Successful Challenge With Brexpiprazole for Idiopathic Hypersomnia in a Patient With Bipolar Disorder: A Case Report.

We describe a 32-year-old Japanese female with hypersomnia and bipolar disorder. She had developed hypersomnia and sleep attacks in her teens. She was misdiagnosed with narcolepsy at a neurology department and then received methylphenidate (MPH) for many years. After giving birth, she developed postpartum depression and suffered from mood swings and irritability. Following 10-year treatment with methylphenidate, she experienced MPH-induced psychosis when she was in a manic state. Her psychosis improved rapidly with the cessation of methylphenidate. Furthermore, brexpiprazole treatment ameliorated her manic symptoms and hypersomnolence. Post-discharge, she was diagnosed with idiopathic hypersomnia based on nocturnal polysomnography and a multiple sleep latency test. This case indicates that brexpiprazole as a serotonin dopamine activity modulator might provide therapeutic effects against not only the patient's manic symptoms but also idiopathic hypersomnia.

Light-inducible carotenoid production controlled by a MarR-type regulator in Corynebacterium glutamicum.

Carotenoid production in some non-phototropic bacteria occurs in a light-dependent manner to protect cells from photo-oxidants. Knowledge regarding the transcriptional regulator involved in the light-dependent production of carotenoids of non-phototrophic bacteria has been mainly confined to coenzyme B12-based photo-sensitive regulator CarH/LitR family proteins belonging to a MerR family transcriptional regulator. In this study, we found that bacteria belonging to Micrococcales and Corynebacteriales exhibit light-dependent carotenoid-like pigment production including an amino acid-producer Corynebacterium glutamicum AJ1511. CrtR is a putative MarR family transcriptional regulator located in the divergent region of a carotenoid biosynthesis gene cluster in the genome of those bacteria. A null mutant for crtR of C. glutamicum AJ1511 exhibited constitutive production of carotenoids independent of light. A complemented strain of the crtR mutant produced carotenoids in a light-dependent manner. Transcriptional analysis revealed that the expression of carotenoid biosynthesis genes is regulated in a light-dependent manner in the wild type, while the transcription was upregulated in the crtR mutant irrespective of light. In vitro experiments demonstrated that a recombinant CrtR protein binds to the specific sequences within the intergenic region of crtR and crtE, which corresponds to -58 to -7 for crtE, and +26 to -28 for crtR with respect to the transcriptional start site, and serves as a repressor for crtE transcription directed by RNA polymerase containing SigA. Taken together, the results indicate that CrtR light-dependently controls the expression of the carotenoid gene cluster in C. glutamicum and probably closely related Actinobacteria.

Achilles tendinitis as a rare extraintestinal manifestation of ulcerative colitis.

Patients with inflammatory bowel disease often have extraintestinal manifestations (EIMs) involving almost all organ systems, but little has been reported on Achilles tendinitis. Herein, we present a unique case of Achilles tendinitis, which manifested shortly after initiation of mesalazine therapy for ulcerative colitis. A 26-year-old Japanese woman with bloody diarrhea and abdominal cramps lasting for 7 days was referred to our hospital. The Lichtiger clinical activity index (CAI) score was 9 at the first visit. Based on the clinical symptoms and examination results, she was diagnosed with ulcerative pancolitis in the active phase, and treatment with mesalazine (2.4 g/day) and probiotics was initiated. Her symptoms resolved within 7 days of treatment (CAI 3). However, she then developed bilateral Achilles tendinitis without any apparent cause. The Achilles tendinitis subsided with conservative management within 2 weeks, despite continuation of mesalazine therapy. This case instructively suggests that Achilles tendinitis should be noted as an EIM of ulcerative colitis.

Identification of ribonucleotide reductase mutation causing temperature-sensitivity of herpes simplex virus isolates from whitlow by deep sequencing.

Herpes simplex virus 2 caused a genital ulcer, and a secondary herpetic whitlow appeared during acyclovir therapy. The secondary and recurrent whitlow isolates were acyclovir-resistant and temperature-sensitive in contrast to a genital isolate. We identified the ribonucleotide reductase mutation responsible for temperature-sensitivity by deep-sequencing analysis.

Development of bullous pemphigoid after change of dialysis membrane.

A 75-year-old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal-epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case.

Elevated serum levels of APRIL, but not BAFF, in patients with atopic dermatitis.

