Tyrosinase-Based Proximity Labeling in Living Cells and In Vivo.

Characterizing the protein constituents of a specific organelle and protein neighbors of a protein of interest (POI) is essential for understanding the function and state of the organelle and protein networks associated with the POI. Proximity labeling (PL) has emerged as a promising technology for specific and efficient spatial proteomics. Nevertheless, most enzymes adopted for PL still have limitations: APEX requires cytotoxic H2O2 for activation and thus is poor in biocompatibility for in vivo application, BioID shows insufficient labeling kinetics, and TurboID suffers from high background biotinylation. Here, we introduce a bacterial tyrosinase (BmTyr) as a new PL enzyme suitable for H2O2-free, fast (≤10 min in living cells), and low-background protein tagging. BmTyr is genetically encodable and enables subcellular-resolved PL and proteomics in living cells. We further designed a strategy of ligand-tethered BmTyr for in vivo PL, which unveiled the surrounding proteome of a neurotransmitter receptor (Grm1 and Drd2) in its resident synapse in a live mouse brain. Overall, BmTyr is one promising enzyme that can improve and expand PL-based applications and discoveries.

Epstein-barr virus infections induce aberrant osteoclastogenesis in immune system-humanized NOD/Shi-scid/IL-2RγCnull mice.

Epstein-Barr virus (EBV) and other viral infections are possible triggers of autoimmune diseases, such as rheumatoid arthritis (RA). To analyze the causative relationship between EBV infections and RA development, we performed experiment on humanized NOD/Shi-scid/IL-2RγCnull (hu-NOG) mice reconstituted human immune system components and infected with EBV. In EBV-infected hu-NOG mice, breakdown of knee joint bones was found to be accompanied by the accumulation of receptor activator of nuclear factor-κB (NF-κB) (RANK) ligand (RANKL), a key factor in osteoclastogenesis, human CD19 and EBV-encoded small RNA (EBER)-bearing cells. Accumulation of these cells expanded in the bone marrow adjacent to the bone breakage, showing a histological feature like to that in bone marrow edema. On the other hand, human RANK/human matrix metalloprotease-9 (MMP-9) positive, osteoclast-like cells were found at broken bone portion of EBV-infected mouse knee joint. In addition, human macrophage-colony stimulating factor (M-CSF), an essential factor in development of osteoclasts, evidently expressed in spleen and bone marrow of EBV-infected humanized mice. Furthermore, RANKL and M-CSF were identified at certain period of EBV-transformed B lymphoblastoid cells (BLBCs) derived from umbilical cord blood lymphocytes. Co-culturing bone marrow cells of hu-NOG mice with EBV-transformed BLBCs resulted in the induction of a multinucleated cell population positive for tartrate-resistant acid phosphatase and human MMP-9 which indicating human osteoclast-like cells. These findings suggest that EBV-infected BLBCs induce human aberrant osteoclastogenesis, which cause erosive arthritis in the joints.

Rational design and implementation of a chemically inducible heterotrimerization system.

Chemically inducible dimerization (CID) uses a small molecule to induce binding of two different proteins. CID tools such as the FK506-binding protein-FKBP-rapamycin-binding- (FKBP-FRB)-rapamycin system have been widely used to probe molecular events inside and outside cells. While various CID tools are available, chemically inducible trimerization (CIT) does not exist, due to inherent challenges in designing a chemical that simultaneously binds three proteins with high affinity and specificity. Here, we developed CIT by rationally splitting FRB and FKBP. Cellular and structural datasets showed efficient trimerization of split pairs of FRB or FKBP with full-length FKBP or FRB, respectively, by rapamycin. CIT rapidly induced tri-organellar junctions and perturbed intended membrane lipids exclusively at select membrane contact sites. By conferring one additional condition to what is achievable with CID, CIT expands the types of manipulation in single live cells to address cell biology questions otherwise intractable and engineer cell functions for future synthetic biology applications.

