Older phase 2 cardiac rehabilitation patients engaged in gardening maintained physical function during the COVID-19 pandemic.

This study aimed to clarify the effects of gardening on hemodynamic response, rating of perceived exertion (RPE) during exercise, and body weight in patients in whom phase 2 cardiac rehabilitation (CR) was interrupted due to the Coronavirus disease 2019 (COVID-19) pandemic. Among 76 outpatients participating in consecutive phase 2 CR in both periods from March to April and June to July 2020, which were before and after CR interruption, respectively, at Sanda City Hospital were enrolled. The inclusion criterion was outpatients whose CR was interrupted due to COVID-19. Patients under the age of 65 were excluded. We compared the data of hemodynamic response and RPE during exercise on the last day before interruption and the first day after interruption when aerobic exercise was performed at the same exercise intensity in the gardener group and the non-gardener group. Forty-one patients were enrolled in the final analysis. After CR interruption, the gardener group did not show any significant difference in all items, whereas the non-gardener group experienced significant increase in HR (Peak) (p = 0.004) and worsening of the Borg scale scores for both dyspnea and lower extremity fatigue (p = 0.039 and p = 0.009, respectively). Older phase 2 CR patients engaged in gardening did not show any deterioration in hemodynamic response or RPE during exercise, despite CR interruption and refraining from going outside. Gardening may be recommended as one of the activities that can maintain or improve physical function in older phase 2 CR patients during the COVID-19 pandemic.

Differential shifts in baroreflex control of renal and lumbar sympathetic nerve activity induced by freezing behaviour in rats.

NEW FINDINGS: What is the central question of this study? Is the arterial baroreflex involved in causing patterned, region-specific changes in sympathetic nerve activity during freezing behaviour in conscious rats? What is the main finding and its importance? Freezing behaviour is accompanied by differential shifts in the baroreflex control of renal and lumbar sympathetic nerve activity and heart rate. It is noteworthy that baroreflex pathways may be discretely separated, allowing differential modification of baroreflex curves that may generate differential changes in sympathetic nerve activity during freezing behaviour. ABSTRACT: The present study was designed to test whether the baroreflex stimulus-response curves for renal sympathetic nerve activity (RSNA), lumbar sympathetic nerve activity (LSNA) and heart rate (HR) were shifted in a regionally specific manner during freezing behaviour in conscious rats. Male Wistar rats were chronically instrumented with electrodes and arterial and venous catheters for measurement of RSNA, LSNA and electrocardiogram. After a 60-min control period, freezing behaviour in conscious rats was induced by exposure to loud white noise (90 dB) for 10 min. The baroreflex curves for RSNA, LSNA and HR were generated by changing systemic arterial pressure using rapid intravenous infusions of vasoactive drugs and then fitted to an inverse sigmoid function curve. During the freezing behaviour, the baroreflex curve for RSNA was expanded upward with a significant (P < 0.001) increase (by 153% compared with the control level) in the upper plateau (maximum capacity of RSNA drive), whereas the baroreflex curve for LSNA remained unchanged. Conversely, the baroreflex curve for HR was shifted leftward with a significant (P = 0.004) decrease (by 11 mmHg relative to the control level) in the midpoint pressure. Our results indicate that baroreflex curve shifts for RSNA, LSNA and HR occur in a regionally specific manner during freezing behaviour. This indicates that baroreflex pathways may be discretely separated, allowing differential modification of baroreflex curves that may generate differential changes in sympathetic nerve activity during freezing behaviour.

Impact of the COVID-19 pandemic on phase 2 cardiac rehabilitation patients in Japan.

This study aimed to clarify the effects of the interruption of cardiac rehabilitation (CR) and refraining from going outside due to the COVID-19 pandemic on hemodynamic response and rating of perceived exertion (RPE) during exercise including differences by age in phase 2 CR outpatients. Among 76 outpatients participating in consecutive phase 2 CR in both periods from March to April and June to July 2020, which were before and after CR interruption, respectively, at Sanda City Hospital were enrolled. The inclusion criterion was outpatients whose CR was interrupted due to COVID-19. We compared the data of hemodynamic response and RPE during exercise on the last day before interruption and the first day after interruption when aerobic exercise was performed at the same exercise intensity in the < 75 years group and ≥ 75 years group. Fifty-three patients were enrolled in the final analysis. Post-CR interruption, peak heart rate increased significantly (p = 0.009) in the < 75 years group, whereas in the ≥ 75 years group, weight and body mass index decreased significantly (p = 0.009, 0.011, respectively) and Borg scale scores for both dyspnea and lower extremities fatigue worsened significantly (both, p < 0.001). CR interruption and refraining from going outside due to the COVID-19 pandemic affected the hemodynamic response, RPE during exercise and body weight in phase 2 CR outpatients. In particular, patients aged ≥ 75 years appeared to be placed at an increased risk of frailty.