Elevated serum levels of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and/or a proliferation-inducing ligand (APRIL) are shown in autoimmune diseases. We determined serum levels of BAFF and APRIL, and clinical association in patients with atopic dermatitis (AD). Serum levels of BAFF and APRIL from 35 patients with AD, 25 patients with psoriasis vulgaris, 25 patients with systemic lupus erythematosus and 25 normal healthy subjects were examined by enzyme-linked immunosorbent assay. Serum levels of APRIL, but not BAFF, were significantly elevated in patients with AD than in healthy controls or patients with psoriasis vulgaris. Patients with severe AD exhibited significantly increased APRIL levels compared to patients with moderate AD and mild AD, and serum APRIL levels were significantly decreased after treatment compared with those before treatment. In addition, increased APRIL levels were significantly associated with serum immunoglobulin E levels and blood eosinophil numbers. These results suggest that elevated serum levels of APRIL are associated with disease severity and activity in AD, and APRIL may have an important role in the pathogenesis of AD.

Genital herpes due to acyclovir-sensitive herpes simplex virus caused secondary and recurrent herpetic whitlows due to thymidine kinase-deficient/temperature-sensitive virus.

Herpes simplex virus (HSV)-2 caused a genital ulcer in a 40-year-old allogenic stem cell recipient, and a secondary herpetic whitlow appeared during 2 months of acyclovir (ACV) therapy. Both genital ulcer, and whitlow were cured 3 months later, but 6 months after recovery the whitlow alone recurred. DNA of the genital, first, and recurrent whitlow isolates showed similar endonuclease digestion fragment profiles. The genital virus was ACV-sensitive, and the two whitlow isolates were ACV-resistant/thymidine kinase (TK)-deficient. The TK gene of the whitlow isolates had the same frame shift from the 274th amino acid and termination at the 347th amino acid due to the deletion of a cytosine at the 819th nucleotide. Because the temperature of the thumb is 33/34 degrees C or lower, the temperature sensitivity of the isolates were compared, and both whitlow isolates were significantly more temperature-sensitive (ts) at 39 degrees C than the genital isolate. The two whitlow isolates showed cutaneous pathogenicity in mouse ear pinna but not midflank, while the genital isolate was pathogenic at both sites, suggesting that temperature adaptation was an important element of pathogenicity in the whitlow. The virus populations of isolates of the genital, and first whitlow were examined by 31, and 82 clones, respectively, and the clones from genital, and whitlow isolates were ACV-sensitive, and -resistant, respectively, showing their homogeneity. The acyclovir-sensitive genital lesion had spread as a TK-deficient/ts herpetic whitlow during ACV treatment, and an apparently TK-deficient virus adapted to the local temperature might have caused the whitlow recurrence.

Phase-dependent roles of E-selectin during chronic contact hypersensitivity responses.

Chronic contact hypersensitivity (CH) models induced by repeated hapten exposure exhibit chronic dermatitis and immunological abnormalities resembling atopic dermatitis. To assess the contribution of endothelial selectins (P- and E-selectins) to cutaneous chronic inflammation, chronic CH responses were assessed in mice lacking P- or E-selectin. Elicitation with oxazolone on the ears of P-selectin(-/-) mice 7 days after the sensitization induced a typical delayed-type hypersensitivity response similar to that found in wild-type mice. By contrast, a significant increase in ear swelling was observed in E-selectin(-/-) mice 36 to 48 hours after first elicitation. E-selectin(-/-) mice showed augmented P-selectin up-regulation, and administration of anti-P-selectin monoclonal antibody significantly inhibited the enhanced ear response, suggesting that the enhanced ear-swelling response in E-selectin(-/-) mice resulted from compensatory increase in P-selectin expression. In the late phase of chronic CH, acceleration of ear swelling was significantly reduced in both E- and P-selectin(-/-) mice relative to wild-type littermates. Thus, the loss of P- or E-selectin suppressed inflammatory responses during the chronic phase of the chronic models, whereas early-phase inflammatory responses were exacerbated by E-selectin blockade. Collectively, P- and E-selectins cooperatively regulate CH response, although their roles may be different depending on the phase of the reaction.

Both Th1 and Th2 chemokines are elevated in sera of patients with autoimmune blistering diseases.

