Safety and Feasibility of Infliximab Therapy in Children With Kawasaki Disease Who Received Live Vaccinations.

BACKGROUND: Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear. METHODS: We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated. RESULTS: Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines. CONCLUSIONS: Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration.

Effect of Plasma Treatment on Titanium Surface on the Tissue Surrounding Implant Material.

Early osseointegration is important to achieve initial stability after implant placement. We have previously reported that atmospheric-pressure plasma treatment confers superhydrophilicity to titanium. Herein, we examined the effects of titanium implant material, which was conferred superhydrophilicity by atmospheric-pressure plasma treatment, on the surrounding tissue in rat femur. Control and experimental groups included untreated screws and those irradiated with atmospheric-pressure plasma using piezobrush, respectively. The femurs of 8-week-old male Sprague-Dawley rats were used for in vivo experiments. Various data prepared from the Micro-CT analysis showed results showing that more new bone was formed in the test group than in the control group. Similar results were shown in histological analysis. Thus, titanium screw, treated with atmospheric-pressure plasma, could induce high hard tissue differentiation even at the in vivo level. This method may be useful to achieve initial stability after implant placement.

Effects of Surface Modification on Adsorption Behavior of Cell and Protein on Titanium Surface by Using Quartz Crystal Microbalance System.

Primary stability and osseointegration are major challenges in dental implant treatments, where the material surface properties and wettability are critical in the early formation of hard tissue around the implant. In this study, a quartz crystal microbalance (QCM) was used to measure the nanogram level amount of protein and bone marrow cells adhered to the surfaces of titanium (Ti) surface in real time. The effects of ultraviolet (UV) and atmospheric-pressure plasma treatment to impart surface hydrophilicity to the implant surface were evaluated. The surface treatment methods resulted in a marked decrease in the surface carbon (C) content and increase in the oxygen (O) content, along with super hydrophilicity. The results of QCM measurements showed that adhesion of both adhesive proteins and bone marrow cells was enhanced after surface treatment. Although both methods produced implants with good osseointegration behavior and less reactive oxidative species, the samples treated with atmospheric pressure plasma showed the best overall performance and are recommended for clinical use. It was verified that QCM is an effective method for analyzing the initial adhesion process on dental implants.

Utility of Soluble CD163 in the Clinical Management of Patients With Kawasaki Disease.

Objective: Intravenous immunoglobulin (IVIG) therapy is a useful first-line treatment for Kawasaki disease (KD); however, 10-20% of patients fail to respond and require additional IVIG. Soluble CD163 (sCD163) is considered a biomarker for macrophage activation. There are no reports measuring serum sCD163 in KD patients. This study aimed to explore its possible utility in the clinical management of patients with KD. Methods: Eighty-seven patients with well-defined KD were retrospectively enrolled together with 19 healthy individuals with comparable ages. KD patients were classified into three groups, Group A (initial IVIG responders), Group B (additional IVIG responders), and Group C (additional IVIG non-responders). Serum sCD163 together with complete blood counts, C-reactive protein, d-dimer, albumin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured before the initial IVIG treatment in all cases, and afterward in a fraction of cases. Results: Serum sCD163 in KD patients before initial IVIG was generally much higher than the control group. The median (interquartile range) of sCD163 was as follows: Control 446 (385-521) ng/mL; Group A, 699 (478-1,072); Group B, 1,349 (1,116-1,390); and Group C, 665 (544-1,094). In general, sCD163 showed close positive correlation with ALT and AST, but none with other markers. Among the KD groups, Group B showed the highest sCD163: Group B vs. A: p = 0.0003; B vs. C: p = 0.035). Serum sCD163 was significantly increased after IVIG in Group A, while no change occurred in others. Conclusion: The serum sCD163 levels could be a useful biomarker in the clinical management of KD, especially for predicting responsiveness to IVIG.

Kawasaki Disease Following Severe Sunburn Injury.

Background: Although an etiology of Kawasaki disease (KD) is unknown, an aberrant innate immune system in predisposed individuals has been proposed to play a key role in the development of KD vasculitis. Various etiological pathogens have been proposed as the trigger of KD and a scaled injury preceding symptom onset has been reported as one of them. Here, we report a 17-month-old Japanese female who was hospitalized due to high fever lasting for 4 days with infection ruled out as a cause. On admission, she displayed severe sunburn all over her body following a prolonged period of outdoor play 5 days ago. On the 5 day of illness, she developed complete KD. Serum levels of high mobility group box 1, a representative for damage-associated molecular patterns (DAMPs), were elevated during acute phase and continued to decrease during subacute phase. This unique course suggested the inflammatory process of KD involving innate immunity via DAMPs.