Japanese guidelines for childhood asthma 2017.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2017 (JAGL 2017) includes a minor revision of the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. The section on child asthma in JAGL 2017 provides information on how to diagnose asthma between infancy and adolescence (0-15 years of age). It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. This guideline will be of interest to non-specialist physicians involved in the care of children with asthma. JAGL differs from the Global Initiative for Asthma Guideline in that JAGL emphasizes diagnosis and early intervention of children with asthma at <2 years or 2-5 years of age. The first choice of treatment depends on the severity and frequency of symptoms. Pharmacological management, including step-up or step-down of drugs used for long-term management based on the status of asthma control levels, is easy to understand; thus, this guideline is suitable for the routine medical care of children with asthma. JAGL also recommends using a control test in children, so that the physician aims for complete control by avoiding exacerbating factors and appropriately using anti-inflammatory drugs (for example, inhaled corticosteroids and leukotriene receptor antagonists).

T-cell epitope-containing hypoallergenic ß-lactoglobulin for oral immunotherapy in milk allergy.

BACKGROUND: Optimally hydrolyzed ß-Lactoglobulin (ßLg) is a promising milk oral immunotherapy (OIT) candidate with respect to showing reduced B-cell reactivity but retaining the T-cell epitope. To demonstrate that an edible hypoallergenic ßLg hydrolysate containing the T-cell epitope is suitable for OIT. We tested how chymotrypsin affected the retention of the T-cell epitope of ßLg when preparing ßLg hydrolysates using food-grade trypsin. METHODS: We investigated the effect of chymotrypsin activity on the formation of the T-cell epitope-containing peptide of ßLg (ßLg102-124 ) and prepared an edible ßLg hydrolysate containing ßLg102-124 using screened food-grade trypsins. B-cell reactivity was determined using immunoassays in which ELISA was performed with anti-ßLg rabbit IgG and Western blotting was performed with a milk-specific IgE antiserum. RESULTS: In ßLg hydrolysis performed by varying the activity of trypsin and chymotrypsin, chymotrypsin activity inhibited the formation of ßLg102-124 with an increase in hydrolysis time in a dose-dependent manner. ßLg102-124 was generated by two of five food-grade trypsins used at a ratio of 1:50 (w/w, enzyme/substrate) for 20 h at 40°C. The edible ßLg hydrolysate retained ßLg102-124 and showed a reduction in molecular weight distribution and antigenicity against IgG and IgE. CONCLUSIONS: Chymotrypsin activity inhibited the formation of ßLg102-124 in the trypsin hydrolysate of ßLg. This ßLg trypsin hydrolysate is a novel candidate for peptide-based OIT in cow's milk allergy for safely inducing desensitization.

Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy.

BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 µg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study. CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan.

PURPOSE: To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. METHODS: Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1ß levels were measured by ELISA. RESULTS: The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3-6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C-reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 ± 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-α and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1ß, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1ß production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes. CONCLUSIONS: Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder-associated genes.

A complement factor B mutation in a large kindred with atypical hemolytic uremic syndrome.

PURPOSE: Gain-of-function mutations in complement factor B (CFB) were recently identified in patients with atypical hemolytic uremic syndrome (aHUS), but are extremely rare. Our purpose is to describe a large kindred with aHUS associated with a CFB mutation and to further understand CFB-mutated aHUS patients. METHODS AND RESULTS: We report a large kindred in which 3 members had aHUS. This kindred revealed that 9 of 12 members, including 2 affected patients, had persistent activation of the alternative pathway with low complement component 3 and that those 9 members showed a CFB mutation (c.1050G > C, p.Lys350Asn) in exon 8. This missense mutation was heterozygous in 8 of them and homozygous in only one. From structural studies, this mutation is shown to be located in close proximity to the Mg2-binding site within a von Willebrand factor type A domain of CFB, resulting in a gain-of-function effect of CFB and predisposition to aHUS. At present, 2 of the 3 members with aHUS have maintained normal renal function for a long-term period. CONCLUSIONS: This kindred illustrates that a CFB mutation (c.1050G > C, p.Lys350Asn) can result in aHUS. In the future, phenotype-genotype correlations and outcome in CFB-mutated aHUS patients need to be further investigated by accumulation of a number of cases.

The role of dendritic cells in the generation of CD4(+) CD25(HI) Foxp3(+) T cells induced by amino acid copolymers.

