +81 99 275 6481Fax +81 99 275 6482Email inoue-pulm@umin.netBackground: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers.Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and

Background Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD. Patients and methods Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0–1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69). Results Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0–1.5 MET activity by 8.64 mins (p=0.040) and significantly increased the duration of ≥2.0 MET and ≥3.0 MET activity by 6.51 mins (p=0.017) and 2.60 mins (p=0.008), respectively, compared with tiotropium alone. Subgroup analyses showed that better lung function, milder dyspnea, and higher levels of physical activity at baseline were associated with reduced sedentary time and increased duration of physical activity. Conclusion Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).

The substances associated with PM2.5-induced inflammatory response were investigated using an elimination method. PM2.5 were heated at temperatures of 120, 250, and 360°C. The results demonstrated microbial substances such as LPS and b-glucan, and chemicals including BaP, 1,2-NQ, and 9,10-PQ were reduced drastically in PM2.5 heated at 120°C. On the other hand, DBA, 7,12-BAQ, and BaP-1,6-Q were not noticeably reduced. Most of these substances had disappeared in PM2.5 heated at 250°C and 360°C. Metals (eg, Fe, Cu, Cr, Ni) in PM2.5 exhibited a slight thermo-dependent increase. RAW264.7 macrophages with or without NAC were exposed to unheated PM2.5, oxidative stress-related and unrelated inflammatory responses were induced. PM2.5-induced lung inflammation in mice is caused mainly by thermo-sensitive substances (LPS, b-glucan, BaP, 1,2-NQ, 9,10-PQ, etc.). Also, a slight involvement of thermo-resistant substances (DBA, 7,12-BAQ, BaP-1,6-Q, etc.) and transition metals was observed. The thermal decomposition method could assist to evaluate the PM2.5-induded lung inflammation.