Objective Clinically useful serum biomarkers for the diagnosis and monitoring of eosinophilic gastrointestinal diseases are not available. This study was conducted to examine the possible value of eosinophil-related proteins as serum biomarkers.

Methods The serum concentrations of 49 cytokines, chemokines, and other proteins were measured in 29 patients with eosinophilic gastrointestinal diseases and 80 controls.

Results The levels of interleukin (IL)-5, IL-33, eotaxin-3, and thymic stromal lymphopoietin (TSLP), previously reported as possible biomarkers of eosinophilic esophagitis, were not significantly elevated in the serum. In contrast, the B cell-attracting chemokine (BCA)-1/chemokine (C-X-C motif) ligand (CXCL) 13 and hemofiltrate C-C chemokine (HCC)-1/CC chemokine ligand (CCL) 14α levels were significantly elevated, while the granulocyte chemotactic protein (GCP)-2/CXCL6 levels were suppressed in patients with eosinophilic esophagitis as well as in those with eosinophilic gastroenteritis. The cutaneus T cell-attracting chemokine (CTACK)/CCL27, stromal cell-derived factor (SDF)-1/CXCL12, macrophage inflammatory protein (MIP)-3β/CCL19, and squamous cell carcinoma antigen (SCCA) 2 levels were elevated only in patients with eosinophilic esophagitis. However, there were large overlaps of data obtained from the patient and control groups, indicating that these serum biomarkers are not adequately sensitive for clinical use with presently available assay systems.

Conclusion Of the 49 investigated serum proteins, none were shown to be adequately sensitive for use as biomarkers for the diagnosis or monitoring of eosinophilic gastrointestinal diseases.

Objective It remains unclear whether the CHADS₂, CHA₂DS₂-VASc, or R₂CHADS₂ score is the most useful for the risk stratification of ischemic stroke/systemic thromboembolism (IS/SE) in Japanese patients with paroxysmal non-valvular atrial fibrillation (PNVAF).

Methods We investigated the incidence of IS/SE on the basis of the CHADS₂, CHA₂DS₂-VASc, and R₂CHADS₂ scores in 332 consecutive PNVAF patients (224 men, mean age: 65±13 years) who had not been administered anticoagulation therapy but who were administered antiarrhythmic drug therapy to maintain sinus rhythm between August 1995 and July 2008 before the 2008 Japanese Circulation Society guideline was issued (mean follow-up period: 53±35 months).

Results The annual rates of IS/SE without underlying antiarrhythmic drug therapy are shown in the table included in this article. Higher CHADS₂, CHA₂DS₂-VASc, and R₂CHADS₂ scores were associated with greater annual rates of IS/SE (p<0.001). In a multivariate logistic regression analysis adjusted for potentially confounding variables, the CHADS₂ scores [odds ratio (OR): 4.74, 95% confidence interval (CI): 2.80-8.00, p<0.001], CHA₂DS₂-VASc scores (OR: 4.15, 95% CI: 2.57-6.71, p<0.001), and R₂CHADS₂ scores (OR: 1.94, 95% CI: 1.48-2.53, p<0.001) were significant independent predictors of IS/SE. The area under the receiver-operator characteristic curve for predicting IS/SE was 0.89 for CHA₂DS₂-VASc scores, 0.87 for CHADS₂ scores, and 0.85 for R₂CHADS₂ scores (all, p<0.001), with no significant difference among the three scores.

Conclusion In Japanese patients with PNVAF, the CHADS₂, CHA₂DS₂-VASc, and R₂CHADS₂ scores are all useful for the risk stratification of IS/SE cases.

Objective An acute exacerbation (AE) of idiopathic pulmonary disease (IPF) represents a life threatening condition. The activities of daily living (ADL) and quality of life of patients who survive an AE of IPF (AE-IPF) are often diminished. However, the association between AE-IPF and the ADL has yet to be evaluated.

To evaluate the effect of AE-IPF on the ADL.

Methods, Patients Patients treated for AE-IPF from 2010 to 2014 were identified. We retrospectively evaluated their ADL before and after AE-IPF using a modified Barthel index (BI) composed of 6 items.

Results Twenty-eight of the 47 AE-IPF patients remained alive at 3 months after the onset of AE-IPF. The BI values of 22 survivors (79%) showed a full score (70 points) before the onset of AE-IPF. The evaluation of the BI scores at four weeks after the onset of AE-IPF revealed that the scores of 12 patients had decreased by >15 points and more than half of the survivors showed scores of <55. Logistic regression analyses showed that persistent hypeoxemia at 28 days after an AE, both at exertion (odds ratio, 24.20; 95% confidence interval, 2.42-242.31; p=0.009) and at rest (odds ratio, 21.00; 95% confidence interval, 2.05-215.18; p=0.010), was associated with a >15-point decrease in the BI score at 4 weeks after AE-IPF.

