Objective The role of esophageal cardiac glands has not been fully determined. This study was performed to clarify the protective role of esophageal cardiac glands against the development of gastroesophageal reflux disease (GERD).
Methods The subjects included 2,656 Japanese individuals who visited our institution for a detailed medical checkup. GERD symptoms were assessed using the Japanese version of the Carlsson-Dent self-administered questionnaire (QUEST) and an upper gastrointestinal endoscopy examination in each subject. The presence of reflux esophagitis, size of diaphragmatic hiatus, degree of gastric mucosal atrophy and existence of visible esophageal cardiac glands in the distal esophagus, based on the detection of yellowish elevated areas, were determined using endoscopy.
Results Esophageal cardiac glands were observed in 355 cases (13.4%). Reflux esophagitis was significantly less frequent in the cases with esophageal cardiac glands than in those without. The esophageal cardiac glands were mainly located on the left-posterior side of the esophageal wall of the distal esophagus. A multiple regression analysis showed that the presence of esophageal cardiac glands was an independent factor for preventing reflux esophagitis. On the other hand, the existence of these glands did not correlate with the presence of GERD symptoms (QUEST score of 6 or more).
Conclusion The presence of visible esophageal cardiac glands may have a protective role against the development of reflux esophagitis.

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Objective We investigated factors related to proton pump inhibitor (PPI) -refractory gastroesophageal reflux disease (GERD) symptoms, particularly with respect to acid, the CYP2C19 genotype and psychological aspects.
Methods Patients with an Frequency Scale for the Symptoms of GERD (FSSG) score of ≥8 after the initial treatment were switched to therapy with rabeprazole at a dose of 20 mg once daily for eight weeks. We investigated the rate of improvement in PPI-refractory GERD symptoms, background factors, the Hospital Anxiety and Depression Scale (HADS) score and the CYP2C19 genotype.
Patients Sixty patients endoscopically diagnosed with reflux esophagitis within the past six months who had received omeprazole at a dose of 20 mg once daily for eight weeks or longer were enrolled.
Results In 71.6% of the patients, the FSSG score decreased to <8 after treatment with omeprazole at a dose of 20 mg once daily for ≥8 weeks, resulting in improvements in their GERD symptoms. Significant factors related to omeprazole-refractory GERD symptoms included a longer disease duration (p=0.0004) and higher HADS score (p=0.01). Among the omeprazole-refractory cases, only 23.5% of the patients showed symptom improvement after switching to rabeprazole. There were no significant differences in the average scores for FSSG (p=0.089) or HADS (p=0.182), before or after the drug change. A total of 92% of the rabeprazole poor responders were homo/hetero extensive metabolizers for the CYP2C19 genotype.
Conclusion Our findings suggest that switching the PPI from omeprazole (20 mg once daily) to rabeprazole (20 mg once daily) is not a significant effective therapeutic strategy for improving PPI-refractory GERD symptoms, taking into consideration possible psychometric factors and patients who require stronger acid suppression than that achieved with a double dose of PPIs for PPI-refractory GERD symptoms.

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Objective To determine the impact of phlebotomy on the laboratory values and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C.
Methods Study patients with chronic hepatitis C were treated with glycyrrhizin injection and oral ursodeoxycholic acid and either with (n=52) or without (n=50) phlebotomy during the period of 2005-2012. Six phlebotomized patients had previously received interferon therapy and were subsequently excluded from the data analysis. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, lactate dehydrogenase, ferritin, iron and albumin, as well as the hemoglobin concentration, platelet count and prothrombin time, were determined. We compared the long-term outcomes based on the incidence of HCC and laboratory values, including the baseline serum ferritin levels, in patients treated with versus without phlebotomy.
Results In the phlebotomy group, the mean AST and ALT levels decreased significantly at each one-year interval over five years (p<0.01), whereas the platelet counts did not. The incidence of HCC in the phlebotomized patients was significantly lower than that observed in the patients treated without phlebotomy: 10.3% vs. 43.7%, respectively, during the 8-year observation period (p=0.04). The incidence of HCC was also lower in the phlebotomized patients with a normal baseline ferritin level: 0.0% vs. 36.0% in the matched subgroup treated without phlebotomy at year 8. Phlebotomy offered a risk ratio of 0.13, thus suggesting protection against the development of HCC.
Conclusion The incidence of HCC can be reduced by phlebotomy treatment, which should be performed in patients with chronic hepatitis C not receiving or not responding to antiviral therapy.

