Assessment of objective visual function following idebenone administration in patients with leber hereditary optic neuropathy.

PURPOSE: To objectively assess visual function in Leber's Hereditary Optic Neuropathy (LHON) patients; this study evaluated pre- and post-idebenone treatment changes in primary visual cortical (V1) responses using functional magnetic resonance imaging (fMRI), given the challenges in subjective testing due to central retinal ganglion cell damage. STUDY DESIGN: A descriptive study involving four confirmed LHON patients. METHODS: Four patients received 900 mg/day of oral idebenone for 24 weeks. Baseline and post-treatment visual acuity, visual fields, and BOLD fMRI responses while passively viewed drifting contrast pattern visual stimuli were compared with self-reported symptoms. RESULTS: Post-idebenone, one patient showed positive trends across subjective tests, reported symptoms, and fMRI. Two patients had stable symptoms and fMRI responses; one improved on subjective tests, and another worsened slightly. Another patient improved in visual field tests despite worsening symptoms and fMRI trends. CONCLUSION: fMRI may offer a valuable objective measure of visual functions in LHON and appears to be more relevant in assessing symptoms. Further research with more participants is needed to ascertain fMRI's role in developing objective visual assessments and treatment evaluation.

Ileal Crohn's Disease Exhibits Reduced Activity of Phospholipase C-ß3-Dependent Wnt/ß-Catenin Signaling Pathway.

Crohn's disease is a chronic, debilitating, inflammatory bowel disease. Here, we report a critical role of phospholipase C-ß3 (PLC-ß3) in intestinal homeostasis. In PLC-ß3-deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-ß3 deficiency in multiple non-hematopoietic cell types. PLC-ß3 deficiency resulted in reduced Wnt/ß-catenin signaling, which is essential for homeostasis and the regeneration of the intestinal epithelium. PLC-ß3 regulated the Wnt/ß-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and, potentially, protein-protein interaction levels. PLC-ß3-deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/ß-catenin signaling. Reduced expression of PLC-ß3 and its signature genes was found in biopsies of patients with ileal Crohn's disease. PLC-ß regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that a reduction in PLC-ß3-mediated Wnt/ß-catenin signaling contributes to the pathogenesis of ileal Crohn's disease.

[Comparison of Bladder Volume Measurement Accuracy between Portable Ultrasound Diagnostic Equipment and CBCT for Pelvic Prostate Radiotherapy].

PURPOSE: We evaluated the measurement accuracy of the CubeScan BioCon-900 (here after BioCon-900), a portable ultrasound imaging diagnostic device capable of measuring bladder volume, to determine if it can accurately assess bladder volume before intensity-modulated radiation therapy (IMRT) for prostate cancer. METHODS: Bladder volume was measured from kV-Cone Beam computed tomography (CBCT) images obtained immediately before the administration of IMRT for prostate cancer using Halcyon. The bladder volume measured from kV-CBCT images (23 patients, total number of scans: 139) immediately before the IMRT procedure was used as the reference value. The difference between the bladder volume measured by the BioCon-900 was then calculated. RESULTS: The bladder volume measured from kV-CBCT images was 117.5±49.4 cc. In contrast, the bladder volume obtained with BioCon-900 was 104.1±48.6 ml, resulting in an absolute mean difference of 18.4% and a correlation coefficient of 0.881. The measurements by BioCon-900 tended to be, on average, 11% smaller than the bladder volume measured by kV-CBCT imaging. CONCLUSION: kV-CBCT images demonstrated a strong positive correlation between bladder volume and bladder urine output obtained with BioCon-900. BioCon-900 can be used before kV-CBCT imaging to accurately and conveniently assess bladder volume.

Clinical outcomes after surgical decompression of median arcuate ligament syndrome-An observational study.