Conclusion AE-IPF survivors with persistent hypoxemia showed diminished ADL after treatment.

Objective To compare the radiological and laboratory data of children and adults with Mycoplasma pneumoniae pneumonia (MPP) and to evaluate the correlation between the total affected lung area and the clinical findings.

Methods We retrospectively examined the data from MPP patients who visited our hospital during the period from April 2006 to July 2014. All data were retrieved at the time of the diagnosis of MPP and were analyzed to investigate the correlation between the clinical findings and the total affected lung area using a chest X-ray scoring system.

Results We identified 71 children and 54 adults with MPP. The incidence of consolidation, which was the most common chest X-ray finding in both groups, was similar (children: n = 62, 87.3%; adults: n = 45, 83.3%). In contrast, air bronchogram, bronchial thickening, and atelectasis were observed significantly more frequently among children than among adults. In both groups, a chest X-ray scoring system revealed a zonal predominance of the affected area (middle-to-lower lung fields). The body temperature and serum data such as the C-reactive protein level, white blood cell count, and lactate dehydrogenase level were significantly higher in the child group than in the adult group. The total score did not significantly correlate with the above-mentioned inflammatory markers or the presence of hypoxemia in either group.

Conclusion This study showed the first evidence of a correlation between the extent of lung abnormalities on chest X-ray (calculated as a total score) and the clinical findings, including the presence of hypoxemia, in children and adults with MPP.

Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation.

Methods We performed an immunohistochemical analysis in 15 AITL patients to determine the expression of the master regulators and several surface markers associated with T-cell differentiation.

Results BCL11B was detected in 10 patients (67%), and the surface marker of T-cells (CD3) was detected in all patients. Only 2 patients (13%) expressed the marker of naïve T-cells (CD45RA), but all patients expressed the marker of effector T-cells (CD45RO). Nine patients expressed Th-POK (60%), and 7 (47%) expressed a set of surface antigens of Th (CD4-positive and CD8-negative). In addition, BCL6 and the surface markers of TFH (CXCL13, PD-1, and SAP) were detected in 11 (73%), 8 (53%), 14 (93%), and all patients, respectively. Th-POK-positive/BCL6-negative patients showed a significantly shorter overall survival (OS) than the other patients (median OS: 33.0 months vs. 74.0 months, p=0.020; log-rank test).

Conclusion Many of the AITL patients analyzed in this study expressed the master regulators of T-cell differentiation. The clarification of the diagnostic significance and pathophysiology based on the expression of these master regulators in AITL is expected in the future.

Objective To assess the correlation between the angiographic appearance of cerebral collateral pathways or the degree of internal carotid artery stenosis (ICAS) and reduced cerebrovascular reactivity (CVR) estimated by single-photon emission computed tomography (SPECT) image analysis in patients with unilateral ICAS.

Methods A retrospective analysis was performed in 42 patients with unilateral ICAS who underwent cerebral angiography and acetazolamide-challenged SPECT of the brain. Cerebral blood flow quantitation was performed using the quantitative SPECT/dual-table autoradiography method. The CVR in the middle cerebral artery (MCA) territory was evaluated using the stereotactic extraction estimation based on the Japanese extracranial-intracranial bypass trial (SEE-JET) program and classified as reduced (<18.4%) or non-reduced (≥18.4%). Angiographic collateralization was classified as circle of Willis (type 1), extracranial-intracranial (type 2), and leptomeningeal (type 3). The degree of ICAS was defined as severe (≥70% stenosis) or non-severe (<70%).

Results Eight patients showed reduced CVR, including 6 (46%) of 13 with type 3 collaterals and 2 (7%) of 29 without type 3 collaterals (p=0.006). In contrast, type 1 and type 2 collaterals and severe ICAS were not significantly associated with reduced CVR.

Conclusion In patients with unilateral ICAS, leptomeningeal collaterals are strongly correlated with reduced CVR in the MCA territory, which presumably increases the risk of cerebral hyperperfusion after carotid artery stenting (CAS). Therefore, these findings may be clinically applicable to the perioperative management of CAS.

Objective The differences in the frequency and clinical features of malignant syndrome (MS) and serotonin syndrome (SS) in same population have only rarely been reported. To report the frequency and clinical features of MS and SS in a general hospital setting.

Methods The clinical and laboratory features of patients with MS and those with SS, who were consecutively admitted to Chiba Rosai Hospital, during the past 4.5 years were reviewed.