Immune complexome analysis of a rich variety of serum immune complexes identifies disease-characteristic immune complex antigens in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and skin fibrosis. Recently, the presence and pathogenic role of immune complexes (ICs) of SSc patients were reported. However, the identities of antigens in these ICs are unknown. Therefore, we examined ICs in the serum of SSc patients to elucidate SSc pathogenesis. In this study, IC concentrations in serum samples from SSc and systemic lupus erythematosus (SLE) patients were measured by C1q enzyme-linked immunosorbent assays; immune complex analysis was used for comprehensive identification and comparison of antigens incorporated into ICs (IC-antigens). The expression patterns of SSc-specific IC-antigens in skin sections were investigated by immunohistochemistry. Compared with SLE patients who developed disease because of IC deposition, SSc patients had a greater number of IC-antigens and a smaller difference in IC concentrations, suggesting that SSc pathogenesis is affected by the proteins present in ICs. In contrast, the IC concentration and number of IC-antigens did not significantly differ according to the clinical phenotype of SSc. We identified 478 IC-antigens in SSc patients, including multiple RNAP II-associated proteins that were targeted by antibodies previously associated with SSc pathogenesis. The most frequently detected RNAP II-associated protein, RNA polymerase II transcription subunit 30 (MED30), was strongly expressed at lesion sites and reportedly regulates endothelial differentiation. Therefore, increased expression of MED30 in lesions may have an antigenic effect, and MED30 function may be impaired or inhibited by IC formation. RNAP II-associated proteins may SSc pathogenesis through mechanisms such as the MED30 pathway.

Macrophage depletion using clodronate liposomes reveals latent dysfunction of the hematopoietic microenvironment associated with persistently imbalanced M1/M2 macrophage polarization in a mouse model of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, is caused by the incessant activation of lymphocytes and macrophages, resulting in damage to organs, including hematopoietic organs. Recently, we demonstrated that repeated lipopolysaccharide (LPS) treatment induces HLH-like features in senescence-accelerated (SAMP1/TA-1) mice but not in senescence-resistant control (SAMR1) mice. Hematopoietic failure in LPS-treated SAMP1/TA-1 mice was attributed to hematopoietic microenvironment dysfunction, concomitant with severely imbalanced M1 and M2 macrophage polarization. Macrophages are a major component of the bone marrow (BM) hematopoietic microenvironment. Clodronate liposomes are useful tools for in vivo macrophage depletion. In this study, we depleted macrophages using clodronate liposomes to determine their role in the hematopoietic microenvironment in SAMP1/TA-1 and SAMR1 mice. Under clodronate liposome treatment, the response between SAMR1 and SAMP1/TA-1 mice differed as follows: (1) increase in the number of activated M1 and M2 macrophages derived from newly generated macrophages and M2-dominant and imbalanced M1 and M2 macrophage polarization in the BM and spleen; (2) severe anemia and thrombocytopenia; (3) high mortality rate; (4) decrease in erythroid progenitors and B cell progenitors in the BM; and (5) decrease in the mRNA expression of erythroid-positive regulators such as erythropoietin and increase in that of erythroid- and B lymphoid-negative regulators such as interferon-γ in the BM. Depletion of residual macrophages in SAMP1/TA-1 mice impaired hematopoietic homeostasis, particularly erythropoiesis and B lymphopoiesis, owing to functional impairment of the hematopoietic microenvironment accompanied by persistently imbalanced M1/M2 polarization. Thus, macrophages play a vital role in regulating the hematopoietic microenvironment to maintain homeostasis.

Hair follicle stem cell progeny heal blisters while pausing skin development.

Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.

Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.

OBJECTIVES: To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). METHODS: For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. RESULTS: The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. CONCLUSIONS: For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.

Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome.

OBJECTIVES: To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. METHODS: For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. RESULTS: After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. CONCLUSIONS: Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.

