Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.

Pathogenic variants in the HIBCH gene cause HIBCH deficiency, leading to mitochondrial disorders associated with valine metabolism. Patients typically present with symptoms such as developmental regression/delay, encephalopathy, hypotonia and dystonia. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the basal ganglia with/without brainstem involvement. Here, we report a case of a Japanese patient with Leigh-like syndrome caused by novel HIBCH variants. Long-term follow-up MRI revealed progressive cerebellar atrophy, which expands the phenotypic spectrum of HIBCH deficiency.

Emaciation, Congestive Heart Failure, and Systemic Amyloidosis in Severe Recessive Dystrophic Epidermolysis Bullosa: Possible Internal Complications Due to Skin-Derived Inflammatory Cytokines Derived from the Injured Skin.

Inherited epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by epithelial tissue fragility. Recessive dystrophic epidermolysis bullosa (RDEB) is the most severe form, characterized by the presence of blisters, erosion, and ulcer formation, leading to scarring and contraction of the limbs. RDEB is also associated with extra-cutaneous complications, including emaciation, congestive heart failure, and systemic amyloidosis. The main cause of these clinical complications is unknown; however, we hypothesized that they are caused by elevated circulating inflammatory cytokines overproduced by injured keratinocytes. We addressed this phenomenon using keratin-14 driven, caspase-1 overexpressing, transgenic (KCASP1Tg) mice in which injured keratinocytes release high levels of IL-1α and ß. KCASP1Tg showed severe spontaneous dermatitis, as well as systemic complications, including aberrant weight loss, cardiovascular disease, and extensive amyloid deposition with organ dysfunction, resembling the complications observed in severe EB. These morbid conditions were partially ameliorated by simultaneous administration of anti-IL-1α and ß antibodies. The skin not only constitutes a physical barrier, but also functions as the largest immune organ. We suggest a novel role for IL-1 in the pathogenesis of EB and the use of anti-IL-1 antibodies as a potential therapy for EB complications.

Swyer-James Syndrome in a 7-Year-Old Female.

Swyer-James syndrome is a rare syndrome that occurs as a result of repeated bronchiolitis and pneumonitis in childhood. Most cases are asymptomatic, and subsequent diagnosis may not occur until adulthood. We present the case of a 7-year-old female with Swyer-James syndrome, which was initially diagnosed and treated as asthma. The patient developed respiratory distress and atelectasis which were treated with biphasic cuirass ventilation. This case suggests that Swyer-James syndrome should be a concern in patients with chronic cough and wheezing, and highlights the importance of taking a careful history and appropriate radiological investigations for diagnosis. Once Swyer-James syndrome is diagnosed, prophylaxis and appropriate management of respiratory infections becomes important.

Maintenance Hemodialysis Using Native Arteriovenous Fistula in a Patient with Severe Generalized Recessive Dystrophic Epidermolysis Bullosa.

Renal failure and infectious disease are strongly associated with morbidity and mortality in patients with severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev gen). However, it is reportedly difficult to introduce hemodialysis with an arteriovenous fistula (AVF). We encountered a 32-year-old man with RDEB-sev gen in whom hemodialysis with a native AVF was introduced that favorably affected his long-term survival. This patient eventually died because of cachexia related to the recurrence of cutaneous squamous cell carcinoma 51 months after hemodialysis introduction. We believe that in this patient, the frequency of vascular access troubles related to infection or reduction of blood flow was probably low as a result of hemodialysis with his native AVF. Thus, it seems likely that patients with RDEB-sev gen with end stage kidney disease who are on hemodialysis can be successfully managed with a native AVF.

Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome.

