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We investigated whether multiple food allergies could be safely prevented by simultaneously administering very small amounts of multiple foods.Infants 3-4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing egg, milk, wheat, soybean, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4, and continued until week 12. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000027837).A total of 163 participants were randomly allocated to either the MP group (n = 83) or the PP group (n = 80). The incidence of food allergy episodes by 18 months was significantly different between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116-0.784]; P = 0.0066). Egg allergies were reduced in the MP group. In addition, food allergy episodes from any of the other five foods were significantly reduced, although the reductions in those due to individual foods were not significant.Gradually increasing the intake of very small amounts of multiple foods in early infancy can safely reduce the incidence of egg allergies. Other foods may also suppress food allergies, but no definitive conclusions could be reached.

Background: There is controversy regarding the efficacy and side effects of proactive administration of allergenic foods in early infancy to prevent food allergies. This is the first trial involving the gradual introduction of trace amounts of multiple foods to infants. Methods: Infants under 4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, double-blind, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing eggs, milk, wheat, soybeans, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4 and continued until week 12. Weaning food was started subsequently according to the Japanese guidelines for nursing/bottle feeding, and for baby food. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old by the physician responsible for each participant. Findings: A total of 163 participants were randomly allocated to either the MP group (n = 83, 50.9%) or the PP group (n = 80, 49.1%). There was a significant difference in the incidence of food allergy episodes by 18 months between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116 – 0.784]; P = 0.008). No serious adverse events attributable to MP were observed. Interpretation: Gradually increasing the intake of trace amounts of multiple foods in early infancy can safely reduce the incidence of food allergies. Clinical Trial Registration Details: UMIN000027837. The protocol for this study and the subsequent changes are available on the UMIN-CTR Trial website. Funding Information: This study was self-funded and did not receive any other support. Declaration of Interests: The authors declare that no conflicts of interest exist. Ethics Approval Statement: Written informed consent was obtained from the parents of the participants at the time of enrollment. The study was approved by the institutional review board of Umezu Clinic.

Pertussis in adolescents has been increasingly documented in recent years, but diagnosis from the clinical symptoms is difficult. Serological diagnosis with IgG antibody to pertussis toxin (IgG PT) is useful for detecting pertussis cases in this population. However, no serological criterion for recent infection has been fully validated and large-scale, longitudinal serological data among Japanese junior and senior high school students are lacking. Paired serum samples of 3243 junior and senior high school students, collected in 2013 and 2014, were analyzed for IgG PT and its relationship to possible risk factors. Regression analysis showed an average decrease of 35% in IgG PT between 2013 and 2014. In 2013, 4.4% of the students showed IgG PT levels ≥100EU/mL, as did 3.7% in 2014. The seroincidence, defined as [IgG PT] change from100 in 2013 to ≥100EU/mL in 2014, was 10.3 cases per 1000 person-years. A 4-fold rise in IgG PT was seen in 2.1% of the students, with significant differences between schools and significant correlations to two risk factors, "over 2weeks coughing" and "exposure to a person with over 2weeks coughing". A substantial number of students had IgG PT ≥100EU/mL despite the observed 35% yearly decrease in IgG PT level. The local foci of ≥4-fold IgG PT increase in specific schools suggests the persistent circulation of B. pertussis in Japanese adolescents. The results also support a "≥4-fold rise in IgG PT" as a useful component of the sero-epidemiological surveillance for pertussis.

Because identification of carriers of X-linked adrenoleukodystrophy (ALD) results in 5-15% false negatives with very long chain fatty acids (VLCFA) assay in plasma, and mutation analysis of plasma VLCFA combined with of the ALD gene is not always practical, we studied whether the analysis of plasma VLCFA combined with lignoceric acid oxidation study in fibroblasts could improve the rate of carrier detection. Lignoceric acid oxidation was abnormal in 19 out of 19 patients (ALD or adrenomyeloneuropathy) and in three out of three obligate heterozygous women. Among ten women at risk of being a carrier, three women who had normal plasma VLCFA had abnormal lignoceric acid oxidation in fibroblasts. These data suggest that this combined biochemical procedure may help to improve carrier detection in families when the ALD gene mutation has not been identified.