BACKGROUND AND OBJECTIVES: Median arcuate ligament syndrome is caused by compression and stenosis of the celiac artery. Incision of the median arcuate ligament improves persistent abdominal symptoms. The study aimed at evaluating the outcomes in patients who underwent median arcuate ligament syndrome decompression using a self-report questionnaire. METHODS: This single-center retrospective study included patients with median arcuate ligament syndrome who underwent decompression surgery between April 2021 and February 2023. The medical records were retrospectively reviewed. RESULTS: Ten patients were included in the study. Laparotomy and laparoscopic surgeries were performed in seven and three patients, respectively. The median operation time was 147 minutes. The median hospitalization period after the operation was seven days. The degrees of celiac artery stenosis before and after surgery were compared and the per cent diameter stenosis did not significantly improve; five of 10 patients (50%) had > 50% stenosis in the celiac artery after the operation. Compared to the baseline, the scores of upper gastrointestinal symptoms significantly improved during the six months' period (p < 0.001). Additionally, we evaluated the influence of post-operative per cent diameter stenosis and divided the patients into two groups (≥ 50% vs, < 50%). The scores of upper gastrointestinal (GI) symptoms in both groups improved significantly from baseline. However, the symptomatic improvement at six months in the post-operative per cent diameter stenosis < 50% group was significantly greater than that in the ≥ 50% group (p = 0.016). The scores of lower gastrointestinal symptoms did not change significantly during the six-month period. CONCLUSION: Decompression surgery for median arcuate ligament syndrome could improve upper gastrointestinal symptoms regardless of the post-operative per cent diameter stenosis.

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice.

INTRODUCTION: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. METHODS: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). RESULTS: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. CONCLUSION: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

Investigation of biomarkers to predict outcomes in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

Expression levels and DNA methylation profiles of the growth gene SHOX in cartilage tissues and chondrocytes.

All attempts to identify male-specific growth genes in humans have failed. This study aimed to clarify why men are taller than women. Microarray-based transcriptome analysis of the cartilage tissues of four adults and chondrocytes of 12 children showed that the median expression levels of SHOX, a growth gene in the pseudoautosomal region (PAR), were higher in male samples than in female samples. Male-dominant SHOX expression was confirmed by quantitative RT-PCR for 36 cartilage samples. Reduced representation bisulfite sequencing of four cartilage samples revealed sex-biased DNA methylation in the SHOX-flanking regions, and pyrosequencing of 22 cartilage samples confirmed male-dominant DNA methylation at the CpG sites in the SHOX upstream region and exon 6a. DNA methylation indexes of these regions were positively correlated with SHOX expression levels. These results, together with prior findings that PAR genes often exhibit male-dominant expression, imply that the relatively low SHOX expression in female cartilage tissues reflects the partial spread of X chromosome inactivation into PAR. Altogether, this study provides the first indication that sex differences in height are ascribed, at least in part, to the sex-dependent epigenetic regulation of SHOX. Our findings deserve further validation.

A case report of concurrent management of acute myocardial infarction complicated by left ventricular thrombus and ischaemic stroke.

Background: Left ventricular thrombus (LVT) formation is a serious complication of acute myocardial infarction (AMI) requiring complicated management strategies and collaboration among cardiologists, cardiovascular surgeons, and neurosurgeons. Case summary: We present the case of an 83-year-old female patient with AMI. Emergency coronary angiography revealed subtotal occlusion of the proximal left anterior descending artery, and the patient was successfully treated with a drug-eluting stent. The following day, she suddenly developed loss of consciousness, global aphasia, and right hemiplegia. Brain magnetic resonance imaging revealed acute ischaemic cerebral infarction caused by multiple mobile LVT, as demonstrated by echocardiography. After a heart-brain team discussion, we decided to perform percutaneous mechanical thrombectomy. Successful recanalization was achieved with mechanical thrombectomy 2 h after presentation, which resulted in significant neurological recovery. Immediately after the thrombectomy, she was transferred to a cardiovascular surgery centre for surgical removal of multiple LV apical thrombi. Two weeks after the operation, the patient was discharged with the recovery of LV systolic function. Discussion: Although AMI complicated by acute stroke caused by LVT remains a clinical challenge, a multidisciplinary approach is critically important for optimal care. Based on an urgent team discussion, we decided to perform endovascular thrombectomy for ischaemic stroke, followed by surgical removal of the LVT, requiring patient transportation to the cardiovascular surgery centre. Given that the heart and brain team-based approach remains confined to large, specialized centres, it might be beneficial to establish a community-based integrated heart-brain team that can address the growing needs of complex patients.

Implication of viruses in the etiology of preeclampsia.

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

A case of Bloom syndrome manifesting with therapy-related myelodysplastic syndromes harboring a novel BLM gene variant.