Although chemokines are critical elements for the selective attraction and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning T helper (Th) 1 or Th2 chemokines in autoimmune blistering disease (ABD). To determine whether serum levels of chemokines that are preferentially chemotactic for Th1 (monokine induced by IFN-gamma (MIG/CXCL9)) and Th2 (thymus and activation regulated chemokine (TARC/CCL17) and macrophage derived chemokine (MDC/CCL22)) cells were elevated and whether they correlated with the clinical features in patients with ABD. Serum chemokine levels were examined using ELISA in patients with pemphigus vulgaris (PV, n=19), pemphigus foliaceous (PF, n=14), or bullous pemphigoid (BP, n=27) and normal controls (n=20). Serum MIG levels were significantly higher in patients with PV, PF, or BP than those in the control subjects. Serum levels of TARC and MDC were also significantly elevated in patients with PV, PF, or BP relative to the normal controls. Among the ABD subgroups, the levels of each chemokine tended to be higher in BP patients than in PV patients. Furthermore, serum TARC levels correlated positively with serum IgE levels in patients with ABD. Levels of TARC, MDC, and MIG were significantly decreased after treatment when the skin lesions disappeared in these patients. Furthermore, serum MIG levels correlated positively with serum levels of TARC and MDC in the ABD patients. These results suggest that both a Th1 chemoattractant MIG and Th2 chemoattractants, TARC and MDC, cooperatively play a role in the development of ABD.

Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis.

BACKGROUND: Although abnormalities of various chemokines are detected in systemic sclerosis (SSc), there are few findings concerning Th1 or Th2 chemoattractants. OBJECTIVE: To determine whether serum levels of chemokines preferentially chemotactic for Th1 cells (IP-10 and MIG) and predominantly chemotactic for Th2 cells (TARC and MDC) are elevated and whether they correlate with clinical features in patients with SSc. METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 34), limited cutaneous SSc (lSSc; n = 30), dermatomyositis (DM; n = 15), systemic lupus erythematosus (SLE; n = 22), and normal controls (n = 30) were examined by sandwich ELISA. RESULTS: Serum TARC levels were significantly elevated in dSSc patients (P < 0.0002) and lSSc patients (P < 0.0001) compared with normal controls. Similarly, serum MDC levels were significantly increased in patients with dSSc (P < 0.02) or lSSc (P < 0.05) relative to normal controls. In addition, serum IP-10 was detected significantly more frequently in patients with dSSc (44%), lSSc (30%), or DM (53%) than normal controls (0%) and patients with SLE (0%). Furthermore, elevated TARC levels correlated with the presence of pitting scars and anti-topoisomerase I antibody, increased titers of anti-topoisomerase I and antinuclear antibody, and decreased glomerular filtration rate. Increased MDC levels were associated with pitting scars and younger ages at onset. CONCLUSION: These results suggest that both Th2 chemoattractants, TARC and MDC, and a Th1 chemoattractant IP-10 play a role in the development of SSc.

Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: possible contribution to skin inflammation.

BACKGROUND: Fractalkine (FKN) induces activation and adhesion of leukocytes expressing its receptor, CX(3)CR1. FKN is released from the cell surface through proteolytic cleavage as soluble FKN (sFKN). OBJECTIVE: We sought to assess FKN and CX(3)CR1 expression in the skin, serum sFKN levels, and CX(3)CR1 expression on blood leukocytes in patients with atopic dermatitis (AD). METHODS: FKN and CX(3)CR1 expression in the skin was examined immunohistochemically. mRNA expression of FKN, thymus and activation-regulated chemokine, and macrophage-derived chemokine in the skin was assessed by means of real-time RT-PCR. Serum sFKN levels were assessed by using ELISA. Blood leukocytes were stained for CX(3)CR1 by means of flow cytometric analysis. RESULTS: FKN was strongly expressed on endothelial cells in skin lesions of patients with AD and psoriasis but not in normal skin. FKN mRNA levels in AD lesional skin increased to a similar extent to thymus and activation-regulated chemokine and macrophage-derived chemokine mRNA levels. CX(3)CR1-expressing cells in the affected skin of patients with AD or psoriasis increased compared with those in normal skin. Serum sFKN levels were increased in patients with AD but not in patients with psoriasis relative to levels in healthy control subjects. Serum sFKN levels were associated with the disease severity and decreased with the improvement of skin lesions in patients with AD. CX(3)CR1(+) cell frequencies and CX(3)CR1 expression levels were decreased in CD8(+) T cells, monocytes, and natural killer cells from patients with AD, but this was not observed in patients with psoriasis. CONCLUSIONS: These results suggest that through functions in both membrane-bound and soluble forms, FKN plays an important role in the trafficking of CX(3)CR1(+) leukocytes during the inflammation caused by AD.

Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis.