The effects of the amino acid copolymers used in the therapy of experimental autoimmune encephalomyelitis, poly(Y,E,A,K)(n) (Copaxone(®)) and poly(Y,F,A,K)(n), on murine myeloid cells have been investigated. After administration of these copolymers to mice, increases in several splenic myeloid cell populations were observed, including CD11b(+) CD11c(+) dendritic cells. The latter were the major splenic cell type that secreted CCL22 (macrophage-derived chemokine) on stimulation with amino acid copolymers. CCL22 secretion was also stimulated from bone marrow-derived dendritic cells (BMDC) generated with GM-CSF in much larger amounts than from bone marrow-derived macrophages generated with M-CSF. Moreover, CCL22 secretion could also be obtained using BMDC generated from two different types of MHC II(-/-) mice, indicating that an innate immune receptor is involved. Finally, incubation of these BMDC or splenic dendritic cells with naive CD4(+) CD25(-) T cells resulted in formation of CD4(+) CD25(HI) Foxp3 T cells (~25% of which were Foxp3(+)). The number of these regulatory cells was doubled by pretreatment of BMDC with amino acid copolymers.

Facial palsy as an unusual presenting symptom associated with acute myeloid leukemia.

Extramedullary infiltration is common in acute myeloid leukemia (AML) patients. Although AML can cause neurological symptoms, especially when associated with extramedullary infiltration, a presenting manifestation of facial palsy is rare. We report on a 1-year-old boy who developed right facial palsy. Detailed examination led to a diagnosis of AML (French-American-British classification M1). Magnetic resonance imaging enhanced with gadolinium-diethylenetriamine penta-acetic acid showed abnormal enhancement of the right facial nerve, which disappeared after chemotherapy. AML should be considered as a differential diagnosis of facial palsy. Enhanced magnetic resonance imaging may be useful for diagnosing facial palsy associated with AML and for evaluating treatment outcome.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Japanese Guideline for Food Allergy 2014.

A food allergy is defined as "a phenomenon in which adverse reactions are caused through antigen-specific immunological mechanisms after exposure to given food." Various symptoms of food allergy occur in many organs. Food allergies are classified roughly into 4 clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type food allergy (urticaria, anaphylaxis, etc.), and (4) food dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate food allergy). The therapy for food allergies includes treatment of and prophylactic measures against hypersensitivity such as anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be used only if necessary because of the patient-related burden. For this purpose, it is very important that causative foods be accurately identified. There are a number of means available to identify causative foods, including the history taking, a skin prick test, detection of antigen-specific IgE antibodies in the blood, the basophil histamine release test, the elimination diet test, and the oral challenge test, etc. Of these, the oral challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions, such as anaphylaxis.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Japanese Guideline for Food Allergy 2014.

A food allergy is defined as "a phenomenon in which adverse reactions are caused through antigen-specific immunological mechanisms after exposure to given food." Various symptoms of food allergy occur in many organs. Food allergies are classified roughly into 4 clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type food allergy (urticaria, anaphylaxis, etc.), and (4) food dependent exercise-induced anaphylaxis and oral allergy syndrome (i.e., specific forms of immediate food allergy). The therapy for food allergies includes treatment of and prophylactic measures against hypersensitivity such as anaphylaxis. A fundamental prophylactic measure is the elimination diet. However, elimination diets should be used only if necessary because of the patient-related burden. For this purpose, it is very important that causative foods be accurately identified. There are a number of means available to identify causative foods, including the history taking, a skin prick test, detection of antigen-specific IgE antibodies in the blood, the basophil histamine release test, the elimination diet test, and the oral challenge test, etc. Of these, the oral challenge test is the most reliable. However, it should be conducted under the supervision of experienced physicians because it may cause adverse reactions, such as anaphylaxis.

Japanese Guideline for Atopic Dermatitis 2014.

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and coun- termeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013" together with those for other allergic diseases.

Japanese Guideline for Atopic Dermatitis 2014.

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013" together with those for other allergic diseases.

Molecular basis of two-exon skipping (exons 12 and 13) by c.1248+5g>a in OXCT1 gene: study on intermediates of OXCT1 transcripts in fibroblasts.

The molecular basis of simultaneous two-exon skipping induced by a splice-site mutation has yet to be completely explained. The splice donor site mutation c.1248+5g>a (IVS13) of the OXCT1 gene resulted predominantly in skipping of exons 12 and 13 in fibroblasts from a patient (GS23) with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. We compared heteronuclear RNA (hnRNA) intermediates between controls' and GS23's fibroblasts. Our strategy was to use RT-PCR of hnRNA to detect the presence or absence of spliced exon clusters in RNA intermediates (SECRIs) comprising sequential exons. Our initial hypothesis was that a SECRI comprising exons 12 and 13 was formed first followed by skipping of this SECRI in GS23 cells. However, such a pathway was revealed to be not a major one. Hence, we compared the intron removal of SCOT transcript between controls and GS23. In controls, intron 11 was the last intron to be spliced and the removal of intron 12 was also rather slow and occurred after the removal of intron 13 in a major pathway. However, the mutation in GS23 cells resulted in retention of intron 13, thus causing the retention of introns 12 and 11. This "splicing paralysis" may be solved by skipping the whole intron 11-exon 12-intron 12-exon 13-mutated intron 13, resulting in skipping of exons 12 and 13.