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Objective Pegylated-interferon/ribavirin (peg-IFN/RBV) therapy with a protease inhibitor is the standard therapy for genotype 1b chronic hepatitis C. Despite improving treatment outcomes, patients with thrombocytopenia are often difficult to treat because interferon commonly exacerbates thrombocytopenia. In this study, partial splenic embolization (PSE) was performed in patients with hypersplenism-induced thrombocytopenia to determine the effectiveness of this method as a potential treatment.
Methods Patients were pretreated with PSE and then received triple combination therapy. The safety and efficacy of PSE was evaluated.
Results Eighteen patients were analyzed, including 12 patients with the interleukin 28B (IL28B) major genotype and 12 patients with the inosine triphosphatase (ITPA) major genotype. The median embolization rate with PSE was 70% (range: 40-85%). PSE increased the patients' platelet counts from 71.5×10³ /μL (53-99×10³ /μL) to 121.5×10³ /μL (70-194×10³ /μL; p=0.0002). The patients' platelet counts fluctuated above 50×10³ /μL during the treatment. Specifically, the increase in the platelet count was significantly associated with the ITPA major genotype compared with the minor genotype (p=0.0057 at 2 weeks, p=0.0031 at 3 weeks, and p=0.0148 at 4 weeks). Adherence to peg-IFN-α2b was sufficient (1.38 μg/kg/week). The rapid viral response rate was 72.2% (13/18), the end of treatment response rate was 88.9% (16/18), and the sustained virological response (SVR) rate was 66.7% (12/18). The SVR rate for patients with the IL28B major genotype was 83.3% (10/12). No adverse effect due to PSE pretreatment was found in any patients. Furthermore, no patient discontinued treatment due to thrombocytopenia.
Conclusion PSE, in conjunction with triple combination therapy, is a useful and safe method to treat genotype 1b chronic hepatitis C patients with hypersplenism-induced thrombocytopenia.

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Objective We investigated the distribution and characteristics of the FIB-4 index of liver fibrosis in 1,441 Japanese men (age 50.7±10.2 years) and 304 women (age 53.9±10.3 years) who underwent comprehensive general health checkups and were identified as having non-alcoholic fatty liver disease. With respect to the FIB-4 index, differences according to sex, metabolic indices, and ultrasonic findings were investigated.
Methods Among 9,255 individuals who underwent comprehensive general health checkups, 2,750 (29.8%) were found to have mild fatty liver or fatty liver based on ultrasound findings. After excluding patients who consumed ≥150 g alcohol/week (818 individuals), those testing positive for hepatitis B surface antigens or hepatitis C virus antibody (184 individuals), and those for whom data were insufficient (three individuals), we investigated the FIB-4 indices in the remaining 1,745 subjects.
Results There were no sex differences in the FIB-4 index. A total of 1,370 patients (78.5%) exhibited a low cut-off index (COI) (<1.30), 357 (20.5%), exhibited an indeterminate COI (1.30-2.67), and 18 (1.0%) exhibited a high COI (>2.67). There were no associations between the FIB-4 index and the constituent factors of metabolic syndrome. In contrast, there was a significant difference in the ln FIB-4 index between the patients with and without mild fatty liver or fatty liver on ultrasound among men (0.006±0.43 and -0.092±0.39, p<0.001), but not women.
Conclusion The FIB-4 index was is significantly lower in men, but not women, with fatty liver. The FIB-4 index must be calculated separately during medical checkups and evaluated in conjunction with ultrasound findings.