Bloom syndrome (BS) is an autosomal recessive genetic disorder caused by variants in the BLM gene. BS is characterized by distinct facial features, elongated limbs, and various dermatological complications including photosensitivity, poikiloderma, and telangiectatic erythema. The BLM gene encodes a RecQ helicase critical for genome maintenance, stability, and repair, and a deficiency in functional BLM protein leads to genomic instability and high predisposition to various types of cancers, particularly hematological and gastrointestinal malignancies. Here, we report a case of BS with a previously unreported variant in the BLM gene. The patient was a 34-year-old woman who presented with short stature, prominent facial features, and a history of malignancies, including lymphoma, breast cancer, and myelodysplastic syndromes (MDS). She was initially treated with azacitidine for MDS and showed transient improvement, but eventually died at age of 35 due to progression of MDS. Genetic screening revealed compound heterozygous variants in the BLM gene, with a recurrent variant previously reported in BS in one allele and a previously unreported variant in the other allele. Based on her characteristic clinical features and the presence of heterozygous variants in the BLM gene, she was diagnosed with BS harboring compound heterozygous BLM variants.

Persistent iatrogenic muscular ventricular septal lead perforation after pacemaker implantation using delivery sheath system.

Ventricular septal perforation is a rare complication of pacemaker implantation. Here, we describe the case of a 69-year-old man with complete atrioventricular block and heart failure. The right ventricular pacemaker was implanted with a long pre-shaped delivery sheath. A new systolic murmur appeared after the procedure. Transthoracic echocardiography revealed a ventricular septal perforation, with a Qp/Qs of 1.09, which was a small shunt rate and required no intervention. The persistent ventricular septal perforation was observed, and the shunt rate remained at 8-month follow-up. Learning objective: Ventricular septal lead perforation (VSP) is a rare complication of pacemaker implantation. Although iatrogenic VSP generally close spontaneously without adverse clinical outcomes, clinicians should pay attention to the possibility of its persistence.

Comparison of standardized prophylactic high-dose and intrathecal methotrexate for DLBCL with a high risk of CNS relapse.

The efficacy of high-dose methotrexate (HD-MTX) for central nervous system (CNS) relapse prophylaxis in patients with high-risk diffuse large B-cell lymphoma (DLBCL) is controversial. We compared the prophylactic effects of HD-MTX and intrathecal methotrexate (IT-MTX) on CNS relapse in high-risk DLBCL, in a multicenter retrospective study. A total of 132 patients with DLBCL at high risk of CNS relapse who received frontline chemotherapy and IT-MTX from 2003 to 2013 (n = 34) or HD-MTX from 2014 to 2020 (n = 98) were included. After a median follow-up of 52 months (range: 9-174), 11 patients had isolated CNS relapse: six (6.1%) in the HD-MTX group and five (14.7%) in the IT-MTX group. The median time until CNS relapse was 38 months (range: 11-122), and the cumulative incidence of CNS relapse at 3 years was 3.9% in the HD-MTX group and 6.1% in the IT-MTX group (P = 0.93). Similar results were obtained after adjusting for background factors using propensity score-matched analysis (4.5% HD-MTX vs. 7.6% IT-MTX, P = 0.84). The CNS relapse rate in HD-MTX-treated patients was equivalent to that in IT-MTX patients, demonstrating that HD-MTX was not superior to IT-MTX in preventing CNS relapse.

Motivated with joy or anxiety: Does approach-avoidance goal framing elicit differential reward-network activation in the brain?

Psychological research on human motivation repeatedly observed that approach goals (i.e., goals to attain success) increase task enjoyment and intrinsic motivation more strongly than avoidance goals (i.e., goals to avoid failure). The present study sought to address how the reward network in the brain-including the striatum and ventromedial prefrontal cortex-is involved when individuals engage in the same task with a focus on approach or avoidance goals. Participants reported stronger positive emotions when they focused on approach goals, but stronger anxiety and disappointment when they focused on avoidance goals. The fMRI analyses revealed that the reward network in the brain showed similar levels of activity to cues predictive of approach and avoidance goals. In contrast, the two goal states were associated with different patterns of activity in the visual cortex, hippocampus, and cerebellum during success and failure outcomes. Representation similarity analysis further revealed shared and different representations within the striatum and vmPFC between the approach and avoidance goal states, suggesting both the similarity and uniqueness of the mechanisms behind the two goal states. In addition, the distinct patterns of activation in the striatum were associated with distinct subjective experiences participants reported between the approach and the avoidance conditions. These results suggest the importance of examining the pattern of striatal activity in understanding the mechanisms behind different motivational states in humans.

Cone-beam computed tomography-guided online adaptive radiotherapy for pharyngeal cancer with whole neck irradiation: dose-volume histogram analysis between adapted and scheduled plans.

