The incidence of atopic diseases, including atopic dermatitis (AD), food allergies, allergic rhinitis, and asthma, has increased in recent decades, and currently affects approximately 20% of the population. Atopic march is the development of AD in infancy and subsequent food allergies, allergic rhinitis, and asthma in later childhood. Patients with infantile eczema may develop typical symptoms of AD, allergic rhinitis, and asthma at certain ages. Some patients' symptoms persist for several years, whereas others may have resolution with aging. Development of these diseases is strongly influenced by the following two factors: skin dysfunction caused by filaggrin mutations and development of colonization of microflora in early infancy. Filaggrin mutations predisposing to asthma, allergic rhinitis, and allergic sensitization, only in the presence of AD, strongly support the role of filaggrin in the pathogenesis of AD and in subsequent progression of the atopic march. Several studies have shown that development of colonization of microflora in early infancy might affect development of allergic disease or food desensitization. Therefore, massive allergen exposure to genetic skin dysfunction in early infancy and an imbalance of microflora might be necessary for development of atopic march.

There are some reports that sympathetic nerve activity (SNA) shows a characteristic pattern a few hours before the onset of lethal ventricular arrhythmias. If so, it could be possible to predict sudden cardiac death a few hours in advance of its occurrence. Recently, we reported that a previously unidentified V-trough of SNA is a potential precursor of lethal cardiac events by examining 24-hour ambulatory electrocardiograms in which such an event was recorded by chance. In contrast, the chaotic nature of heart rate variability has been noted recently from the viewpoint of nonlinear dynamics. This study models the hemodynamics, consisting of heart rate, SNA, and blood pressure (BP), by modifying a known chaotic electrical circuit, the Chua circuit. A V-trough of the SNA appears when the resistive element between the SNA and BP in the circuit is increased, which corresponds to the impaired regulation of BP by the SNA. This finding is consistent with an acknowledged finding that a depressed baroreflex (a reflex of the BP by SNA) may trigger a lethal arrhythmia. This study indicates that a V-trough of the SNA is a possible precursor of sudden cardiac death on the basis of experimental and clinical findings as well as mathematical modeling.

Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To obtain further insights into this "orphan disease," we have established the ATC Research Consortium of Japan (ATCCJ) in 2009. It represents a multicenter registry for ATC that have been treated in Japan. To date, 67 institutions have taken part in the collaborative research system and over 1,200 cases have been accumulated in its database. Using this big data, several retrospective studies were carried out to evaluate 1) prognostic factors to determine initial treatment policy, 2) significance of extended radical surgery for Stage IVB cases, 3) characteristics of ATC incidentally found on pathological examination and 4) pathological features of ATC with long-term survival. Moreover, the ATCCJ has conducted an investigator-initiated, nationwide, prospective clinical trial since 2012; namely, the feasibility, safety and efficacy study of weekly paclitaxel administration for patients with ATC (UMIN: 000008574). Revised Japanese guidelines for treatment of thyroid tumors are going to adopt the recommendations from the results of this research. Since 2016, the ATCCJ has started the phase II study assessing the efficacy and safety of lenvatinib, a newly developed tyrosine kinase inhibitor for ATC (UMIN: 000020773). Our nationwide clinical trial network will strengthen the activity to recruit orphan disease patients and may discover new strategies to conquer this dismal malignancy in the near future.

Background and Purpose: It is clinically important to evaluate time course changes in symptomatic middle cerebral artery (MCA) stenotic plaques because of likely recurrence. The objective of this study is to determine whether contrast-enhanced high-resolution magnetic resonance imaging (MRI) is a feasible method for this purpose. Methods: Contrast-enhanced, high-resolution, 3D turbo spin-echo images with low refocusing flip angle control (3D LOWRAT) applied to 7 patients with symptomatic MCA stenosis were evaluated at the initial (1 month after stroke onset) and follow-up (7 months after stroke onset) stages, and statistical variables, including plaque-to-thalamus signal intensity ratio, degree of stenosis, and stroke recurrence obtained at the 2 stages, were compared. Stenotic change at the initial stage was compared to that at the follow-up stage using MR angiography. Results: In 4 of the 7 patients, the signal intensity ratio measured at the follow-up stage was lower than that measured at the initial stage and in 1 patient, the stenosis subsequently improved. We used a Chi-Square Test. In the other 3 patients, the signal intensity ratios did not differ between the 2 stages, and ischemic stroke occurred in 2 of these 3 patients. Conclusion: Gadolinium contrast enhancement was found to be useful for effective evaluation of time course changes in the stability of symptomatic MCA stenotic plaques.

The introduction of the Haemophilus influenzae type b (Hib) vaccine and the 7-valent pneumococcal conjugate vaccine (PCV7) has led to dramatic reductions in cases of invasive H. influenzae disease and invasive pneumococcal disease (IPD). After the introduction of the PCV7 and the 13-valent pneumococcal conjugate vaccine (PCV13), the number of children with IPD markedly decreased in our hospital. However, since 2015, three children with IPD have been admitted to our hospital. We analyzed the serotype, multilocus sequence type, and antimicrobial susceptibility of Streptococcus pneumoniae strains isolated in these newly diagnosed cases. The strains were serotypes 7F and 12F. In addition, we analyzed the incidence of invasive bacterial disease before and after the introduction of conjugate vaccines and found no change in the incidences. We found that cases of IPD and invasive H. influenzae disease clearly decreased following the introduction of the PCV7, the PCV13, and the Hib vaccine, as well as disease caused by antibiotic-resistant strains.