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Objective We examined the effects of intervention performed by a multidisciplinary cardiac rehabilitation (CR) team on the social rehabilitation of patients with cardiogenic out-of-hospital cardiopulmonary arrest (OHCA) in the acute phase.
Methods This study included 122 patients who were resuscitated after cardiogenic OHCA during a 10-year period. They were divided into two groups: including a non-CR group of patients (n=58) who were admitted before the CR team started performing systematic intervention and a CR group (n=64) who were admitted after the intervention was initiated. The following items were examined for each group: treatment condition at onset, contents of treatment, primary disease, presence or absence of underlying disease, presence or absence of complications, general physical and neurological outcome, duration of hospital stay, and status of social rehabilitation.
Results Although the number of patients with cardiogenic OHCA did not markedly change, the number of bystanders participating in cardiopulmonary resuscitation (CPR) was significantly higher in the CR group versus the non-CR group (p<0.01). The effect of bystanders participating in CPR also significantly reduced the mortality outcome (p<0.05 versus the group without CPR), and patients in the CR group were more likely to achieve social rehabilitation (p<0.05 versus the group without CPR). Moreover, the number of patients who returned to society one year later was increased in the CR group versus the non-CR group (p<0.05). The incidence of respiratory complications was also significantly lower in the CR group versus the non-CR group (p<0.05).
Conclusion Along with the usefulness of rapid pre-hospital aid, our results suggest that systemic intervention performed by the CR team administered while the patient was in the acute phase may have promoted social rehabilitation of patients resuscitated after cardiogenic OHCA.

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Objective The aim of this study was to assess the relationship between the duration of diabetes and the physiological serum bilirubin concentration in association with antioxidant properties in patients with type 2 diabetes.
Methods A total of 1,746 patients with type 2 diabetes were investigated in this cross-sectional study. An analysis of covariance was performed after adjusting for other covariates. Simple correlation analyses and a multivariate regression model were used to assess the association between the duration of diabetes and the serum bilirubin concentration.
Results The mean total bilirubin value differed significantly according to the tertile of diabetes duration (<5 years, 12.38 μmol/L, 95% confidence interval (CI) 12.02-12.76; 5-11.9 years, 12.33 μmol/L, 95% CI 11.97-12.69; ≥12 years, 11.73 μmol/L, 95% CI 11.35-12.11; p for trend =0.033), after adjustment for other covariates. In addition, an inverse correlation was found between the serum bilirubin concentration and diabetes duration (ρ=-0.211, p<0.001). According to a multivariate model, the association between the diabetes duration and serum bilirubin concentration remained significant, even after adjustment for confounding factors (β=-0.074, p=0.008).
Conclusion The duration of diabetes is inversely associated with a serum bilirubin concentration within the physiologic range in patients with type 2 diabetes.

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Objective Ultrastructural studies of IgG4-related kidney disease (IgG4-RKD) characterized by tubulointerstitial nephritis (TIN) are limited in previous reports due to the rarity of the condition. In the present report, we performed ultrastructural examinations and assessed the pathogenesis of this disease.
Patients Clinicopathological studies were conducted in eight patients diagnosed with IgG4-RKD. Routine light, immunofluorescence and electron microscopy examinations and immunohistochemical assessments of IgG4 were performed using renal biopsy samples.
Results Hypocomplementemia, positive anti-nuclear antibodies and eosinophilia were confirmed in more than half of the cases. Electron dense deposits (EDDs) were frequently found in the glomeruli and interstitium. The rate of deposition was 62.5% in both mesangial areas and Bowman's capsule. EDDs were frequently detected on the tubular basement membrane (TBM) (87.5% of patients). The interstitium also contained EDDs on collagen fibers in 87.5% of the cases and on basement membrane-like materials in areas of fibrosis in 37.5% of the cases. The creatinine clearance levels were significantly lower in the patients with the latter pattern. Meanwhile, the rate of immunoglobulin and/or complement deposition on the TBM was observed in less than 37.5% of patients, and these findings were not entirely coincident with the cases of EDDs on the TBM.
Conclusion EDDs are frequently found in the glomeruli and interstitium in patients with IgG4-RKD; however, immunohistological studies do not provide evidence that IgG4-RKD involves TIN with immune complex nephropathy. The presence of interstitial EDDs may be related to the progression of interstitial fibrosis in the setting of IgG4-RKD.

