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Competing Interests: Declarations of competing interest The authors declare they have no conflict of interest.

Anterior cutaneous nerve entrapment syndrome (ACNES) is characterized by abdominal wall neuralgia. We report an 85-year-old woman with ACNES caused by a fixation device during the bipolar hip arthroplasty. To prevent ACNES as a perioperative peripheral nerve injury, it is important to maintain patients in the appropriate position during the operation. A positive Carnett's sign means the abdominal pain originates from the abdominal wall and is useful in diagnosing ACNES. Thus, physicians should examine Carnett's sign to differentiate ACNES in patients with abdominal pain developing after an operation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

A 75-year-old Japanese woman was admitted to our hospital and diagnosed with hemophagocytic syndrome secondary to severe fever with thrombocytopenia syndrome (SFTS). The patient recovered after steroid treatment and was discharged from the hospital. Two months after the onset of SFTS, the patient revisited our hospital with a fever and palpable purpura on the extremities and trunk. A histopathological examination of a punch skin biopsy specimen revealed leukocytoclastic vasculitis. Symptomatic treatment resolved the fever, and palpable purpura disappeared 14 days later. No other clinical symptoms or abnormal immunological findings contributed to the leukocytoclastic vasculitis. This is the first report to describe leukocytoclastic vasculitis secondary to SFTS, highlighting a potential association between the two conditions.

We report a case of Sphingobium yanoikuyae bacteremia in an 89-year-old patient in Japan. No standard antimicrobial regimen has been established for S. yanoikuyae infections. However, ceftriaxone and ceftazidime treatments were effective in this case. Increased antimicrobial susceptibility data are needed to establish appropriate treatments for S. yanoikuyae.

Cefmetazole is active against extended-spectrum β-lactamase-producing Escherichia coli (ESBLEC) and is a potential candidate for carbapenem-sparing therapy. This multicenter, observational study included patients hospitalized for invasive urinary tract infection due to ESBLEC between March 2020 and November 2021 at 10 facilities in Japan, for whom either cefmetazole or meropenem was initiated as a definitive therapy within 96 h of culture collection and continued for at least 3 d. Outcomes included clinical and microbiological effectiveness, recurrence within 28 d, and all-cause mortality (14 d, 30 d, in-hospital). Outcomes were adjusted for the inverse probability of propensity scores for receiving cefmetazole or meropenem. Eighty-one and forty-six patients were included in the cefmetazole and meropenem groups, respectively. Bacteremia accounted for 43% of the cefmetazole group, and 59% of the meropenem group. The crude clinical effectiveness, 14 d, 30 d, and in-hospital mortality for patients in the cefmetazole and meropenem groups were 96.1% vs 90.9%, 0% vs 2.3%, 0% vs 12.5%, and 2.6% vs 13.3%, respectively. After propensity score adjustment, clinical effectiveness, the risk of in-hospital mortality, and the risk of recurrence were similar between the two groups ( P = 0.54, P = 0.10, and P = 0.79, respectively). In all cases with available data (cefmetazole : n = 61, meropenem : n = 22), both drugs were microbiologically effective. In all isolates, bla CTX-M was detected as the extended-spectrum β-lactamase gene. The predominant CTX-M subtype was CTX-M-27 (47.6%). Cefmetazole showed clinical and bacteriological effectiveness comparable to meropenem against invasive urinary tract infection due to ESBLECs., Competing Interests: The authors declare no conflict of interest.

Question: I frequently see adolescents with recurrent abdominal pain in my family medicine clinic. While the diagnosis frequently is a benign condition such as constipation, I recently heard that after 2 years of recurrent pain, an adolescent was diagnosed with anterior cutaneous nerve entrapment syndrome (ACNES). How is this condition diagnosed? What is the recommended treatment?, Answer: Anterior cutaneous nerve entrapment syndrome, first described almost 100 years ago, is caused by entrapment of the anterior branch of the abdominal cutaneous nerve as it pierces the anterior rectus abdominis muscle fascia. The limited awareness of the condition in North America results in misdiagnosis and delayed diagnosis. Carnett sign-in which pain worsens when using a "hook-shaped" finger to palpate a purposefully tense abdominal wall-helps to confirm if pain originates from the abdominal viscera or from the abdominal wall. Acetaminophen and nonsteroidal anti-inflammatory drugs were not found to be effective, but ultrasound-guided local anesthetic injections seem to be an effective and safe treatment for ACNES, resulting in relief of pain in most adolescents. For those with ACNES and ongoing pain, surgical cutaneous neurectomy by a pediatric surgeon should be considered., (Copyright © 2023 the College of Family Physicians of Canada.)