Background — Increased vascular permeability is an important event during the initial process of Kawasaki disease (KD). One potential responsible candidate for the induction of vascular hyperpermeability is vascular endothelial growth factor (VEGF). Methods and Results — We investigated the expression of VEGF and its receptors (flt-1, KDR) in acute KD tissues at 7 days to 5 weeks of illness. Neuropilin-1, which enhances the binding of VEGF 165 to KDR, was also studied. Abundant expression of VEGF and flt-1 was documented immunohistochemically in many organs from acute KD, including heart and lung. VEGF and flt-1 were colocalized in all vessels that showed edema. These molecules resided in endothelium and vascular media and also in migrating smooth muscle cells in neointima and infiltrating macrophages. Compared with controls, coronary vessels of acute KD had upregulation of VEGF and flt-1 but not KDR or neuropilin-1. KDR was expressed by vessels at 7 days of illness but not later in the illness. Plasma proteins were more extensively bound to the extracellular matrix in coronary vessels in acute KD than controls. Furthermore, elevation of serum VEGF levels was correlated with low serum albumin in acute KD (n=220, r =−0.53, P Conclusions — These findings suggest that VEGF and flt-1 are upregulated in blood vessels in many organs of acute KD. Expression of KDR was limited to the early stage of acute KD. The roles of VEGF in acute KD may involve promotion of vascular permeability and macrophage activation. Low serum albumin may indicate overproduction of VEGF in acute KD.

症例は生後3カ月の男児。生後2カ月頃より徐々に浮腫が出現し当科入院となった。入院時低蛋白血症，高コレステロール血症，1日尿蛋白10gを認め，ネフローゼ症候群と診断した。腎組織検査はdiffuse mesangial sclerosisであった。ステロイドおよび免疫抑制剤は無効であった。1歳よりACEI (エナラプリル0.06mg/kg/day) 投与を開始したところ尿蛋白は減少し始め，エナラプリル投与を0.2mg/kg/dayまで増加した時点で尿蛋白は消失した。2回目の腎生検 (2歳) では，糸球体硬化病変は進行し，間質への細胞浸潤が増加していた。エナラプリル投与開始2年6カ月後の現在，腎機能は正常範囲を維持し，身体発育，精神運動発達は良好である。またエナラプリルによると考えられる副作用は特に認めていない。したがって本症例のような多剤に抵抗性の乳児ネフローゼ症候群においても，ACEIは試みられるべき治療法と考えられた。

Japanese patients with peroxisomal disorders in the pediatric field were screened. Very long chain fatty acid analysis in the serum sphingomyelin was introduced since 1987 and was useful for the first screening of peroxisomal disorders. Seventy-five patients were diagnosed since 1980: 15 patients with Zellweger syndrome, 2 with neonatal adrenoleukodystrophy (ALD), 1 with rhizomelic chondrodysplasia punctata, 1 with Zellweger-like syndrome, 2 with acyl-CoA oxidase deficiency, 2 with bifunctional enzyme deficiency and 52 with X-linked ALD. The incidence of peroxisome-deficienct disorders was estimated to be approximately 1 in 800,000 births which is far less than that in the USA. However, the incidence in Okinawa Islands was 1 in 30,000. Japanese Zellweger patients belonged to 5 complementation groups (A, B, C, E, F) and the patients in Okinawa Islands belonged to groups A and C. The results of this screening were useful for genetic counseling, prenatal diagnosis, carrier detection and early medical care of patients with peroxisomal disorders.

Prenatal diagnoses of peroxisomal disorders, including peroxisome-deficient Zellweger syndrome, isolated deficiency of peroxisomal β-oxidation enzyme and rhizomelic type chondrodysplasia punctata were investigated by means of the lignoceric acid oxidation assay, indirect immunofluorescence staining and pulse-chase experiments, using cultured amniocytes. Assessment of peroxisomal β-oxidation activity by means of [1- 14 C]lignoceric acid oxidation is essential for the diagnosis of a single enzyme deficiency of peroxisomal β-oxidation with detectable enzyme protein. For the diagnosis of Zellweger syndrome, the absence of peroxisomes was readily determined by immunofluorescence staining of only a few aminocytes. Evidence for abnormal processing of 3-ketoacyl-CoA thiolase leads to the diagnosis of rhizomelic chondrodysplasia punctata. All the fetuses were considered to be normal and the neonates were normal. Use of these methods requires only a small number of amniocytes and will facilitate the prenatal diagnosis of peroxisomal disorders.

Genetic heterogeneity in peroxisome-deficient disorders, including Zellweger's cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease, was investigated. Fibroblasts from 17 patients were fused using polyethylene glycol, cultivated on cover slips, and the formation of peroxisomes in the fused cells was visualized by immunofluorescence staining, using anti-human catalase IgG. Two distinct staining patterns were observed: (1) peroxisomes appeared in the majority of multinucleated cells, and (2) practically no peroxisomes were identified. Single step 12-(1'-pyrene) dodecanoic acid/ultraviolet (P12/UV)-selection confirmed that the former groups were resistant to this selection, most of the surviving cells contained abundant peroxisomes, and the latter cells died. In the complementary matching, [1-14C]lignoceric acid oxidation and the biosynthesis of peroxisomal proteins were also normalized. Five complementation groups were identified. Group A: Zellweger syndrome and infantile Refsum disease; Groups B, C and D: Zellweger syndrome; Group E: Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. We compared these groupings with those of Roscher and identified eight complementation groups. There was no obvious relation between complementation groups and clinical phenotypes. These results indicate that the transport, intracellular processing and function of peroxisomal proteins were normalized in the complementary matching and that at least eight different genes are involved in the formation of normal peroxisomes and in the transport of peroxisomal enzymes.