Purpose: The aim of this study was to identify a useful biomarker to predict the efficacy of polymyxin B-immobilized fiber direct hemoperfusion (PMX-DHP) in patients with septic shock. Methods: The 44 patients included in this study were divided into two groups. Group A had an increase in systolic blood pressure (SBP) over 30 mmHg after PMX-DHP treatment. Group B had an increase in SBP less than 30 mmHg after PMX-DHP treatment. We evaluated the clinical characteristics and demographics of both groups. We also assessed whether the cause of sepsis affected the efficacy of PMX-DHP and compared the prognosis of both groups. Finally, we investigated whether there were any significant differences in the levels of sepsis-related biomarkers, including sphingosine-1-phosphate (S1P), between both groups before PMX-DHP in an effort to identify a biomarker that could predict the efficacy of PMX-DHP. Results: PMX-DHP significantly increased SBP regardless of the cause of sepsis. Although there was some tendency, PMX-DHP did not significantly improve the prognosis of effective cases in comparison with non-effective cases, probably because of the limited number of patients included. Among the sepsis-related biomarkers, only S1P values were significantly different between the two groups before PMX-DHP, and S1P levels were significantly increased after treatment in the effective cases. Conclusion: S1P levels prior to PMX-DHP can be used to predict its efficacy. In addition, continuous monitoring of S1P levels can indicate the effectiveness of PMX-DHP in patients with septic shock.

Verrucous carcinoma (VC) is an uncommon, distinct type of well-differentiated squamous cell carcinoma. Here we present two cases of VC, one arising from the lower leg and the other from genital skin. Case 1, a female patient, aged 95 years, had a brownish verrucous plaque on her right lower leg. Histopathologically, epithelial tumor cells grew pushing the stroma, while the basement membrane was intact. No prominent cellular atypia or hyperchromatin was found. Case 2, a male patient, aged 53 years, had a verrucous plaque at the border between his scrotum and inner aspect of his thigh. A pathological diagnosis of VC was made using an excisional specimen. Making a definitive diagnosis of VC is challenging but crucial. Pathological diagnosis using a small specimen might cause underdiagnosis or overdiagnosis. To avoid this, pertinent pathological diagnosis using an ample specimen is required. We also revisited the definition of VC to precisely understand its nature.

Carcinosarcoma (CS) is a rare tumor, consisting of both carcinomatous and sarcomatous components. In this paper, we present a case of CS arising from a pleomorphic adenoma (PA) of the submandibular gland. A 64-year-old Japanese man presented with a left submandibular mass that had developed for 20 years with complaints of pain for the last 3 months. Magnetic resonance imaging showed a lesion involving the left submandibular gland. The patient underwent total dissection of the left submandibular gland and left cervical lymph nodes. Upon gross examination, the mass appeared completely covered by fibroadipose tissue measuring 46×42×45 mm; sectioning revealed a solid-white nodule with central bleeding and necrosis, invading into the surrounding adipose tissue. Microscopically, the presence of carcinomatous and sarcomatous components in the fibro-myxomatous stroma was detected, suggestive of pre-existing PA. The carcinoma component was diagnostic of salivary adenocarcinoma, not otherwise specified, whereas the sarcomatous component exhibited features of osteosarcoma characterized by formation of osteoid. As the border between the carcinomatous and sarcomatous components was not evident, CS may have occurred via transformation of the carcinoma into sarcoma. Tumor metastasis was detected in the cervical lymph nodes. Immunohistochemically, AE1/AE3 expression was noted in the carcinomatous component, but not in the osteosarcoma component. Both components were diffusely positive for vimentin. Four months after the operation, the patient developed a metastatic CS lesion in the lung, suggesting tumor aggression.

Purpura fulminans associated with antithrombin 3 (AT 3) deficiency is very rare in adults and neonates. It can be categorized into three principal forms - neonatal, idiopathic and acute infectious. Purpura fulminans has been reported to cause cardiac, pulmonary and renal damage in rare cases. We describe an adult case of purpura fulminans developing in association with AT 3 deficiency without infection following a surgical procedure, and acute kidney injury (AKI) developing secondary to rhabdomyolysis and disseminated intravascular coagulation (DIC). To the best of our knowledge there have been no previous cases of purpura fulminans and AKI developing in association with acquired AT 3 deficiency without infection after surgery.

Medial epicondyle fractures of the humerus account for 11%-20% of all elbow injuries in children. Although intra-articular incarceration of the medial epicondyle occurs in 5%-18% of medial epicondyle fractures associated with an elbow dislocation, the mechanism of intrusion of the fracture fragment is unknown. We report a case of an irreducible elbow fracture and dislocation due to incarceration of the medial epicondyle fragment of the humerus, classified as a Watson-Jones type 3 fracture of the medial epicondyle, and present the mechanism of the intra-articular incarceration of the medial epicondyle fragment. The patient was a 9-year-old boy who injured his right elbow in a fall, and was diagnosed with a Watson-Jones type 3 fracture of the medial epicondyle. As we could not achieve a good reduction under fluoroscopic imaging, surgery was immediately performed using a medial approach. We discovered that the incarcerated fracture fragment was attached to the flexor-pronator muscles, the medical collateral ligament (MCL), and the anterior articular capsule. The medial epicondyle was fixed with Kirschner-wires augmented with tension band wiring. After fixation, there was no remaining instability. After 4 months the patient's fracture had proceeded to union and the internal fixation was removed. After 30 months he was asymptomatic and able to perform all of his daily life activities without any limitation. Our case, a Watson-Jones type 3 medial epicondyle fracture, is suggestive of the mechanism of incarceration of the medial epicondyle fragment into the elbow joint. Our findings support the idea that the attachment of both the MCL and the articular capsule can result in the entrapment of a fracture fragment in the elbow joint.