Case Presentation: An 85-year-old woman with a history of depression treated with polypharmacy including selective serotonin reuptake inhibitor presented to the emergency department with head, and upper and lower limb tremors four hours after increasing the dose of quetiapine from 12.5 milligrams (mg) per day to 25 mg/day. She was diagnosed with serotonin syndrome (SS), and all medications except clotiazepam were discontinued. The symptoms subsided within 48 hours., Discussion: The use of atypical antipsychotics alone seldom increases the risk of SS. However, combining atypical antipsychotics with serotonergic agents increases the risk of SS because the activity of serotonin receptor subtype 1A is relatively enhanced. This report suggests that physicians should be aware that even a small increase in quetiapine could pose a risk of developing SS.

Competing Interests: Competing interests: None declared.

Perinephric fat stranding (PFS) is often detected on computed tomography (CT) in patients with acute pyelonephritis (APN). However, its clinical impact remains unclear. This study aimed to evaluate the clinical impact of PFS detected on CT in patients with APN. This retrospective observational study included patients with APN who underwent CT (median age, 79.5 years). Patients were classified into PFS (patients with PFS observed on CT) and non-PFS (patients without PFS observed on CT) groups, which were further classified into bacteraemia and non-bacteraemia groups. Clinical findings between the groups were compared. Among 194 patients who underwent CT, 111 (57.2%) patients demonstrated PFS. The rate of bacteraemia was significantly higher in the PFS group than in the non-PFS group (55.2 vs. 23.1%, p < 0.001). CT findings other than PFS were not associated with bacteraemia. The median peak body temperature was significantly higher in the PFS group than in the non-PFS group (38.8 vs. 38.5 °C, p < 0.001); however, the duration of fever and in-hospital mortality rates were not significantly different between the groups. Concordance between blood and urine culture results was observed in 75.0% of the patients; the presence of PFS was not different between patients with concordant and discordant results, regardless of the pre-treatment antibiotic used. Our findings suggest that the presence of PFS in patients with APN predicts bacteraemia; thus, clinicians should consider obtaining blood cultures if PFS is found on CT in patients with APN, even if the patients had received antibiotics prior to admission.

Background: The identification of anterior cutaneous nerve entrapment syndrome is often challenging, due to no widely accepted standard guidelines regarding laboratory and imaging tests for the diagnosis of ACNES., Case Presentation: A 77-year-old Japanese man presented with mild lower abdominal pain that had been present for the past 3 years. Physical examination revealed no abdominal pain during palpation, with normal laboratory and imaging testing; therefore, conservative therapy was initiated. However, the abdominal pain continued. Re-examination 16 days later revealed three tender points in accordance with intercostal nerves Th10, Th11, and Th12, with the pain occurring only during Carnett's sign testing. A cutaneous injection of 1% lidocaine was administered, and the abdominal pain was resolved about 30 min later. Based on these results, anterior cutaneous nerve entrapment syndrome was diagnosed., Conclusions: It is sometimes hard to diagnose anterior cutaneous nerve entrapment syndrome without testing for Carnett's sign. If patients present with chronic abdominal pain, clinicians should test for Carnett's sign even if no pain is elicited during regular abdominal palpation.