The effects of sodium 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA), a potent inhibitor of carnitine palmitoyltransferase I, on fatty acid oxidation were investigated using fibroblasts from control subjects and from patients with peroxisomal disorders. [1-14C]Palmitate oxidation was inhibited by 8% of the control value when 15 microM POCA was added to the medium. The inhibition by POCA was significantly (P less than 0.05) stronger in fibroblasts from patients with Zellweger syndrome or with neonatal adrenoleukodystrophy, in which peroxisomes and peroxisomal beta-oxidation enzymes were absent. However, the inhibition in fibroblasts from patients with X-linked adrenoleukodystrophy, in which a specific defect of peroxisomal lignoceroyl-CoA synthetase was speculated, was similar to that in the controls. [1-14C]Lignocerate oxidation was not influenced by the addition of POCA, in samples from the controls and from the patients. These results indicate that peroxisomes account for a small but demonstrable proportion of palmitate oxidation, and add new evidence to the concept that lignocerate is oxidized exclusively in the peroxisomes. Our findings also support the hypotheses that the activity of palmitoyl-CoA synthetase and the enzymes of beta-oxidation cycle in peroxisomes are normal in patients with X-linked adrenoleukodystrophy and that a specific defect of lignoceroyl-CoA synthetase is responsible for the accumulation of very long chain fatty acids in these patients.

Ten Japanese boys with childhood adrenoleukodystrophy (ALD), one adult patient with adrenomyeloneuropathy (AMN), and two presymptomatic ALD boys were treated with dietary erucic acid (C22:1) for more than 12 months; except in a case of childhood ALD patient who died 7 months after beginning erucic acid therapy. During erucic acid therapy, the serum levels of very long-chain fatty acid (VLCFA) (C24:0/C22:0) decreased within 1-2 months in all patients, and these levels in four of the patients decreased to the normal range. Neurological examination and MRI findings in all 10 of the childhood ALD patients showed progression of the disease while they were receiving the dietary therapy. However, the mean interval between the onset of awkward gait and a vegetative state in diet-treated patients was significantly longer than that in the untreated patients. One AMN patient showed slight improvement of spastic gait and lessened pain in the lower limbs due to spasticity. The two presymptomatic ALD boys remained intact on clinical examination and on MRI findings for 38 and 23 months, respectively, after starting the diet.

A 5-year-old boy with adrenoleukodystrophy, with clinical symptoms of visual, mental and motor disturbances which progressed rapidly, was treated with Lorenzo's oil consisting 1 volume of glyceryl trierucate and 4 volumes of glyceryl trioleate. Five months after initiation of this therapy, ability to swallow was enhanced and T2-weighted magnetic resonance imaging of the brain revealed regression of high intensity area of the parieto-occipital white matter.

Human skin fibroblasts deficient in peroxisome biogenesis were transformed by transfecting SV40 ori- DNA with the use of an electroporator, and the biochemical, immunocytochemical, and cytogenetic properties of the transformants were analyzed. Cells (1 x 10(6)) from a patient with Zellweger syndrome and one with neonatal adrenoleukodystrophy were suspended with 2 micrograms of SV40 ori- DNA in PBS; then a high-voltage pulse (2000 V, 30 microseconds) was generated two times. Several colonies expressing large T-antigen were picked up 4 weeks after transfection. Doubling time of the transformants was about half of that and the saturation density was 5 to 10 times greater than that of the parental cells. Biochemical abnormalities including defective lignoceric acid oxidation, dihydroxyacetone phosphate acyltransferase deficiency, and disturbed biosynthesis of peroxisomal beta-oxidation enzymes were preserved in the transformants. Peroxisomes were defective in all colonies, as determined by immunofluorescence staining using anti-catalase IgG. Cell fusion studies confirmed that the transformants belong to the same complementation groups as those of the parental cells. These transformed mutant cell lines are expected to be useful tools for investigating the pathogenesis of inherited diseases related to defects in peroxisome biogenesis.

We investigated intracellular localization of peroxisomal proteins in fibroblasts from patients with Zellweger syndrome and neonatal adrenoleukodystrophy in whom peroxisomes were morphologically deficient or severely decreased. Indirect immunofluorescence staining revealed that catalase was mainly detected in the cytosol of fibroblasts from these patients, but a small amount of catalase was detected in granular pattern in a small percentage of cells. Double immunofluorescence staining revealed that catalase-containing particles in these patients also contained acyl-CoA oxidase and nonspecific lipid transfer protein. However, a 70 kD integral membrane protein and 3-ketoacyl-CoA thiolase were detected in all cells in granular pattern. Subcellular fractionation using digitonin after cell labeling revealed that a small amount of acyl-CoA oxidase and about half of thiolase in the precursor form were detected in the particulate fraction. These data suggest that the mechanisms of the transport and processing of catalase, acyl-CoA oxidase and nonspecific lipid transfer protein are different from those of the 70 kD integral membrane protein and 3-ketoacyl-CoA thiolase.