Successful use of oral prostaglandin E1 derivative for maintaining ductus-dependent systemic circulation in a neonate with trisomy 18.

A Japanese female infant with trisomy 18 was diagnosed with hypoplastic left heart syndrome variant. She was administered oral prostaglandin E1 every 6 hours through a feeding tube as an alternative drug for lipo-prostaglandin E1. Oral prostaglandin E1 was effective for maintenance of the ductus arteriosus and may serve as a palliative treatment approach.

Assessing the Efficacy of Very Early Motor Rehabilitation in Children with Down Syndrome.

Among children with Down syndrome, the frequency of motor rehabilitation intervention and the age at the start of this intervention are independently related to the age at onset of independent walking. Early motor rehabilitation, before age 6 months, may be effective in reducing motor delay in children with Down syndrome.

Circulating endothelial glycocalyx components as a predictive marker of coronary artery lesions in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is acute and self-limited vasculitis caused by unknown origin, and the critical complication in KD patients is coronary artery lesions (CALs). The endothelial glycocalyx is a network of membranes luminally covering the endothelium. This study aimed to evaluate the clinical utility of serum glycocalyx components as biomarkers of predicting the onset CALs in KD. METHODS: Seventy subjects with complete type KD, 18 subjects as febrile control (FC), and 15 subjects as afebrile controls (AC) were enrolled. Medical, demographic, echocardiography, and laboratory data from the medical records were retrospectively analyzed. Serum syndecan-1 and hyaluronan levels prior to intravenous immunoglobulin (IVIG) therapy were measured at the acute phase, immediately after IVIG, the subacute phase, and the time of discharge at the convalescent phase. RESULTS: Serum syndecan-1 and hyaluronan levels were higher in the KD group than in the AC and FC groups at all three phases. Further, these levels were compared between KD patients with and without the development of CALs. Serum syndecan-1 and hyaluronan levels at the acute phase were significantly elevated in KD patients with the CALs than in those without CALs. Serum hyaluronan, not syndecan-1, was determined as the most contributory parameter to predict CALs by a multiple logistic analysis. CONCLUSIONS: Circulating syndecan-1 and hyaluronan can be useful biomarkers to predict the development of CALs in KD.

Erythema Nodosum Masking Kawasaki Disease with an Initial Manifestation of Skin Lesions.

We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.

Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus.

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.

[A case of HER2 overexpressing advanced breast cancer with CTF therapy [cyclophosphamide, pirarubicin (THPADM), fluorouracil] showed long-term effectiveness after paclitaxel shock].

A 53-year-old woman with left breast tumor was diagnosed as bilateral breast cancer(left; T3N3M0, Stage III C/right; T2N0M0, Stage II )in our hospital, both of which were revealed as invasive ductal carcinoma shown to be ER-negative, PgR negative and HER2-positive by core needle biopsy. In December 2004, paclitaxel and trastuzumab combination therapy was tried, but she went into shock just during administration of paclitaxel, and this therapy was discontinued. After that the triweekly CTF therapy was tried as an anthracycline containing regimen, and the lymph node metastases obtained a complete response after a month and a 38. 5% reduction of left primary breast tumor, which was the best response observed after three months. Time to progression was prolonged to 7 months(9 cycles). Although febrile neutropenia occurred in the first cycle, the therapy could be continued safely thereafter as an outpatient. Anthracycline-containing regimens are likely to be avoided because of the difficulty of combining with trastuzumab in the treatment of HER2 overexpressing advanced/metastatic breast cancer. But the CTF therapy of less cardiotoxicity and less alopecia, can expect longer use and better QOL as an alternative for HER2 overexpressing advanced/metastatic breast cancer patients.

Preoperative dynamic lymphoscintigraphy predicts sentinel lymph node metastasis in patients with early breast cancer.

BACKGROUND: Preoperative lymphoscintigraphy is commonly used in sentinel lymph node biopsy (SLNB) for patients with early breast cancer; however, its significance to predict SLN metastasis remains to be determined. PATIENTS AND METHODS: Sixty patients were enrolled in a feasibility study of SLNB. Patients with clinically node-negative breast cancer were eligible for this study. Dynamic lymphoscintigraphy was performed before SLNB. All patients underwent SLNB followed by axillary lymph node dissection. RESULTS: A dual mapping procedure using isotope and dye injections was performed. SLNs were identified in 59 of 60 patients (98.3%), with a node-positive rate of 41.7% and a false-negative rate of 1.7%. No SLN was identified in 4 of 60 patients (6.7%) on preoperative lymphoscintigraphy. Interestingly, abnormal accumulation of the radiotracer close to hot spots was observed in 29 of 56 patients (51.8%). Lymph node metastases were detected in 18 of 29 patients (62.0%) with this pattern and 5 of 27 patients (18.5%) without this pattern (P < 0.05). Micrometastases were more frequently detected in node-positive patients without this pattern than in those with this pattern (80 vs. 16.7%). Diagnostic parameters of this pattern to predict SLN metastases, including micrometastases, were 62.1% for sensitivity, 81.5% for specificity, and 71.4% for accuracy. CONCLUSIONS: Abnormal accumulation of the radiotracer close to radioactive spots may indicate SLN metastasis. When dynamic lymphoscintigraphy shows this pattern, surgeons should consider the presence of SLN metastasis and carefully remove additional lymph nodes surrounding radioactive lymph nodes so as not to leave metastatic SLNs behind.