BACKGROUND: Chemokines and their receptors are important elements for the selective attraction and activation of various subsets of leukocytes. Expression of CXCR3 ligands, such as monokine induced by IFN-gamma (Mig) leads to preferential Th1 recruitment, whereas CCR4 ligands, thymus and activation regulated chemokine (TARC) or macrophage derived chemokine (MDC), mediate preferential Th2 recruitment. Although atopic dermatitis (AD) has been shown to be a Th2-type disease, recent studies have revealed that Th1-type cytokines, such as IFN-gamma, especially in chronic skin lesions, play important roles in pathogenesis of AD. OBJECTIVE: The purpose of this study was to investigate serum levels of Th2 chemokines TARC and MDC and a Th1 chemokine Mig in the same samples from patients with AD and their clinical correlation. METHODS: Serum chemokine levels in patients with AD (n = 55), contact dermatitis (CD; n = 15), and normal controls (n = 30) were examined by ELISA. RESULTS: Serum levels of TARC and MDC in AD patients and CD patients were significantly higher than those found in normal controls. Serum levels of these chemokines were similar for AD patients and CD patients. Furthermore, these levels correlated positively with disease severity, total IgE levels, and peripheral eosinophilia in AD patients. Serum Mig levels in AD patients and CD patients were significantly higher than those in control subjects. However, serum Mig levels were significantly elevated in CD patients relative to AD patients. Furthermore, serum Mig levels correlated positively with levels of both TARC and MDC in AD patients. CONCLUSION: These results suggest that both Th2 and Th1 chemokines may play roles in the development of AD.

L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis.

The development of bleomycin-induced lung injury, a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. At present, the identity and role of the adhesion molecules involved in the fibrotic process are unknown. Therefore, bleomycin-induced pulmonary fibrosis was examined in mice lacking L-selectin (L-selectin(-/-)) expression, intercellular adhesion molecule-1 (ICAM-1) expression, or both. After 16 days of intratracheal bleomycin challenge, collagen deposition was inhibited in both L-selectin(-/-) and ICAM-1(-/-) mice when compared with wild-type littermates. Interestingly, collagen deposition was virtually eliminated in L-selectin/ICAM-1(-/-) mice relative to either the L-selectin(-/-) or ICAM-1(-/-) mice. Decreased pulmonary fibrosis was associated with reduced accumulation of leukocytes, including neutrophils and lymphocytes. Decreased mRNA expression of proinflammatory cytokines and transforming growth factor (TGF)-beta1 paralleled the inhibition of collagen deposition. The present study indicates that L-selectin and ICAM-1 play a critical role in pulmonary fibrosis by mediating the accumulation of leukocytes, which regulate the production of proinflammatory cytokines and TGF-beta1. This suggests that these adhesion molecules are potential therapeutic targets for inhibiting human pulmonary fibrosis.

The cutaneous reverse Arthus reaction requires intercellular adhesion molecule 1 and L-selectin expression.

The deposition of immune complexes (IC) induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by expression of multiple adhesion molecules. To assess the role of L-selectin and ICAM-1 in this pathogenetic process, the cutaneous reverse passive Arthus reaction was examined in mice lacking L-selectin (L-selectin(-/-)), ICAM-1 (ICAM-1(-/-)), or both (L-selectin/ICAM-1(-/-)). Edema and hemorrhage, which peaked 4 and 8 h after IC challenge, respectively, were significantly reduced in L-selectin(-/-), ICAM-1(-/-), and L-selectin/ICAM-1(-/-) mice compared with wild-type littermates. In general, edema and hemorrhage were more significantly inhibited in ICAM-1(-/-) mice than in L-selectin(-/-) mice, but were most significantly reduced in L-selectin/ICAM-1(-/-) mice compared with ICAM-1(-/-) or L-selectin(-/-) mice. Decreased edema and hemorrhage correlated with reduced neutrophil and mast cell infiltration in all adhesion molecule-deficient mice, but leukocyte infiltration was most affected in L-selectin/ICAM-1(-/-) mice. Reduced neutrophil and mast cell infiltration was also observed for all mutant mice in the peritoneal Arthus reaction. Furthermore, cutaneous TNF-alpha production was inhibited in each deficient mouse, which paralleled the reductions in cutaneous inflammation. These results indicate that ICAM-1 and L-selectin cooperatively contribute to the cutaneous Arthus reaction by regulating neutrophil and mast cell recruitment and suggest that ICAM-1 and L-selectin are therapeutic targets for human IC-mediated disease.