Dravet syndrome (DS) is a severe childhood epilepsy typically caused by de novo dominant mutations in SCN1A. Although patients with DS frequently have neurocognitive abnormalities, the precise neural mechanisms responsible for their expression have not been elucidated. There are wide phenotypic differences among individuals with SCN1A mutations, suggesting that factors other than the SCN1A mutation modify the phenotype. Therefore, a well-controlled cellular model system is required to improve our understanding of the mechanisms underlying DS. Here we generated induced pluripotent stem cell (iPSC) lines from an individual with SCN1A mutation mosaicism, and separately cloned iPSC lines both with and without the SCN1A mutation. These clones theoretically have the same genetic backgrounds, except for the SCN1A gene, and should serve as an ideal pair for investigating the pathophysiology caused by SCN1A mutations. Quantitative reverse transcription-PCR and western blot analysis revealed higher tyrosine hydroxylase mRNA and protein expression levels in mutant neurons than in wild-type neurons. Moreover, dopamine concentrations in media collected from mutant neural cultures were higher than those from wild-type neural cultures. Our findings suggest that SCN1A mutation leads to changes in the dopamine system that may contribute to the behavioral abnormalities in DS.

Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy.

Syntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of control-derived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy.

Olopatadine, a non-sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis.

We have demonstrated for the first time that a second-generation antihistamine ameliorates nocturnal scratching behavior in atopic dermatitis patients using a modified wristwatch-type acoustic scratching counting system that we have recently developed. We also analyzed the sleep quality by simultaneous recording of electroencephalogram, and found that sleep quality was unaffected.

Efficacy of the combined use of a facial cleanser and moisturizers for the care of mild acne patients with sensitive skin.

Acne is a common skin disease that involves the seborrheic area of the face and results from the obstruction of hair follicles followed by inflammation. Careful face washing helps to improve and prevent acne; however, intensive washing has a risk of inducing skin barrier impairment and dry skin, especially in sensitive skin. We hypothesized that skin care combining mild skin cleansing and intensive moisturizing ("combination skin care") may be effective in the care of acne in subjects with dry skin and/or sensitive skin. We developed a combination skin care with a weakly acidic foaming facial skin cleanser based on a mild detergent, an aqueous lotion with eucalyptus extract and a moisturizing gel containing pseudo-ceramide and eucalyptus extract. To optimize an ideal facial skin care system for mild acne on sensitive skin, we performed a 4-week clinical trial with 29 post-adolescent Japanese women with mild acne with dry and sensitive skin. The acne significantly decreased after this trial accompanied by the improvement of dry skin, a significantly increased endogenous ceramide level in the stratum corneum and an elongated alkyl chain length of the non-hydroxy acyl sphingosine type ceramide. No adverse events due to the test samples were observed. Based on diagnosis by a dermatologist, 97% of the subjects found the combination skin care to be "useful" or "slightly useful". Based on these findings, the combined use of a facial skin cleanser and moisturizers is safe and effective for the care of acne in post-adolescent Japanese women with sensitive skin.

Persistent release of IL-1s from skin is associated with systemic cardio-vascular disease, emaciation and systemic amyloidosis: the potential of anti-IL-1 therapy for systemic inflammatory diseases.

The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1ß antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.

Novel acoustic evaluation system for scratching behavior in itching dermatitis: rapid and accurate analysis for nocturnal scratching of atopic dermatitis patients.

Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.

Effects of chemotherapy on the brain in childhood: diffusion tensor imaging of subtle white matter damage.

INTRODUCTION: With reducing mortality in children with hematological malignancies, the survivors' quality of life regarding development of chronic neurological disturbances is important. We aimed to determine whether chemotherapy affects white matter (WM). METHODS: Using brain diffusion tensor imaging, we evaluated 17 patients (15 with acute lymphoblastic leukemia, 2 with non-Hodgkin's lymphoma; 9 male, 8 female; age, 1.6-13 years) before and after chemotherapy. We measured the quantitative values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at the regions of interest (ROIs) such as periventricular WM, corona radiata, posterior limb of the internal capsule, and corpus callosum. We assessed sensorimotor and callosal tracts by tractography. RESULTS: Reduction in FA and increase in ADC were significant at the ROIs of the left and right anterior periventricular WM and corona radiata and at the tract passing through the genu. A significant reduction in FA with a nonsignificant increase in ADC was seen at the ROI of the genu and at the tracts passing through the body and isthmus. CONCLUSION: Chemotherapy in children with hematological malignancies predominantly affects the frontal WM. This finding might indicate a negative effect of chemotherapy on neurological development in children with hematological malignancies.