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder characterized by progressive demyelination of cerebral white matter and adrenal insufficiency. ALD is the most common peroxisomal disease, afflicting 1 in 20 000 male newborns. Patients with childhood ALD manifest changes of character or behavior and a decline of intelligence and visual or motor dysfunction as the first symptoms during school age. Most of them lapse into a vegetative state and die within several years of onset (1). Patients with all clinical subtypes, including childhood ALD, adolescent ALD, adult ALD (cerebral type), adrenomyeloneuropathy, and Addison disease without neurological symptoms, have defects in the ALD gene (2). Defective activity of peroxisomal lignoceroyl-CoA ligase is considered to lead to the accumulation of very long chain fatty acid (VLCFA) in various tissues and fluids as a secondary phenomenon (3)(4). Dietary erucic acid (C22:1) therapy may help prevent neurological deterioration in presymptomatic boys (5)(6). Patients in the early or presymptomatic stages may be candidates for bone marrow transplantation (5)(7). Gene therapy may also become possible. Screening for ALD, especially in the presymptomatic stage, will be important when these therapeutic methods are established, as in the cases of phenylketonuria or maple syrup urine disease. ALD is usually diagnosed by plasma VLCFA analysis (1)(8), sometimes followed by measurement of β-oxidation activity in cultured skin fibroblasts (9) and mutation analysis of the ALD gene (2)(10)(11)(12)(13)(14)(15)(16). However, screening requires a simpler and more economical method to deal with a large number of subjects. Utilization of a dried blood spot on filter paper …

Purpose: In December 1997, an animated TV program called “Pocket Monsters” induced photosensitive seizures simultaneously over widespread regions of Japan, and several hundreds of viewers were rushed to emergency hospitals. We investigated factors involved in determining why only some photosensitive individuals had seizures while watching the program. Methods: Cathode ray tube (CRT) emissions were evaluated for 7 patients with induced seizures in response to the program (induced patients) and 4 photosensitive patients without seizures in response to the program (photosensitive controls) using a spectroradiometer. The color bars televised by TV-AICHI stations that aired the program in the Chukyou district were recorded on videotape via receiving systems in the patients houses. The recorded color bar was played on each CRT in a darkened room of the patients houses, and in blue, green, red, white, and black images of the color bar, luminance energy was measured by spectroradiometer. Testing was performed l hour after turning on the CRTs. Luminance energy at 4 subdivided ranges: 380-480 nm (blue range), 480–590 nm (green range), 590–720 nm (red range), and 720–780 nm (long-wavelength red range) were integrated from the spectroradiometer data. Results: Black color bar emissions showed characteristic longwavelength red light patterns. All CRTs of induced patients emitted light containing long-wavelength red light at a higher rate than the CRTs of photosensitive controls. CRTs of patients 1,5, and 7 presented long-wavelength red light at higher rate (patients 1, 5 and 7), and the characteristic emission extended to the red range. CRTs of photosensitive controls lacked the characteristic emissive pattern, and only the CRT of patient 9 emitted a few long-wavelength red light. Each CRT of induced patients and photosensitive controls seemed to have almost consistent emission level of long-wavelength red light independent of color of images. The mean amount of long-wavelength red light emitted from CRTs of induced patients was significantly more than that in CRTs of photosensitive controls in blue (p = 0.02, Mann-Whitney U), green (p = 0.04), and black images (p = O.Ol), but was not significantly more in red and white images. The mean amount of total visible rays emitted from CRTs was not significantly different between CRTs of induced patient and CRTs of photosensitive controls. The mean ratio of long-wavelength red range to total visible range was significantly higher in CRTs of induced patients than that in CRTs of photosensitive controls in every color of images (P= 0.008–0.023, Mann-Whitney U). The mean contrast of luminance energy between red and blue images in CRTs of induced patients was not significantly different from that in CRTs of photosensitive controls, at blue, green, red, and long-wavelength red ranges. Conclusions: The emission of long-wavelength red light from CRTs played a decisive role in induction of seizures in photosensitive patients. Long-wavelength red light components from CRTs 011 flashing images (redlblue) of the program correlated strongly with subsequently induced seizures. CRTs with high long-wavelength red light emission stimulated wavelength-dependent pathophysiological mechanism and might have increased the level of photosensitivity of photosensitive viewers by everyday use of such CRTs. We must consider limiting long-wavelength red emission from CRTs in order to prevent photosensitive seizures produced by watching TV.