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Objective To comprehensively evaluate the association between the CC16 gene A38G polymorphism and the risk of asthma.
Methods Studies were retrieved from databases including PubMed, EMBASE, Web of Science and the Chinese Biomedical Literature Database according to the inclusive and exclusive criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations.
Materials Fifteen case-control studies with 1,623 cases and 3,294 controls were recruited for the analysis of the association between the CC16 gene A38G polymorphism and the risk of asthma.
Results The overall ORs showed no significant associations between the CC16 gene A38G polymorphism and the risk of asthma (AA vs. GG: OR=1.04, 95%CI=0.86-1.25; AG vs. GG: OR=1.08, 95%CI=0.94-1.24; AA + AG vs. GG: OR=1.07, 95%CI=0.94-1.22; AA vs. AG + GG: OR=1.01, 95%CI=0.85-1.19; A vs. G: OR=1.04, 95%CI=0.95-1.14). Moreover, similar results were obtained in the subgroup analysis stratified by ethnicity (Asian: AG vs. GG: OR=1.02, 95%CI=0.87-1.21; Caucasian: AG vs. GG: OR=1.22, 95%CI=0.94-1.57) and age (Child: AG vs. GG: OR=1.21, 95%CI=0.84-1.74; Adult: AG vs. GG: OR=1.06, 95%CI=0.91-1.23).
Conclusion CC16 gene A38G polymorphism is not associated with the risk of asthma.

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Objective The purpose of this study was to examine the effect of an intervention for chronic obstructive pulmonary disease (COPD) on COPD awareness in a regional city in Japan.
Methods Self-administered questionnaires were completed by the residents of the city of Matsuura, Japan. Residents (≥50 years) of the mainland in Matsuura were included in a COPD intervention project (mainland group), while residents of the islands district received no intervention due to geographical issues (island group). The rates of COPD awareness and accuracy of responses to the questions about COPD were compared between the two groups.
Materials The study included 5,891 residents 40 to 74 years of age of Matsuura in 2013. The mainland group comprised 4,419 subjects, and the island group 1,472 included subjects.
Results The overall response rate to the questionnaire was 24.6%, with similar response rates between the two groups. The rate of COPD awareness in the mainland group was 24.5%, which was significantly higher than that observed in the island group (11.8%) (p<0.01). The rate of awareness tended to decrease in association with increasing age. Among 276 responders who stated they were aware of COPD, the accuracy rate for responses to the questions about COPD was not significantly different between the groups.
Conclusion In the present study, there was a difference in COPD awareness between the two groups, suggesting that COPD interventions may increase awareness of the disease. However, the level of knowledge regarding COPD remained low and modifications to the intervention are required to improve awareness of the condition, especially among elderly subjects.

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Objective Prehospital delay is the major cause of treatment delay in stroke. This study was conducted to clarify the contribution of specific stroke-related symptoms to prehospital delay.
Methods A consecutive series of 469 patients hospitalized within 2 weeks of stroke onset was collected. In this study, prehospital delay was defined as the time interval from recognition of stroke-related symptoms to hospital arrival. The prevalence of each symptom or sign and prehospital delay were analyzed.
Results Weakness of the lower limb (43.5%) was the most common symptom followed by weakness of the upper limb (37.1%) and dysarthria (31.6%). Conversely, the most common sign was weakness of the upper limb (54.1%) followed by dysarthria (53.3%), weakness of the lower limb (53.1%), and sensory disturbance (39.0%). The presence of confusion/decreased level of consciousness (p<0.001), aphasia (p<0.001), headache (p=0.017), and nausea/vomiting (p=0.035) were associated with earlier hospital visitation compared with the absence of these symptoms in univariate analyses. Conversely, the presence of sensory disturbance (p=0.0017) and vertigo/dizziness (p=0.044) were associated with a significant delay in hospital visitation compared with the absence of these symptoms. There was a discrepancy in the prevalence between symptoms recognized by the patients or bystanders and signs diagnosed by the physicians.
Conclusion There was a significant overall correlation between prehospital delay and the National Institute of Health Stroke Scale scores. Public education is therefore necessary to encourage early hospital visitation even with the appearance of mild symptoms.