Rare case of disseminated cysticercosis and taeniasis in a Japanese traveler after returning from India.

We report disseminated cysticercosis concurrent with taeniasis in a 31-year-old male Japanese, who had visited India three times and stayed for 1 month each time during the previous 1 year. The patient presented increasing numbers of subcutaneous nodules and expelled proglottids, although numerous cysts were also found in the brain in imaging findings, though no neurological symptoms were observed. Histopathological and serological findings strongly indicated cysticercosis. We found taeniid eggs in his stool by microscopic examination and revealed them as the Indian haplotype of Taenia solium by mitochondrial DNA analysis. We concluded that disseminated cysticercosis was caused by the secondary autoinfection with eggs released from the tapeworm carrier himself. After confirming the absence of adult worms in the intestine by copro-polymerase chain reaction, the patient was successfully treated with albendazole at a dose of 15 mg/kg/day for 28 days. Subcutaneous and intracranial lesions had completely disappeared by the end of the treatment period.

Single step modified ink staining for Tzanck test: quick detection of herpetic giant cells in Tzanck smear.

Tzanck test has been recently re-evaluated as a method for the diagnosis of herpes virus infection. Giemsa staining for the Tzanck test is time-consuming and laborious. There is a need to develop simple and quick staining methods for bedside diagnosis of this disease. We report a single step and quick method for staining herpes giant cells in Tzanck smears using routinely available inks and physiological saline. A keratinocyte cell line (HaCaT) was cultured on a slide glass and stained with various commercially available blue, blue-black and black inks serially diluted with physiological saline. Clinical smear samples from herpes lesions were also stained with these solutions without specific pretreatment. The nuclei of HaCaT were clearly stained showing high contrast with the cytoplasm using 5% Parker-Quink blue-black ink saline solution. Concentration of ink solution higher or lower than 5% resulted in less contrast. Blue or black inks or other manufacturers' inks can also be used, but staining of the cultured keratinocytes was less clear. Smear of clinical samples from herpes lesions were also stained with 5% ink solution. The nuclei of the multinucleated giant cells were clearly stained, and the sample could be immediately used for microscopic examination. One step staining of Tzanck smear using this diluted ink solution is an inexpensive and a convenient bedside diagnostic tool for the dermatologist.

Treatment of cloth with a fabric softener ameliorates skin dryness.

Dry skin is a condition characterized by impaired skin barrier function including atopic dermatitis and senile eczemas. Fabric softening chemicals (FSC) smoothens the surface of fabrics and thus decreases friction with the skin. Scientific evaluation of fabric softener on skin dryness is very limited. We evaluated the effectiveness and safety of FSC-treated T-shirts in subjects with dry skin. This is a randomized double-blind control study that included 40 male volunteers with apparent dry skin. Subjects were randomly divided into two groups: 20 men received 28 pieces of FSC-treated T-shirts wearing them for 4 weeks, and another 20 men received non-treated T-shirts. The effect of trial was evaluated by visual grading, subjective symptom, stratum corneum water content (SCWC), transepidermal water loss (TEWL), and dermoscopic skin surface analysis on days 0, 7, 14 and 28. A significant improvement of SCWC was observed in the skin of the shoulder (days 7-28) and lateral abdomen (day 14) wearing the treated T-shirts, but not in the non-treated T-shirts. In a stratified analysis of the low and high SCWC group, significant improvement was identified in the low SCWC groups but not in high SCWC groups. The visual grading of the shoulder improved significantly in the treated T-shirts group. No significant improvement was found in TEWL, dermoscopic analysis and subjective symptom in both groups. No remarkable side-effect was identified throughout this investigation. Addition of a fabric softener during clothes laundering is a potent preventive tool for dry skin.

Development of corpus callosum in preterm infants is affected by the prematurity: in vivo assessment of diffusion tensor imaging at term-equivalent age.