Results Of the 2005 patients admitted, MS was observed in 16 patients (0.8%) and SS in 2 (0.1%). In the 16 patients with MS, the underlying disorder included depression (n = 5), and dementia or parkinsonism (n = 11). The underlying etiology of the 2 patients with SS was depression. In 5 patients, MS was difficult to distinguish from SS because of overlapping symptoms and signs and/or treatments with both neuroleptic and serotoninergic drugs. Of the 16 patients with MS, 1 died, 1 remained wheelchair-bound, 4 were able to walk with assistance, and 10 regained their ability to ambulate independently. The 2 patients with SS recovered after cyproheptadine therapy and were discharged on foot.

Conclusion MS occurs more frequently than SS in the general hospital setting. Underlying aetiologies in patients with MS were more common due to dementia or parkinsonism than in patients with psychiatric disorders. The differential diagnosis of MS and SS is often difficult and the diagnostic sensitivities largely differ for each of the diagnostic criteria. As a result, the establishment of new diagnostic criteria that specifically focus on distinguishing MS from SS is therefore required.

Objective The characteristics of olfactory impairment in Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) have not been determined in detail. We assessed the olfactory function among PD, MSA and PSP patients.

Methods A card-type odor identification test, Open Essence (OE, Wako, Japan), which consists of 12 different odorants familiar to Japanese subjects, was administered to 98 PD patients, 32 MSA patients, 17 PSP patients and 96 control subjects ≥50 years of age.

Results The PD patients had significantly lower OE scores than the other groups. The OE scores of the MSA and PSP patients fell between those of the PD patients and the control subjects. A cut-off OE score of 6 was beneficial for differentiating PD patients from controls with 84.7% sensitivity and 85.4% specificity. A cut-off OE score of 4 had 60.2% sensitivity and 77.6% specificity for differentiating PD patients from MSA and PSP patients. The correct answer rates for the curry, Japanese orange and perfume odorants in the PD patients were lower than those in the MSA and PSP patients and controls. The PD patients also had the highest ratio of "not detected" choices across the 12 odors.

Conclusion Marked olfactory impairment was a feature of the patients with PD, while mild olfactory impairment was observed in those with MSA or PSP. The answer patterns and the specific odorants may also be useful in differentiating PD from related disorders.

Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment.

A 54-year-old man was treated with mycophenolate mofetil (MMF) after undergoing living donor renal transplantation. Two years later, he experienced repeated episodes of diarrhea, and his C-reactive protein (CRP) level was found to be 12.63 mg/dL. Ileocolonoscopy showed multiple deep, punched-out ulcers that were similar to Behçet's disease (BD) and cytomegalovirus (CMV) in the ileum. CMV infection was suspected. However, anti-cytomegalovirus agents were ineffective. The patient was subsequently diagnosed with gastrointestinal toxicity of MMF and MMF was switched to mizoribine. His symptoms improved immediately, and his CRP level normalized. Six months later, the patient's mucosa was healed.

The efficacy of repeated lusutrombopag administration for thrombocytopenia in patients with chronic liver disease who undergo two or more planned invasive procedures is unknown. We herein report our findings regarding the effects of repeated lusutrombopag administration given to avoid platelet transfusion in a patient with chronic liver disease and thrombocytopenia. The platelet count showed a positive response to lusutrombopag treatment prior to the initial invasive procedure to treat a hepatoma, so platelet transfusion was not necessary. In conclusion, lusutrombopag may be a useful drug for patients with thrombocytopenia to avoid platelet transfusion in those undergoing two or more planned invasive procedures.

The effect of non-vitamin K antagonist oral anticoagulants on left atrial appendage (LAA) thrombus has not been fully elucidated. There are a few reports showing resolution of LAA thrombus with apixaban. An 84-year-old woman was admitted to our hospital due to acute exacerbation of chronic heart failure and marked tachycardia with atrial fibrillation. She had permanent atrial fibrillation and was treated with warfarin; however, transthoracic echocardiography revealed a non-mobile thrombus in the LAA. Therefore, we switched warfarin to apixaban at a dose of 5 mg/day. After two weeks on that therapy, the thrombus in the LAA was successfully resolved.

We report an 80-year-old woman with EGFR-mutant lung adenocarcinoma with multiple brain metastases (BMs). All lesions including BM showed a successful resolution after initiating daily 150 mg erlotinib. However, a grade 2 bilirubin-increase developed, and it was necessary to reduce the dose of erlotinib to 50 mg every other day, which aggravated BM. Switching erlotinib to afatinib led to the resolution of BM without an increase in the bilirubin level. Our results indicate that afatinib is an important treatment option when erlotinib-induced hepatotoxicity develops, regardless of the patients' age. Particularly in those patients with BM, switching to afatinib may be preferable to reducing the dose of erlotinib.