Guided parent-delivered cognitive behavioural therapy for Japanese children and parents: a single-arm uncontrolled study.

BACKGROUND: Guided parent-delivered cognitive behavioural therapy (GPD-CBT) is an effective low-intensity treatment for childhood anxiety disorder in Western countries and can increase access to evidence-based psychological therapies. AIM: This study aimed to examine its feasibility in a Japanese sample. METHOD: Twelve children with anxiety disorders and their parents participated in the study, and ten children and parents completed the program. Participants were assessed at pre-, post- and one-month follow-up using a diagnostic interview for anxiety disorders, self- and parent-report measures for anxiety, depression, parental behaviour, and parental anxiety. RESULTS: Four children (40% of completers) were free from their primary diagnoses immediately following the brief treatment, and seven children (70%) at the one-month follow-up. Changes in disorder severity, child and parent reported anxiety symptoms, and child reported depression symptoms were consistent with those found in Western trials of GPD-CBT and of Japanese trials of more intensive CBT for child anxiety disorders that involves both the child and the parent. Moderate increases were also found in child reported parental autonomy behaviours; however, there were only small changes in parent self-reported anxiety. CONCLUSION: These results support the potential of GPD-CBT to increase access to evidence-based treatments for anxiety disorders in Japanese children.

Prediction of radiographic progression during a treat-to-target strategy by the sequential application of MRI-proven bone marrow oedema and power-Doppler grade ≥2 articular synovitis in rheumatoid arthritis: Retrospective observational study.

OBJECTIVES: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). METHODS: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. RESULTS: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. CONCLUSION: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA.

Abatacept ameliorates both glandular and extraglandular involvements in patients with Sjögren's syndrome associated with rheumatoid arthritis: Findings from an open-label, multicentre, 1-year, prospective study: The ROSE (Rheumatoid Arthritis with Orencia Trial Toward Sjögren's Syndrome Endocrinopathy) and ROSE II trials.

OBJECTIVE: To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). MATERIALS AND METHODS: We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon's test, Schirmer's test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. RESULTS: 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients. CONCLUSION: Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in SS associated with RA.

[Thrombotic microangiopathy with gastrointestinal hemorrhage during carfilzomib therapy for multiple myeloma].

A 70-year-old woman was admitted to the hospital with loss of appetite and melena. She was diagnosed with multiple myeloma 7 years ago and had been on carfilzomib, lenalidomide, and dexamethasone (KRd) therapy for a month because her disease had a relapsed/refractory. On admission, her laboratory tests revealed hemolytic anemia with schizocytes, thrombocytopenia, and acute renal dysfunction. TMA (thrombotic microangiography) caused by carfilzomib was suspected. The possibility of thrombotic thrombocytopenia was considered, and steroid pulse therapy was initiated. Her condition improved significantly after she stopped taking carfilzomib, plasma exchange, hemodiafiltration, steroid pulse therapy, and abstaining from food. The previously reported cases of carfilzomib-induced TMA included fever, gastrointestinal symptoms (nausea/vomiting, diarrhea), and acute renal disorders (lower extremity edema, decreasing urine output). As far as we know, this is the first case of carfilzomib-induced TMA with bleeding as the first symptom.

[A new method for measuring spinal kyphosis using CT images and a study of its relationship with reflux esophagitis].

[Purpose] This study aimed to examine the validity and reproducibility of a new quantitative method for measuring spinal kyphosis using computed tomography (CT), and to investigate its relationship with reflux esophagitis. [Method] Using a new method to measure the index of kyphosis in CT images (IKCT), 10 examiners evaluated 10 cases of spinal kyphosis. One examiner measured 47 cases twice and 20 cases were examined to assess the validity with the kyphosis index. A case-control study was conducted on 303 cases of reflux esophagitis, of which 241 were mild and 62 severe. [Results] Regarding IKCT reproducibility, the inter-rater intraclass correlation coefficient was 0.977. The intra-rater intraclass correlation coefficient was 0.974. The correlation index with the kyphosis index was 0.731. A greater IKCT value, not contracting serious atrophic gastritis, and severe hiatal hernia were identified as risk factors for severe reflux esophagitis. [Conclusion] IKCT is a simple and useful method for measuring kyphosis. The prevention of kyphosis can help suppress severe reflux esophagitis.