The present study aimed to evaluate whether an adapted plan with Ethos™ could be used for pharyngeal cancer. Ten patients with pharyngeal cancer who underwent chemoradiotherapy with available daily cone-beam computed tomography (CBCT) data were included. Simulated treatments were generated on the Ethos™ treatment emulator using CBCTs every four to five fractions for two plans: adapted and scheduled. The simulated treatments were divided into three groups: early (first-second week), middle (third-fourth week), and late (fifth-seventh week) periods. Dose-volume histogram parameters were compared for each period between the adapted and scheduled plans in terms of the planning target volume (PTV) (D98%, D95%, D50% and D2%), spinal cord (Dmax and D1cc), brainstem (Dmax) and ipsilateral and contralateral parotid glands (Dmedian and Dmean). The PTV D98%, D95% and D2% of the adapted plan were significantly higher than those of the scheduled plans in all periods, except for D98% in the late period. The adapted plan significantly reduced the spinal cord Dmax and D1cc compared with the scheduled plan in all periods. Ipsilateral and contralateral parotid glands Dmean of the adapted plan were lower than those of scheduled plan in the late period. In conclusion, the present study revealed that the adapted plans could maintain PTV coverage while reducing the doses to organs at risk in each period compared with scheduled plans.

Peritoneal Dialysis-associated Peritonitis Due to Streptococcus oralis Three Weeks after Peritoneal Dialysis Initiation.

A 60-year-old man with end-stage renal disease due to nephrosclerosis had a peritoneal dialysis catheter (PD) embedded with stepwise initiation of peritoneal dialysis using Moncrief and Popovich's technique three months ago. PD was initiated three weeks after creating an exit site. He presented with abdominal pain and fever a day before admission and was diagnosed with PD-associated peritonitis caused by Streptococcus oralis. Medical consultation after admission revealed a history of wisdom tooth extraction following PD catheter placement, resulting in delayed wound healing. Transient bacteremia can occur after tooth extraction, leading to PD-associated peritonitis. Contemplating the oral milieu in patients undergoing PD is pertinent.

Clinical significance of total nucleated cell count in bone marrow of patients with acute lymphoblastic leukemia who underwent allogeneic hematopoietic stem cell transplantation.

The clinical implications of recipient bone marrow nucleated cell count (NCC) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unknown. We conducted a multicenter retrospective study to evaluate the clinical significance of bone marrow NCC prior to allo-HSCT in patients with acute lymphoblastic leukemia. Patients who were in remission and underwent the initial allo-HSCT were included and stratified into high- and low-NCC groups using an NCC of 10 × 104/µL as the cut-off. The 3-year overall survival (OS), non-relapse mortality (NRM), and relapse rates for the high- and low-NCC groups were 51.2 vs. 84.5% (p < 0.001), 27.5 vs. 6.5% (p < 0.001), and 31.1 vs. 24.4% (p = 0.322), respectively. The high-NCC group had significantly poorer OS and higher NRM when compared with the low-NCC group. In summary, high recipient bone marrow NCC is associated with higher NRM and lower OS following allo-HSCT.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Prognostic significance of the CFA ratio for newly diagnosed acute myeloid leukemia: A multicenter retrospective study.

The CFA ratio, calculated using pretreatment C-reactive protein (CRP), fibrinogen, and albumin levels (CRP × fibrinogen/albumin), was previously reported to be a significant prognostic factor for acute myeloid leukemia (AML). This multicenter retrospective study evaluated the prognostic value of the CFA ratio in 328 adult patients with newly diagnosed AML from April 2000 to March 2018. The median age was 49.5 years (range, 15-75 years), and 60.7% of the population were males. According to the European LeukemiaNet (ELN) risk classification, 67 patients (20.4%) were in the favorable-risk group, 197 patients (60.1%) in the intermediate-risk group, and 58 patients (17.7%) in the adverse-risk group. The median CFA ratio was 1.07 (0-67.69). Based on the calculated cutoff CFA ratio of 1.44, the cohort included 176 and 152 patients with low and high CFA ratios, respectively. At a median follow-up of 91.2 months, the 7-year overall survival (OS) and disease-free survival (DFS) rates were 51.2% and 48.6%, respectively, in the overall cohort. The 7-year OS rates were 61.7% and 39.0% in the low and high CFA ratio groups, respectively (p < 0.001). The 7-year DFS rates were 58.1% and 37.0% in the low and high CFA ratio groups, respectively (p = 0.004). In univariate analysis, age ≥50 years, male sex, ELN risk class, and comorbidities were associated with poor OS. Age, ELN risk class, comorbidities, and high CFA ratio were associated with poor OS in multivariate analysis. Subgroup analysis revealed that the CFA ratio was significant in the intermediate and adverse ELN risk classes. These findings indicate the prognostic significance of the CFA ratio in AML.