Two distinct alpha-L-fucosidases from Bifidobacterium bifidum are essential for the utilization of fucosylated milk oligosaccharides and glycoconjugates.

Bifidobacteria are predominant bacteria present in the intestines of breast-fed infants and offer important health benefits for the host. Human milk oligosaccharides are one of the most important growth factors for bifidobacteria and are frequently fucosylated at their non-reducing termini. Previously, we identified 1,2-alpha-l-fucosidase (AfcA) belonging to the novel glycoside hydrolase (GH) family 95, from Bifidobacterium bifidum JCM1254 (Katayama T, Sakuma A, Kimura T, Makimura Y, Hiratake J, Sakata K, Yamanoi T, Kumagai H, Yamamoto K. 2004. Molecular cloning and characterization of Bifidobacterium bifidum 1,2-alpha-l-fucosidase (AfcA), a novel inverting glycosidase (glycoside hydrolase family 95). J Bacteriol. 186:4885-4893). Here, we identified a gene encoding a novel 1,3-1,4-alpha-l-fucosidase from the same strain and termed it afcB. The afcB gene encodes a 1493-amino acid polypeptide containing an N-terminal signal sequence, a GH29 alpha-l-fucosidase domain, a carbohydrate binding module (CBM) 32 domain, a found-in-various-architectures (FIVAR) domain and a C-terminal transmembrane region, in this order. The recombinant enzyme was expressed in Escherichia coli and was characterized. The enzyme specifically released alpha1,3- and alpha1,4-linked fucosyl residues from 3-fucosyllactose, various Lewis blood group substances (a, b, x, and y types), and lacto-N-fucopentaose II and III. However, the enzyme did not act on glycoconjugates containing alpha1,2-fucosyl residue or on synthetic alpha-fucoside (p-nitrophenyl-alpha-l-fucoside). The afcA and afcB genes were introduced into the B. longum 105-A strain, which has no intrinsic alpha-l-fucosidase. The transformant carrying afcA could utilize 2'-fucosyllactose as the sole carbon source, whereas that carrying afcB was able to utilize 3-fucosyllactose and lacto-N-fucopentaose II. We suggest that AfcA and AfcB play essential roles in degrading alpha1,2- and alpha1,3/4-fucosylated milk oligosaccharides, respectively, and also glycoconjugates, in the gastrointestinal tracts.

[Evaluation of irinotecan hydrochloride (CPT-11) and trastuzumab combination therapy as salvage treatment in patients with HER2 overexpressing metastatic breast cancer].

BACKGROUND: Though irinotecan hydrochloride(CPT-11)was approved in Japan in 1994, there have been few reports since that evaluated the efficacy of CPT-11. The position of this agent in the treatment of patients with metastatic breast cancer(MBC)is not definite. In addition, no report has been published to date about CPT-11 and trastuzumab combination therapy. PURPOSE: To evaluate retrospectively the efficacy of CPT-11 and trastuzumab combination therapy as salvage treatment in patients with human epidermal growth factor receptor 2 (HER2)overexpressing MBC. PATIENTS AND METHOD: We examined ten cases who received this therapy against MBC since February 2002 till March 2007 in our hospital. Overall response rate, change of tumor markers, time to treatment failure (TTF), time to progression( TTP), overall survival (OS)after start of CPT-11 and adverse events were examined for efficacy and tolerability. RESULTS: Median age was 57 (40-67)and median number of prior chemotherapies was 5(2-9). Though the overall response rate was 20%, some tumor reduction was observed totally in seven cases. CEA and CA15-3 were decreased in 78%(7/9)and 63%(5/8) of cases, respectively. Median TTF, TTP and OS were 3, 4, and 6 months, respectively. Adverse events included three cases of severe neutropenia, one of whom died of treatment-related sepsis. Slight diarrhea occurred in seven and severe nausea occurred in two cases. Dose modification of CPT-11 was necessary in 5 cases, and three discontinued CPT-11 administration, mainly due to easy fatigability, nausea and neutropenia. During the therapy, four cases were all inpatients, and 6 eventually became outpatients. DISCUSSION: This therapy for patients with HER2 overexpressing metastatic cancer resistant to multi-agents demonstrated a good result in terms of antitumor effect. But high tolerability could not be documented by our experience with this therapy. It was supposed that the risk management with prediction of adverse events and preparation of better supportive therapy could make for the higher tolerability of this therapy for more effective clinical use.