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Objective Paragonimiasis, or lung fluke infection, is a food-borne parasitic disease caused by infection with trematodes belonging to the genus Paragonimus. Although paragonimiasis was once considered successfully controlled in the 1970s, new cases began to emerge in the late 1980s. To apprehend the current-day situation of the re-emergent cases of paragonimiasis in Japan, we conducted a retrospective review of 443 patients who were referred to our laboratory and diagnosed as having paragonimiasis during 2001-2012.
Methods Patients were diagnosed as having paragonimiasis based primarily on immunodiagnostic methods in addition to clinical, laboratory, and radiographic findings. Patient data were extracted from consultation sheets from attending physicians and were analyzed.
Results Majority of the patients were residents of Kyushu Island. However, a substantial number of cases were also from other parts of Japan. Immigrants (mostly from China, Thailand, and Korea) accounted for a quarter of the cases. Native Japanese contracted paragonimiasis by consuming wild boar meat or freshwater crabs, whereas immigrants contracted the infection almost exclusively by consumption of freshwater crabs. Eosinophilia and elevated serum IgE levels were found in around 80% of the patients. Parasite egg detection was documented only in 11.7% of the cases, showing the reliance on serological tests for diagnosing paragonimiasis in current clinical practice.
Conclusion Paragonimiasis remains a public health issue in Japan, and the situation should be closely monitored.

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Objective Soft tissue sarcoma (STS) originating from the non-extremities has a poor prognosis and risk for visceral crisis; therefore, combination chemotherapy with a high response rate is desired.
Methods We retrospectively reviewed the cases of 30 patients with advanced STS that originated from the non-extremities who were treated between October 2005 and February 2012 at our institute with the CYVADIC chemotherapy regimen, which consists of cyclophosphamide, vincristine, doxorubicin, and dacarbazine. The patients' objective responses, progression-free survival (PFS), and overall survival (OS) were evaluated, and a statistical analysis was conducted to identify the predictive factors related to response and survival.
Results The median follow-up time was 16.5 months. The response rate was 33%, the median PFS was 7.4 months, and the 1-year OS was 81% (the OS did not reach the median). The median number of treatment cycles was six. Eleven patients failed to complete 6 cycles due to disease progression. The number of involved organs (>3) was a significant predictive factor of early refractoriness by the logistic regression analysis. Thirteen patients had an objective response or PFS longer than 1 year, and an alkaline phosphatase (ALP) level within the normal limits were the significant predictive factors of a good response.
Conclusion The patients' responses to the CYVADIC therapy for advanced STS originating from the non-extremities were moderate; therefore, CYVADIC therapy may be a treatment option of choice as combination chemotherapy for such patients. We propose that the number of involved organs and ALP concentration may be useful measures to predict the response to the CYVADIC therapy.

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Emphysematous gastritis is an extremely rare disease with an unfavorable prognosis. To date, very few studies have been conducted regarding the intragastric recovery process based on endoscopic findings. We herein report a case of emphysematous gastritis that improved with long-term (five months) conservative treatment in which we were able to observe the intragastric recovery process endoscopically. In cases in which emphysematous gastritis is suspected, it is important to provide prompt diagnostic imaging (including CT) and early appropriate treatment in order to improve the prognosis.

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The development of de novo Crohn's disease (CD) after orthotopic liver transplantation (OLT) is rare, possibly due to the continuous use of immunosuppressive treatment. Although several cases of CD following OLT have been reported worldwide, there are currently so such cases in Japan. We herein report the case of a patient who newly developed CD after undergoing OLT for congenital biliary atresia. The patient subsequently underwent ileocecal resection and has since maintained clinical remission. This is the first report of this condition in Japan. We also review the literature concerning cases of de novo inflammatory bowel disease (IBD) developing after OLT, and discuss the causes of and role of immunosuppressive agents in treating IBD.