Background: A live attenuated yellow fever (YF) vaccination is required of all travellers visiting countries where YF virus is endemic. Although the risk of serious adverse events (AEs) after YF vaccination is known to be greater in elderly people than in younger people, information about other AEs among elderly travellers is lacking., Methods: A prospective observational questionnaire study was conducted to investigate the occurrence of AEs after YF vaccination in travellers who attended a designated YF vaccination centre in Tokyo, Japan, from 1 November 2011 to 31 October 2012. A questionnaire enquiring about any AEs experienced in the 2 weeks following YF vaccination was distributed to all vaccinees enrolled in this study, and responses were collected subsequently by mail or phone. For child vaccinees, their parents were allowed to respond in their stead., Results: Of the 1298 vaccinees who received the YF vaccine, 1044 (80.4%) were enrolled in the present study and 666 (63.8%) responded to the questionnaire. Of these 666 respondents, 370 (55.6%) reported AEs, of which 258 (38.7%) were systemic and 230 (34.5%) were local. No severe AEs associated with YF vaccination were reported. Elderly vaccinees (aged ≥60 years) reported fewer total AEs than those aged <60 years (42.9% vs 60.3%;P < 0.001)., Conclusion: Our study showed that fewer general AEs after yellow vaccination reported among elderly vaccinees than among non-elderly vaccinees. These results could provide supplementary information for judging the adaptation of vaccination in elderly travellers., (© International Society of Travel Medicine, 2016. All rights reserved. Published by Oxford University Press. For permissions, please e-mail: journals.permissions@oup.com.)

A 26-year-old woman presented with fever and pharyngitis. She previously experienced four periodic febrile episodes at 30- to 40-day intervals. We suspected periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, and prescribed predisolone, thereby her fever rapidly subsided. Her febrile episodes improved after daily cimetidine treatment. Genetic testing results of genomic DNA for periodic fever syndromes were negative, although she was heterozygous for p.Glu148Gln variation in MEFV, supporting the diagnosis of PFAPA syndrome.

Background: Intramuscular benzathine penicillin G (BPG) is widely used for the treatment of syphilis. However, BPG is not available in some countries. This study examined the effectiveness and safety of high-dose oral amoxicillin plus probenecid for the treatment of syphilis in patients with human immunodeficiency virus type 1 (HIV-1)., Methods: This retrospective observational study included 286 HIV-infected male patients with syphilis (median age, 36 years; median CD4 count, 389 cells/µL) who were treated with oral amoxicillin 3 g plus probenecid. Syphilis was diagnosed by both serum rapid plasma reagin (RPR) titers ≥8 and positive Treponema pallidum hemagglutination test. Patients with neurosyphilis diagnosed by cerebrospinal fluid examination were excluded. Successful treatment was defined as a at least 4-fold decrement in RPR titer., Results: The overall treatment efficacy was 95.5% (95% confidence interval [CI], 92.4%-97.7%; 273/286 patients), and efficacy for primary, secondary, early latent, late latent, and unknown duration syphilis was 93.8% (95% CI, 68.1%-99.8%; 15/16), 97.3% (95% CI, 92.9%-99.2%; 142/146), 100% (95% CI, 90.5%-100%; 37/37), 85.7% (95% CI, 58.6%-96.4%; 18/21), and 92.4% (95% CI, 81.9%-97.3%; 61/66), respectively. Treatment duration was mostly 14-16 days (49.7%) or 28-30 days (34.3%), with efficacy of 94.4% (134/142) and 95.9% (94/98), respectively; 96.3% of successfully treated patients achieved a ≥4-fold decrement in RPR titer within 12 months. Adverse events were noted in 28 (9.8%) patients, and 25 of these (89.3%) were successfully treated. Only 6% of patients underwent lumbar puncture., Conclusions: The combination of oral amoxicillin 3 g plus probenecid was highly effective and tolerable for the treatment of syphilis in patients with HIV-1 infection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Identifying the causative agent of pyogenic osteomyelitis is often challenging, especially when antibiotics are administered before a biopsy. We herein present a case of osteomyelitis in the cervical vertebrae presenting with progressive paralytic symptoms, in which we successfully identified Escherichia coli from a biopsy specimen using broad-range 16S rRNA gene polymerase chain reaction (PCR) even though sensitive antibiotics had been used for more than 50 days before the biopsy. Broad-range 16S rRNA gene PCR is a useful diagnostic method, especially when prebiopsy antibiotics are unavoidably used for a clinically unstable state.

