A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation

Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin deposition in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy

Is oral food challenge useful to avoid complete elimination in Japanese patients diagnosed with or suspected of having IgE-dependent hen's egg allergy? A systematic review

Background: IgE-mediated egg allergy is a common food allergy worldwide. Patients with egg allergy are known to easily achieve tolerance compared to other allergens such as nuts. Oral food challenge (OFC) is often performed on patients diagnosed with or suspected of having IgE-mediated food allergy, but whether hen's egg OFC is useful in IgE-dependent egg allergy patients to avoid complete elimination remains unknown. Methods: We identified articles in which OFCs were performed in Japanese patients diagnosed with or suspected of having IgE-mediated egg allergy. We evaluated whether the OFCs were useful to avoid the complete elimination of eggs by assessing the following: (1) the number of patients who could avoid complete elimination; (2) the number of patients who experienced serious adverse events (SAEs); or (3) adverse events (AEs); (4) improvement in quality of life (QOL); and (5) immunological changes. Results: Fifty-nine articles were selected in the study; all the references were case series or case studies in which OFC was compared to pre-challenge conditions. The overall negative ratio against egg OFC was 62.7%, but an additional 71.9% of OFC-positive patients could take eggs when expanded to partial elimination. Of the 4182 cases, 1146 showed AEs in the OFC, and two cases reached an SAE. Two reports showed an improvement in QOL and immunological changes, although the evidence was weak. Conclusions: OFCs against eggs may be useful to avoid complete elimination, but medical professionals should proceed with the test safely and carefully

Japanese guidelines for atopic dermatitis 2020.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice

Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria

Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria). However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC. Reactive oxygen species (ROS) scavengers completely inhibited MALM. A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. Deficiency of NIX also completely impaired MALM. When MALM was inhibited, Mieap induced vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulfed and degraded the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impaired both MALM and MIV generation, leading to accumulation of unhealthy mitochondria. These results suggest that (1) mitochondrial ROS and NIX are essential factors for MALM, (2) MIV is a novel mechanism for lysosomal degradation of mitochondria, and (3) the p53-Mieap pathway plays a pivotal role in MQC by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively

Possible Existence of Lysosome-Like Organella within Mitochondria and Its Role in Mitochondrial Quality Control

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect

Development of a Japanese Culturally Modified Version of the Childhood Atopic Dermatitis Impact Scale (JCMV-CADIS)

Background: The Childhood Atopic Dermatitis Impact Scale (CADIS) was developed to measure the impact of AD on QoL in both affected children and their families. However, no scale of this kind exists in Japan. The aims of this study were to validate the Japanese Culturally Modified Version of the CADIS (JCMV-CADIS) and to describe the family impact of children with AD in a Japanese context. Methods: Participants included primary-caregivers for children with AD between 2 and 6 years of age. Interviews were conducted, and new items for the Japanese version were drafted. Reliability and validity were evaluated and compared with the original CADIS, and unique features of the Japanese version were analyzed. Results: Exploratory factor analysis revealed the following factors: “Symptoms” and “Activity Limitations and Behavior” in the Child domain, and “Emotions Related to Social Factors,” “Emotions Related to the Child's Condition,” “Family and Social Function,” “Complexity of Care,” and “Approaches to Management of AD in Daily Life” in the Parent domain. The latter two factors were unique to the JCMV-CADIS and were not derived from the Original. “Emotion” was split into two independent factors. All factors showed good reliability (internal consistency and stability) and validity (concurrent validity and discriminant validity), except for the concurrent validity of “Approaches to Management of AD in Daily Life.” This factor seemed to reflect characteristics similar to the family-related function. Conclusions: The JCMV-CADIS is a QoL scale developed for Japanese children with AD and their families. Further evaluation of clinical applicability is needed

Environmental Exposure to Endotoxin and Decreased Risk of Childhood Atopy

The hygiene hypothesis implies, in immunological terms, that microbial stimulation in early life skews the immune system towards the development of a T helper type 1 (Th1)-type lymphocyte population, and away from a T helper type 2 (Th2)-type development that is associated with atopy. The hygiene hypothesis originally theorized that increased infections protected against atopy. This theory has evolved since harmful infections may not be as critical as exposure to microbial burden because exposure to microbes can occur in the absence of infections. Despite substantial public hygiene measures in modern metropolitan communities, an atopy-protective effect of endotoxin in these metropolitan environments still occurs. This article is a review of clinical and experimental studies concerning the protective effect of endotoxin exposure on the susceptibility to atopic responses. The discussion includes : (1) factors influencing household endotoxin levels ; (2) recent developments in the potential use of endotoxin for the prevention of atopy and asthma ; (3) association of endotoxin and pets with atopic sensitization and diseases ; (4) animal studies on the protective effects of timing of endotoxin exposure on atopy and asthma and (5) animal studies on the protective effects of endotoxin dose on atopy and asthma

Factors determining parenting stress in mothers of children with atopic dermatitis

Background: Atopic dermatitis (AD) influences a child's emotional and social well-being, as well as his or her physical health. The influence of AD on the daily lives of parents and caregivers has also been documented. This study examined how parenting stress is affected by demographic background, characteristics of children's AD, and their family systems. Methods: The participants were mothers of children, aged 2–6 years old, who had been diagnosed with AD. The predictive power of a model of parenting stress was examined using multiple regression analysis (stepwise), with parenting stress (PSI-SF) as the dependent variable, and children's demographics, including characteristics of AD; parents' demographics; QoL of families of children with AD (JCMV-CADIS); and family functioning (FAI) as independent variables. We handled missing values using a multiple imputation method. Results: The pooled coefficients obtained from the multiple regression analysis after multiple imputation indicated that “family cohesion,” “family system flexibility,” “emotions related to social factors” and “occupation of mother” determined parenting stress. Lower family cohesion and family system flexibility predicted higher parenting stress. The high impact of “emotions related to social factors” on families’ QoL predicted higher parenting stress. Full-time work by mothers predicted lower parenting stress. Conclusions: The current results reveal that “family cohesion,” “family system flexibility,” “emotions related to social factors” and “full-time work by mothers” predicted parenting stress of mothers who had children with AD. Keywords: Atopic dermatitis, Family, Multiple imputation, Multiple regression, Stres