[A case of paclitaxel and trastuzumab-resistant recurrent breast cancer with liver metastasis responding to S-1].

We experienced a case of paclitaxel- and trastuzumab-resistant recurrent breast cancer with liver metastases showing significant improvement by S-1. A 76-year-old woman was diagnosed with left breast cancer (T2N1M0, Stage II B). She received total mastectomy and CEF (cyclophosphamide 500 mg/m(2), epirubicin 60 mg/m(2), 5-FU 750 mg/m(2)) as adjuvant chemotherapy in March 2004. But twelve months later, she was referred to our clinic for management of lung and left supraclavicular lymph node metastases. Then weekly paclitaxel (80 mg/m(2)) and trastuzumab were started. After 2 cycles of weekly paclitaxel and trastuzumab treatment, lung and lymph node metastases were reduced and the patient showed a clinical response (CR), so she was treated by trastuzumab only. But seven months later, she was diagnosed as a recurrence of liver metastases. She was treated by combined paclitaxel and trastuzumab again, but liver metastases and tumor marker were progressive. S-1 was administered orally 100 mg/day every day for 4 weeks, followed by a 2-week rest interval as 1 cycle, and trastuzumab was injected at 2 mg/kg/week for every weeks. After 2 courses of the treatment, the level of tumor marker and tumor size of liver metastases were reduced. Only rash (grade 1) was observed during treatment. The treatment of S-1 is thought to be effective for taxane-resistant recurrent breast cancer.

[Efficacy of sequential treatment with anastrozole following exemestane compared with exemestane following anastrozole in patients with metastatic breast cancer].

BACKGROUND: There are three third-generation aromatase inhibitors (AI) available in Japan. Though it is supposed that they can be administered sequentially because of their little cross-resistant effect, it is not definite which sequential treatment is best. PURPOSE: To examine retrospectively the difference in efficacy by the AI sequence when anastrozole ( ANA) and exemestane (EXE) are clinically administered sequentially for patients with metastatic breast cancer. PATIENTS: We examined 22 patients with metastatic breast cancer administered ANA alone as first-line AI treatment, EXE alone as second-line (A--> E group), and 13 patients given EXE alone as first-line AI treatment (E --> A group) since December 2002 in our hospital. METHOD: In the A --> E and E --> A group, we examined overall response rate, clinical benefit (CB) rate, time to progression (TTP) for the first- and second-line treatment, respectively, overall survival (OS) after starting AI and successive efficacy of the two AIs. RESULTS: There were no significant differences between the two groups in patient characteristics and history of prior treatments. Overall response rate of the first-line treatment in the A--> E and the E--> A group was 31.8% and 38.5%, and the CB rate was 68.2% and 53.8%, respectively. Overall response rate of the second-line treatment in the A --> E (22 cases) and the E --> A (3 cases) group was 13.6% and 0%, and the CB rate was 36.4% and 33.3%, respectively, reflecting no particular differences. In the A --> E group, five (33.3%) among 15 cases obtained CB by EXE and three (42.6%) among 7 cases who did not obtain CB by ANA did so by EXE. Also, in the E--> A group, one among 3 cases who did not obtain CB by EXE did so by ANA. No significant differences were observed in TTP and OS between the two groups. CONCLUSION: When ANA and EXE are administered sequentially, no particular difference in efficacy occurs due to the sequence. In some cases, 2 agents become effective successively, and cases resistant to first-line treatment can expect efficacy from second-line treatment. Sequential treatment with the two agents seems to provide very significant efficacy in clinical practice regardless of the order of administration.

Pressure on anterior region of palate during thumb-sucking.

Measurement of the pressure applied to the anterior region of the palate and incisor region of the mandible during thumb-sucking was carried out 3 female children. A polyethylene bag embedded with a high-sensitivity small pressure sensor was fixed on the ventral side of the thumb so that the baroreceptor could be interposed between the thumb and palate during thumb-sucking. The children were allowed to perform habitual thumb-sucking, and the resulting pressure signals were detected with a high-response dynamic strainmeter and recorded. Measured peak pressures were about 2-4.5 kgw, with large individual variation, and waveform patterns also varied. Characteristics of thumb-sucking habits and thumb-sucking pressure were related to malocclusion. Measurement of thumb-sucking pressure is believed to be effective for assessment of the qualitative relationship between thumb-sucking and malocclusion.