Background: Rapid diagnostic tests (RDTs) are used widely in the diagnosis of malaria. Although the effectiveness of RDTs for malaria has been described in many previous studies, the low performance of RDT particularly for Plasmodium ovale malaria in traveller has rarely been reported., Methods: This was a retrospective cohort study conducted on Japanese travellers diagnosed with malaria at the National Center for Global Health and Medicine between January 2004 and June 2013. The diagnosis of malaria was confirmed by microscopic examination, RDT, and polymerase chain reaction in all patients. The RDTs used in our study were Binax NOW Malaria (Binax Inc., Scarborough, Maine, USA) (BN) and SD Malaria Antigen Pf/Pan (Standard Diagnostics Inc., Korea) (SDMA). We compared the sensitivity of the RDTs to P. ovale malaria and Plasmodium vivax malaria., Results: A total of 153 cases of malaria were observed, 113 of which were found among Japanese travellers. Nine patients with P. ovale malaria and 17 patients with P. vivax malaria undergoing RDTs were evaluated. The overall sensitivity of RDTs for P. ovale malaria and P. vivax malaria was 22.2% and 94.1%, respectively (P < 0.001). The sensitivity of SDMA for P. ovale malaria and P. vivax malaria was 50% and 100%, respectively. The sensitivity of BN for P. vivax malaria was 90.0%, but it was ineffective in detecting the cases of P. ovale malaria., Conclusions: The sensitivity of RDTs was not high enough to diagnose P. ovale malaria in our study. In order not to overlook P. ovale malaria, therefore, microscopic examination is indispensable.

This is the first case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia. In September 2012, a previously healthy 35-year-old Japanese man presented to National Center for Global Health and Medicine in Tokyo with a two-day history of daily fever, mild headaches and mild arthralgia. Malaria parasites were found in the Giemsa-stained thin blood smear, which showed band forms similar to Plasmodium malariae. Although a nested PCR showed the amplification of the primer of Plasmodium vivax and Plasmodium knowlesi, he was finally diagnosed with P. knowlesi mono-infection by DNA sequencing. He was treated with mefloquine, and recovered without any complications. DNA sequencing of the PCR products is indispensable to confirm P. knowlesi infection, however there is limited access to DNA sequencing procedures in endemic areas. The extent of P. knowlesi transmission in Asia has not been clearly defined. There is limited availability of diagnostic tests and routine surveillance system for reporting an accurate diagnosis in the Asian endemic regions. Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.

β-Catenin plays a dual role as a key effecter in the regulation of adherens junctions as well as a transcriptional co-activator. Tyrosine phosphorylation of β-catenin affects the cell adhesion, migration, and gene transcription in many types of human cancer cells, including acute myeloid leukemia cells with FLT3 internal tandem duplication (FLT3/ITD-AML). Here, we investigated the relationship between three tyrosine residues (Y86, Y142, and Y654) in β-catenin and oncogenic FLT3/ITD kinase. In the experiments using COS-7 cells expressing FLT3/ITD and Wt or mutant β-catenin, FLT3/ITD phosphorylated Y654, and this residue was essential for β-catenin's nuclear localization by FLT3/ITD. Promoter-reporter assays demonstrated that Y654 phosphorylation of β-catenin was closely related to TCF transcriptional activity. In vitro kinase assays, using recombinant FLT3 and biotinylated β-catenin peptide including Y654 showed that FLT3 directly phosphorylated Y654 of β-catenin. These results explain how FLT3/ITD affects the tyrosine phosphorylation, nuclear localization, and transcriptional activity of β-catenin. Targeting Y654 phosphorylation may lead to the development of novel approaches to therapy for FLT3/ITD-AML., (© 2012 John Wiley & Sons A/S.)

Internal tandem duplication of FMS-like receptor tyrosine kinase 3 (FLT3/ITD) within its juxtamembrane domain is a frequent mutation in adult acute myeloid leukaemia (AML). This mutation causes constitutive activation of FLT3 and is associated with poor prognosis. The high relapse rate of FLT3/ITD-positive AML might be partly because of insufficient eradication of slow-cycling leukaemic stem cells in the bone marrow microenvironment. β1 integrin mediates haematopoietic stem and progenitor cell homing along with their retention in the bone marrow and also inhibits haematopoietic proliferation and differentiation. Here, we demonstrate that inhibition of FLT3/ITD kinase activity by a FLT3 selective inhibitor named FI-700 decreases affinity of α4β1 integrin to soluble VCAM-1. α4β1 integrin deactivation by FI-700 is independent of Rap1, which is the critical regulator of integrin inside-out signalling. In addition, selective inhibition of FLT3/ITD induces Pyk2 dephosphorylation together with the inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Both wild-type and ITD-FLT3 proteins co-immunoprecipitated with β1 integrin and Pyk2 indicating the signal crosstalk between FLT3, β1 integrin and Pyk2. These results collectively indicated that the inhibition of FLT3 kinase might contribute not only to the induction of apoptosis, but also to the leukaemia cell detachment from the bone marrow microenvironment in the treatment of AML., (© 2011 John Wiley & Sons A/S.)