Cas9-guided haplotyping of three truncation variants in autosomal recessive disease.

An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5' and 3' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5' and 3' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.

Comparison of salivary gland MRI and ultrasonography findings among patients with Sjögren's syndrome over a wide age range.

OBJECTIVES: This retrospective study compared MRI and US findings among patients with SS over a wide age range. METHODS: Ninety patients with SS aged 8-84 years who had undergone both MRI and US examinations were divided into four groups according to age, as follows: <18 years (juvenile SS, JSS), 9 patients; 18-39 years, 12 patients; 40-69 years, 53 patients; >69 years, 16 patients. Imaging findings of parotid glands (PGs) and submandibular glands (SMGs) were compared among the four groups. Furthermore, the relationships within and between imaging findings and various clinical findings were examined. RESULTS: On MRI, patients with JSS commonly exhibited multiple high-intensity spots in the PGs on MR sialography and fat-suppressed T2-weighted imaging. With increasing SS group age, the frequencies and numbers of the high-intensity spots were lower. Fat areas on MRI and hyperechoic bands on US were rarely observed in the PGs and SMGs of patients with JSS, whereas they were more common in patients with adult SS. In addition, the presence of hyperechoic bands on US, the presence of fat areas on MRI, and decreased salivary flow were associated with one another. CONCLUSION: Salivary gland imaging findings in patients with JSS were characterized by punctate sialectasis, whereas those findings in patients with adult SS were characterized by fatty degeneration. Distinct findings in patients with JSS and adult SS are likely to reflect differences in glandular lesion stage. MRI and US are presumably useful for evaluation of glandular lesion severity during follow-up.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

von Willebrand factor activity levels are influenced by driver mutation status in polycythemia vera and essential thrombocythemia patients with well-controlled platelet counts.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (<600 × 109 /L), low vWF activity (<50%) was more frequently observed in JAK2+ PV patients than in JAK2+ ET (p = .013) or CALR+ ET (p = .013) groups, and in PV and ET patients with ≥50% JAK2+ allele burden than in those with allele burden <50% (p = .015). High vWF activity (>150%) was more frequent in the JAK2+ ET group than in the CALR+ ET group (p = .005), and often associated with vasomotor symptoms (p = .002). This study suggests that some patients with JAK2+ PV or ET have vWF activity outside the standard range even with well-controlled PLT, and that the measurement of vWF activity is useful for assessing the risk of thrombosis and hemorrhage.

Relationship between Carnitine Deficiency and Tyrosine Kinase Inhibitor Use in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Some chemotherapeutic agents cause carnitine deficiency, which causes general fatigue. However, there is no study on carnitine deficiency in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) therapy. OBJECTIVE: In this study, we investigated carnitine concentrations in patients with CML receiving TKI therapy. METHOD: This study included patients with well-controlled CML. Total carnitine and free carnitine concentrations were evaluated using the enzyme cycling method. The brief fatigue inventory (BFI) and cancer fatigue scale (CFS) were used to assess general fatigue developed during TKI therapy. RESULTS: Fifty-five patients on TKI therapy were included. Of these, 12 (21.8%) patients had low free carnitine concentrations. Free carnitine concentrations were higher in men than in women. Younger age was closely associated with lower free carnitine concentrations. TKI type, TKI dose, treatment response, or therapy duration were not associated with free carnitine concentrations. None of the scores (the global fatigue score with the BFI and CFS score) correlated with carnitine concentrations. Concentrations of free carnitine in patients in the treatment-free remission group were slightly higher than those in the TKI group, with only 9.1% having a low concentration of free carnitine. CONCLUSION: Carnitine deficiency is probably not a major cause of general fatigue but may occur in patients with CML receiving TKI therapy.