Common variable immunodeficiency (CVID) is a heterogeneous subset of immunodeficiency disorders. Recurrent bacterial infection is the main feature of CVID, but various non-infectious complications can occur. A 42-year-old woman presented with cough and abnormal chest X-ray shadows. Laboratory tests showed remarkable hypogammaglobulinemia. Computed tomography revealed multiple consolidation and nodules on the bilateral lung fields, systemic lymphadenopathy, and splenomegaly. A surgical lung biopsy specimen provided the final diagnosis of lymphoproliferative disease in CVID, which was grouped under the term granulomatous lymphocytic interstitial lung disease. Interestingly, the lung lesions of this case resolved immediately after the initiation of intravenous immunoglobulin monotherapy.

Cases of drug-induced lung injury caused by tamoxifen are rare. A 74-year-old man underwent surgery for the treatment of right breast cancer; tamoxifen was administered as an adjuvant therapy after surgery. The patient developed cough and dyspnea and chest computed tomography showed ground glass opacification in the lower lobe of the right lung. He was diagnosed with tamoxifen-induced lung injury. The diagnosis was made based on the exclusion of other causes and recurrence with the re-administration of tamoxifen. Physicians should therefore be aware of the potential for the development of tamoxifen-induced lung injury.

Mucosa-associated lymphoid tissue lymphoma is a common type of primary pulmonary carcinoma, but the presence of polypoid nodules is extremely rare. We herein report two cases with multiple nodules in the trachea. One case involved polypoid nodules and airway stenosis mimicking asthma; the other case had concurrent nontuberculous mycobacterial infection. The diagnosis of both cases was confirmed by bronchoscopy. The two cases were sensitive to radiotherapy and chemotherapy, respectively.

We describe a case in which uncontrolled chronic disseminated intravascular coagulation (DIC) caused by an aortic aneurysm that was exacerbated by chemotherapy for lung cancer, showed dramatic improvement when warfarin, which was being administered for atrial fibrillation, was replaced by rivaroxaban, a direct oral anticoagulant (DOAC). The present case is interesting because a DOAC was effective in treating DIC due to an aortic aneurysm, whereas warfarin, another oral anticoagulant, was ineffective. In controlling DIC, it is important to inhibit activated coagulation factors such as thrombin and activated factor X, rather than the coagulation factors, which act as substrates.

Hemophagocytic lymphohistiocytosis (HLH) associated with herpes simplex virus (HSV)-1 infection (HSV-1-HLH) is uncommon and is potentially fatal without appropriate treatment. We herein report the case of an adult patient with HSV-1-HLH who was successfully treated with acyclovir. A 69-year-old man developed fever, pancytopenia and liver enzyme elevation after the resolution of pneumonia. These findings and the presence of hemophagocytosis in the patient's bone marrow were consistent with a diagnosis of HLH. The patient was diagnosed with HSV-1-HLH based on the results of a polymerase chain reaction (PCR) for HSV-1. The early administration of acyclovir improved his clinical symptoms and laboratory results within two weeks. In the present case, the rapid and precise diagnosis facilitated the successful treatment of HSV-1-HLH.

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease.

Unilateral oculomotor nerve palsy can result from various neurological disorders. We herein report the case of a 68-year-old man with complete unilateral oculomotor nerve palsy following campylobacter infection. Based on the antecedent infection and the patient's decreased tendon reflexes, incomplete Miller Fisher syndrome (MFS) without ataxia was suspected. His serum tested positive for anti-GQ1b antibodies. He recovered over a period of 87 days without immunotherapy. We conclude that incomplete MFS following campylobacter infection can cause unilateral oculomotor nerve palsy without ataxia. Mild MFS should be considered in patients presenting with unilateral isolated ophthalmoplegia and decreased tendon reflexes.

We herein report a patient who developed transient prosopometamorphopsia restricted to the left eye caused by ischemia of the right splenium of the corpus callosum. A 66-year-old right-handed woman suddenly noticed that the left eyes of people she encountered appeared markedly adducted to their noses. On emergent admission, neurological and ophthalmological examinations revealed no abnormalities. Diffusion-weighted magnetic resonance imaging showed a small, hyperintense lesion at the right splenium of the corpus callosum. In this case, information on the right visual field projected to the left occipital lobe might have been obstructed on transmission to the right hemisphere through the splenium of the corpus callosum.

The encephalopathy that occurs in association with hemolytic uremic syndrome (HUS), which is caused by enterohemorrhagic Escherichia coli (E. coli), has a high mortality rate and patients sometimes present sequelae. We herein describe the case of a 20-year-old woman who developed encephalopathy during the convalescent stage of HUS caused by E.coli O26. Hyperintense lesions were detected in the pons, basal ganglia, and cortex on diffusion-weighted brain MRI. From the onset of HUS encephalopathy, we treated the patient with methylprednisolone (mPSL) pulse therapy alone. Her condition improved, and she did not present sequelae. Our study shows that corticosteroids appear to be effective for the treatment of some patients with HUS encephalopathy.

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.