Stem cells of acute myeloid leukemia (AML) have been identified as immunodeficient mouse-repopulating cells with a Lin(-)CD34(+)38(-) phenotype similar to normal hematopoietic stem cells. To identify the leukemia-propagating stem cell fraction of Philadelphia chromosome-positive (Ph(+)) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n = 3) or Ph(+) acute lymphoblastic leukemia (n = 3) into NOD/SCID/IL-2Rgammac(-/-) mice. Engrafted cells were almost identical to the original leukemia cells as to phenotypes, IGH rearrangements, and karyotypes. CD34(+)CD38(-)CD19(+), CD34(+)38(+)CD19(+), and CD34(-)CD38(+)CD19(+) fractions could self-renew and transfer the leukemia, whereas the CD34(-)CD38(+)CD19(+) fraction did not stably propagate in NOD/SCID mice. These findings suggest that leukemia-repopulating cells in transformed Ph(+) leukemia are included in a lineage-committed but multilayered fraction, and that CD34(+) leukemia cells potentially emerge from CD34(-) populations.

Objective: We investigated the mechanism responsible for imatinib (IM) resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) cell lines., Methods: We established cell lines from a patient with Ph(+) ALL at the time of first diagnosis and relapsed phase and designated as NPhA1 and NPhA2, respectively. We also derived IM-resistant cells, NPhA2/STIR, from NPhA2 under gradually increasing IM concentrations., Results: NPhA1 was sensitive to IM (IC(50) 0.05 microm) and NPhA2 showed mild IM resistance (IC(50) 0.3 microm). NPhA2/STIR could be maintained in the presence of 10 microm IM. Phosphorylation of MEK and ERK was slightly elevated in NPhA2 and significantly elevated in NPhA2/STIR compared to NPhA1 cells. After treatment with IM, phosphorylation of MEK and ERK was not suppressed but rather increased in NPhA2 and NPhA2/STIR. Active RAS was also increased markedly in NPhA2/STIR after IM treatment. The expression of BCL-2 was increased in NPhA2 compared to NPhA1, but no further increase in NPhA2/STIR. Proliferation of NPhA2/STIR was significantly inhibited by a combination of MEK inhibitor and IM. Analysis of tyrosine phosphorylation status with a protein tyrosine kinase array showed increased phosphorylation of EphB4 in NPhA2/STIR after IM treatment. Although transcription of EphB4 was suppressed in NPhA1 and NPhA2 after IM treatment, it was not suppressed and its ligand, ephrinB2, was increased in NPhA2/STIR. Suppression of EphB4 transcripts by introducing short hairpin RNA into NPhA2/STIR partially restored their sensitivity to IM., Conclusions: These results suggest a new mechanism of IM resistance mediated by the activation of RAS/MAPK pathway and EphB4.

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.

The Rho family of small GTPases, including Rho, Rac and Cdc42, has been well characterised as a molecular switch that transduces signals from plasma membrane to the downstream effectors. RhoH gene, a member of the Rho family, is specifically expressed in haematopoietic cells. The known function of RhoH is antagonising Rac and mediating activation of ZAP-70 in T lymphocytes; however, biological roles of RhoH in myeloid cells remain unknown. Here, we analysed the prognostic implication of the expression level of the RhoH gene transcript in bone marrow samples from 90 newly diagnosed acute myeloid leukaemia (AML) patients using a real-time fluorescence detection method. Kaplan-Meier analysis demonstrated that low expression of the RhoH transcript was a predictor of worse prognosis in both overall and disease-free survival. Multivariate analysis demonstrated that low expression of RhoH was an independent unfavourable prognostic factor for both overall and disease-free survival of AML patients. Overexpression of RhoH leads to dephosphorylation of Bad at Serine 75 residue possibly through deactivation of Rac. It is possible that low expression of RhoH (i.e. high GTP-Rac) contributes to chemotherapy resistance in leukaemia cells. Our result suggests that inhibition of Rac and its signalling components might provide a useful anti-leukaemic strategy.