A case of cerebral paragonimiasis misdiagnosed as eosinophilic granulomatosis with polyangiitis.

Paragonimiasis is a parasitic disease caused by Paragonimus westermani infection, and migration to the brain results in cerebral paragonimiasis. Cerebral paragonimiasis is now extremely rare, but a few cases are still reported. A 48-year-old Japanese woman presented with right-hand convulsion, right-hand numbness, sputum, and fatigue. Chest computed tomography demonstrated multiple nodular lesions, and head computed tomography revealed a hemorrhagic lesion in the left motor cortex. Magnetic resonance imaging revealed multiple small ring-shaped lesions with surrounding edema. Laboratory evaluation demonstrated peripheral eosinophilia. We considered eosinophilic granulomatosis with polyangiitis and started steroid treatment as a diagnostic therapy since we wanted to avoid cerebral lesion biopsy if possible. However, the patient underwent craniotomy surgery after steroid treatment for four months because a new intracerebral mass lesion had appeared. Trematode eggs were detected in the sample, and the final diagnosis was cerebral paragonimiasis. The patient was successfully treated with praziquantel. Cerebral paragonimiasis is extremely rare but should be considered in the differential diagnosis if atypical intracranial hemorrhage and peripheral eosinophilia are observed.

Unguided Computer-Assisted Self-Help Interventions Without Human Contact in Patients With Obsessive-Compulsive Disorder: Systematic Review and Meta-analysis.

BACKGROUND: Computer-assisted treatment may reduce therapist contact and costs and promote client participation. This meta-analysis examined the efficacy and acceptability of an unguided computer-assisted therapy in patients with obsessive-compulsive disorder (OCD) compared with a waiting list or attention placebo. OBJECTIVE: This study aimed to evaluate the effectiveness and adherence of computer-assisted self-help treatment without human contact in patients with OCD using a systematic review and meta-analysis approach. METHODS: Randomized controlled trials with participants primarily diagnosed with OCD by health professionals with clinically significant OCD symptoms as measured with validated scales were included. The interventions included self-help treatment through the internet, computers, and smartphones. We excluded interventions that used human contact. We conducted a search on PubMed, Cochrane Central Register of Controlled Trials, EMBASE, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov, as well as the reference lists of the included studies. The risk of bias was evaluated using version 2 of the Cochrane risk-of-bias tool for randomized trials. We calculated the standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes. The primary outcomes were short-term improvement of OCD symptoms measured by validated scales and dropout for any reason. RESULTS: We included 11 randomized controlled trials with a total of 983 participants. The results indicated that unguided computer-assisted self-help therapy was significantly more effective than a waiting list or psychological placebo (standard mean difference -0.47, 95% CI -0.73 to -0.22). Unguided computer-assisted self-help therapy had more dropouts for any reason than waiting list or psychological placebo (risk ratio 1.98, 95% CI 1.21 to 3.23). However, the quality of evidence was very low because of the risk of bias and inconsistent results among the included studies. The subgroup analysis showed that exposure response and prevention and an intervention duration of more than 4 weeks strengthen the efficacy without worsening acceptability. Only a few studies have examined the interaction between participants and systems, and no study has used gamification. Most researchers only used text-based interventions, and no study has used a mobile device. The overall risk of bias of the included studies was high and the heterogeneity of results was moderate to considerable. CONCLUSIONS: Unguided computer-assisted self-help therapy for OCD is effective compared with waiting lists or psychological placebo. An exposure response and prevention component and intervention duration of more than 4 weeks may strengthen the efficacy without worsening the acceptability of the therapy. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) CRD42021264644; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=264644.