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A 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid β (Aβ) coding sequence in the amyloid precursor protein (APP) gene (c.2080_2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimer's pedigree without amyloid deposits. Furthermore, an increase in high-molecular-weight Aβ-reactive bands was detected in the patient's CSF. Our findings suggest that soluble Aβ-oligomers induce neuronal toxicity, independent of insoluble Aβ fibrils.

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We herein describe the case of a 48-year-old woman who presented with nonconvulsive status epilepticus refractory to antiepileptic drugs caused by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis without any tumors. She developed nausea and psychiatric symptoms, followed by fever and an acute progressive disturbance of consciousness. On admission to our hospital, she presented with involuntary orofacial movements and central hypoventilation, and an electroencephalogram showed a generalized slow activity consistent with nonconvulsive status epilepticus. The patient's drug-resistant status epilepticus markedly improved following second-line immunotherapy with rituximab and cyclophosphamide. Physicians should consider the early initiation of second-line therapy in certain cases of anti-NMDAR encephalitis.

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A 74-year-old woman was hospitalized due to dysuria, weakness and dysesthesia of the lower extremities. She was in an immunosuppressed state following the administration of methylprednisolone therapy for idiopathic interstitial pneumonia. Cerebrospinal fluid and blood cultures were negative, and no infectious biomarkers were found. A gadolinium (Gd)-enhanced T1-weighted image of magnetic resonance imaging (MRI) revealed disseminated nodular lesions along the spinal cord. We suspected a diagnosis of seronegative deep mycosis and initiated anti-fungal therapy with voriconazole, which subsequently alleviated all of the patient's symptoms and MRI findings. Therefore, the presence of Gd-enhanced disseminated nodules on spinal MRI may be a good marker of deep meningeal mycosis.

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Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disease. PERM consists of the same symptoms as stiff person syndrome, in addition to sensory, brainstem and autonomic features. We herein report a case of PERM in a 48-year-old woman who initially presented with spasticity of the lower limbs and subsequently developed upper limb spasticity, perioral myoclonus and restlessness after three months. The onset of potentially fatal dysautonomia was observed at the peak of the disease. Treatment with high-dose immunoglobulin (400 mg/kg, 5 days), levetiracetam and azathioprine resulted in a drastic and sustained improvement of these symptoms. This is an interesting case of PERM in which the patient showed a dramatic improvement following immune moderation.

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Human immunodeficiency virus (HIV) infection disturbs the host's immune function and often coexists with various autoimmune and/or systemic rheumatic diseases with manifestations that sometimes overlap with each other. We herein present the case of a 43-year-old Japanese man infected with HIV who exhibited elevated serum creatine kinase and transaminases levels without any symptoms. He was diagnosed with autoimmune hepatitis, polymyositis and Sjögren's syndrome and received combined antiretroviral therapy (cART); however, the laboratory abnormalities persisted. We successfully administered cART with the addition of oral prednisolone, and the patient's condition recovered without side effects related to the metabolic or immunosuppressive effects of these drugs.

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We herein report the case of a 39-year-old man who developed bilateral auricular chondritis, conjunctivitis, and central neurological symptoms. He was diagnosed with encephalitis associated with relapsing polychondritis (RP) based on the findings of an ear cartilage biopsy, cerebrospinal fluid examination and magnetic resonance imaging. Although oral prednisolone (60 mg/day) was administered, the initial steroid therapy did not improve his symptoms. In contrast, methylprednisolone (mPSL) pulse therapy followed by prednisolone gradually ameliorated his condition. There were no episodes of recurrence during the two-year follow-up period. A review of the literature revealed that meningoencephalitis and encephalitis are rare, but important, complications of RP responsive to mPSL pulse therapy.

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This study is the first case report of the treatment of methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis using therapeutic drug monitoring of the serum and wound exudate concentrations of linezolid in a renal dysfunction patient. In the present study, the serum trough concentration of linezolid was maintained between 2 and 7 μg/mL. Therapeutic drug monitoring dosage adjustments may be especially useful in patients with renal dysfunction and severe MRSA infection.

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