Callosal injury in preterm infants is a key factor affecting neurodevelopmental outcome. We investigated the characteristics of corpus callosum (CC) in preterm infants without apparent white matter lesions. We studied 58 preterm infants divided into three groups of 23-25, 26-29, and 30-33 wk GA. Diffusion tensor imaging (DTI) was obtained at term-equivalent age. The CC was parcellated into the genu, body, isthmus, and splenium. We measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of each CC subdivision using tractography and manual region of interest analysis. The cross-sectional areas were also measured. At the isthmus and splenium in the 23-25 GA group, the FA was significantly lower and the size was also significantly reduced. Furthermore, the FA and cross-sectional areas in the posterior CC decreased linearly with decreasing GA. There were no differences in FA and cross-sectional areas in other CC subdivisions, and no differences in ADC in any CC subdivisions, among the GA groups. We demonstrated that preterm infants without apparent white matter lesions affect development of the posterior CC depending on the degree of prematurity.

Immunohistochemical study of cytokeratin expression in nevus sebaceous.

BACKGROUND: The histogenesis of nevus sebaceous (NS) is unclear. METHODS: To elucidate the histogenesis of NS, cytokeratin (CK) profiles were examined immunohistochemically using 10 anti-keratin antibodies in the three stages of NS. RESULTS: In the first stage, stratified differentiated keratins (CK1 and 10) were reduced, and basal keratin (CK14) was increased in the epidermis and primitive follicular structure (PFS). In the second stage, in addition to reduced CK1 and CK10 expressions and increased CK14 expression, CK17 expression was strongly expressed in the sebaceous ducts in proportion to the development of sebaceous gland. In the third stage, CK14, CK17 and CK19 were expressed in secondary tumors. CK16 was not detected throughout all stages of NS. CONCLUSION: These results suggest that NS is not hyperproliferative but involves hamartomatous differentiation with undifferentiated keratins.

Primary cutaneous apocrine carcinoma arising within a congenital nevus: Keratins and filaggrin expression suggesting differentiation into the secretory cells of apocrine glands.

Primary cutaneous apocrine carcinoma (PCAC) is a rare neoplasm of skin appendages. To determine the differentiation of apocrine carcinoma, we studied the expression of epithelial keratins and filaggrin immunohistochemically using 10 anti-keratin antibodies againt keratin (K) 1, 7, 8, 10, 14, 15, 16, 17, 18, 19 and the anti-filaggrin antibody. PCAC demonstrated strong positivity for K7, K8, K18 and K19. These keratins are distributed in secretory cells of normal apocrine glands. The tumor cells were negative for K14 and K17. The two keratins exist in myoepithelial cells in normal apocrine glands. Results suggest that PCAC shows differentiation into secretory cells of apocrine glands, although it does not differentiate into myoepithelial cells. K14 is also known as undifferentiated keratin, whereas K17 is considered to be a hyperproliferative keratin. Absence of the expression of K14 and K17 may reflect an indolent clinical course of PCAC.

Effects of stress of postnatal development on corticosterone, serotonin and behavioral changes.

Stressful events early in life are associated with later psychiatric disorders. We focused on developmental stage and evaluated changes in the corticosterone and serotonergic systems as well as in later anxiety-related behavioral tests. Stressed male Wistar rats were divided into two groups: stressed from postnatal day 11 (PND 11) to 15 and stressed from PND 16 to 20. The rats were exposed to an elevated open platform. Stress increased corticosterone in both experimental groups. In the hypothalamus, amygdala and hippocampus, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased in the rats stressed from PND 11 to 15, and decreased in the rats stressed from PND 16 to 20. In a later behavioral test, rats stressed from PND 11 to 15 traveled shorter distances and tended to spend less time in the center than control rats following restraint stress. There were no significant changes in 5-HT and 5-HIAA in hypothalamus, amygdala and hippocampus after restraint stress in adults. These findings indicate that stress reactions and later effects are different depending on the developmental stage during which the rats were stressed. Stress during the PND 11-15 period may enhance later anxiety-related behaviors without altering 5-HT and 5-HIAA content.

Neuro-Sweet disease: report of the first autopsy case.

BACKGROUND: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. OBJECTIVE: To describe post-mortem findings of the first case of neuro-Sweet disease. RESULTS: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. CONCLUSIONS: THE CORE NEUROPATHOLOGICAL FINDINGS WERE: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive.