Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan.

PURPOSE: Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency. METHODS: This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023. RESULTS: We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency. CONCLUSION: GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.

Utility of Positional Instillation of Contrast Cystography for Diagnosing Occult Vesicoureteral Reflux in Children: A Report of Two Cases.

Positional instillation of contrast (PIC) cystography is effective for detecting occult vesicoureteral reflux (VUR), which can not be revealed by standard voiding cystourethrography (VCUG). We experienced two cases of young female patients; one had repeated urinary tract infection with a negative VUR on standard VCUG, and the other had findings suggestive of reflux hydronephrosis and intolerance of standard VCUG. They underwent PIC cystography, and occult VUR was detected in both cases. Both were successfully treated with simultaneous endoscopic injection therapy with dextranomer/hyaluronic acid. PIC cystography is useful for detecting occult VUR in children with negative VUR findings on standard VCUG or who are unable to tolerate standard VCUG.

Influence of patients' walking ability at one-week post-proximal femur fracture surgery on the choice of discharge destination in Japan.

[Purpose] With the innovation of healthcare delivery systems, a need for early determination of patients' discharge outcomes arises after proximal femur fracture surgery, to reduce the burden on healthcare infrastructure. Several studies have examined the extent of walking ability early in the postoperative period to predict the outcome destination. In this study, as an additional validation of these studies, we examined the effect of walking ability on the hospital discharge prognosis of patients in the first week after proximal femur fracture surgery in Japan. [Participants and Methods] Medical records of 228 patients with proximal femur fractures, aged ≥75 years old, admitted between April 2015 and March 2019, were retrospectively analyzed. The objective variable was discharge destination. The main evaluation factor was walking ability one-week post-surgery. [Results] Good walking ability and the company of a relative living together one week post-surgery were significant determining factors of discharge destination. [Conclusion] The ability to walk and the presence of a co-resident one week after surgery increased the likelihood of proximal femur fracture patients to be discharged directly to home. Our findings may help rehabilitation professionals make better decisions regarding discharge destination.

Early Ambulation Shortened the Length of Hospital Stay in ICU Patients after Abdominal Surgery.

The optimal time to ambulation remains unclear for intensive care unit (ICU) patients following abdominal surgery. While previous studies have explored various mobilization techniques, a direct comparison between ambulation and other early mobilization methods is lacking. Additionally, the impact of time to ambulation on complications and disuse syndrome prevention requires further investigation. This study aimed to identify the optimal time to ambulation for ICU patients after abdominal surgery and considered its potential influence on complications and disuse syndrome. We examined the relationship between time to ambulation and hospital length of stay (LOS). Patients were categorized into the nondelayed (discharge within the protocol time) and delayed (discharge later than expected) groups. Data regarding preoperative functioning, postoperative complications, and time to discharge were retrospectively collected and analyzed. Of the 274 postsurgical patients managed in the ICU at our hospital between 2018 and 2020, 188 were included. Time to ambulation was a significant prognostic factor for both groups, even after adjusting for operative time and complications. The area under the curve was 0.72, and the cutoff value for time to ambulation was 22 h (sensitivity, 68%; specificity, 77%). A correlation between time to ambulation and complications was observed, with both impacting the hospital LOS (model 1: p < 0.01, r = 0.22; model 2: p < 0.01, r = 0.29). Specific cutoff values for time to ambulation will contribute to better surgical protocols.

Clinical features and treatment outcomes of isolated secondary central nervous system lymphomas in Miyazaki Prefecture.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) without extra-central nervous system (CNS) involvement is characterized by isolated secondary CNS relapse in malignant lymphoma patients. SCNSL is a rare disease, and no standard treatment has yet been established. PATIENTS AND METHODS: To elucidate the clinical characteristics and outcomes of SCNSL, we retrospectively analyzed 12 patients (median age 67 years) in Miyazaki prefecture for the last 5 years. RESULTS: The initial histological diagnoses of the patients were diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma, and adult T-cell lymphoma in 9, 2, and 1 patient, respectively. We focused on analysis of the 9 SCNSL cases originating from DLBCL. The locations of CNS relapse were the cerebral hemisphere, basal ganglia, and cerebellum in 7, 1, and 1 patient, respectively. Three patients were treated with high-dose methotrexate (HD-MTX) therapy; 4 with whole-brain radiation therapy (WBRTX); and 1 with both HD-MTX and WBRTX. The remaining patients were treated with rituximab. Partial remission was achieved in 6 out of 9 patients (67%); the other 3 patients (33%) did not respond to therapy. Median survival of the 9 patients with CNS relapse was 253 days; 6 of the 9 patients survived for more than 6 months. As of March 2011, 2 HD-MTX group patients but none of the WBRTX group patients were alive. CONCLUSIONS: In this retrospective study, 6 of 9 patients with SCNSL originating from DLBCL survived for more than 6 months. Both HD-MTX and WBRTX had clinical benefits in the treatment of SCNSL.

Clostridioides difficile Toxin B PCR Cycle Threshold as a Predictor of Toxin Testing in Stool Specimens from Hospitalized Adults.

Rapid, accurate detection of Clostridioides difficile toxin may potentially be predicted by toxin B PCR cycle threshold (tcdB Ct). We investigated the validity of this approach in an inpatient adult population. Patients who tested positive by C. difficile PCR (Cepheid GeneXpert) from December 2016 to October 2020 (n = 368) at a tertiary medical center were included. All stool samples were further tested by rapid glutamate dehydrogenase (GDH)/toxin B EIA and cell cytotoxin neutralization assay (CCNA). Receiver operating characteristic curves were analyzed. The area under the curve for tcdB Ct predicting toxin result by EIA was 0.795 (95% confidence interval (CI) 0.747−0.843) and by CCNA was 0.771 (95% CI 0.720−0.822). The Youden Ct cutoff for CCNA was ≤27.8 cycles (sensitivity 65.0%, specificity 77.2%). For specimens with Ct ≤ 25.0 cycles (n = 115), CCNA toxin was positive in >90%. The negative predictive value of tcdB Ct for CCNA was no greater than 80% regardless of cutoff chosen. In summary, very low Ct values (≤25.0) could have limited value as a rapid indicator of positive toxin status by CCNA in our patient population. A broad distribution of Ct values for toxin-negative and toxin-positive specimens precluded more robust prediction. Additional data are needed before broader application of Ct values from qualitatively designed assays to clinical laboratory reporting.

Factors Affecting the Length of Hospital Days After Laparoscopic Gastrectomy for Elderly Patients with Gastric Cancer.

PURPOSE: To clarify the factors affecting the length of hospitalization after laparoscopic gastrectomy based on the physical function, body composition, and postoperative course of the patients. METHODS: Of the patients with gastric cancer who underwent laparoscopic resection at the Ageo Central General Hospital, Japan, during 2018-2019, 51 underwent physical therapy. Data regarding the objective variables, such as length of postoperative hospital stay, and baseline attributes, such as age, body weight, body mass index (BMI), and corrected limb muscle mass, postoperative course (operation time, the estimated blood loss, the day before walking independently), preoperative physical function (grip strength, 6-min walking distance), and preoperative respiratory function (vital capacity [VC]%, one-second rate) were collected retrospectively from the medical records and analyzed using multiple regression plots. RESULTS: The most suitable hospital day model after surgery is one that incorporates the total postoperative course, respiratory function, physical function (R2 = 0.45, p < 0001), and operation time (ß = 0.12, p < 0.06). The information of the day before independent walking (ß = 0.68, p < 0.001) and % VC (ß = -0.19, p < 0.04) was extracted as factors. CONCLUSION: We concluded that the operation time, walking independence days, and % VC influence the postoperative length of hospital days.

The possible association between epidemics of hand-foot-and-mouth disease and responsiveness to immunoglobulin therapy in Kawasaki disease.

Background: Enterovirus causing hand-foot-mouth disease (HFMD) has been reported to be associated with the development of Kawasaki disease (KD), whereas the involvement of enterovirus in the clinical course of KD is uncertain. The aim of this study is to investigate the association between the clinical course of KD and HFMD epidemics. Methods: This study included 108 patients who developed KD during HFMD epidemic seasons (July and August) from 2010 to 2014 and who were initially treated with high-dose intravenous immunoglobulin (IVIG). A mean of ≥5.0 HFMD patients reported weekly from each sentinel medical facility was considered to represent a large HFMD epidemic. We compared the clinical characteristics of KD patients in summers of years with and without large HFMD epidemics. Results: Large HFMD epidemics occurred in 2011 and 2013. The number of KD patients in summer was the highest in 2011. The proportion of patients with resistance to the IVIG therapy in summers of years with the large epidemics (14%) was significantly lower than that in summers of other years (31%, P = 0.030), whereas the proportion of patients with coronary artery abnormalities did not differ to a statistically significant extent. The development of KD during large HFMD epidemics was significantly associated with a lower risk of resistance to the IVIG therapy (incidence rate ratio 0.92, P = 0.049). Conclusion: Patients developing KD during large HFMD epidemic may have good responsiveness to IVIG. It is important to identify microbes from KD patients to predict responsiveness to IVIG therapy.

A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies.

WT2725 is a Wilms' tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56-81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309-648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6-19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

Impacts of surgical interventions on the long-term outcomes in individuals with trisomy 18.

OBJECTIVE: We aim to clarify whether surgical interventions can contribute to improve the long-term outcomes among individuals with trisomy 18. METHODS: We retrospectively studied 69 individuals with trisomy 18 admitted to 4 tertiary neonatal centers between 2003 and 2017. A cohort was divided into two groups: subjects with surgical interventions and conservative treatments. We compared the rates of survival and achieving homecare between the groups. RESULTS: Gestational age and birth weight were 37 (27-43) weeks and 1,700 (822-2,546) g, respectively. There were 68 patients with congenital heart disease and 20 patients with digestive disease. Surgical interventions including cardiac and digestive surgery were provided in 41% of individuals. There was no difference in gestational age (p=0.30), birth weight (p=0.07), gender (p=0.30), and fetal diagnosis (p=0.87) between the groups. During the median follow up duration of 51 (2-178) months, overall survival rates in 6, 12 and 60 months were 57%, 43% and 12%, respectively. Survival to hospital discharge occurred in 23 patients, and the rates of achieving homecare in 1, 6, and 12 months are 1%, 18% and 30%, respectively. There was no significant difference in survival rate (p=0.26) but in the rate of achieving home care (p=0.02) between the groups. Cox hazard analysis revealed that prenatal diagnosis (hazard ratio 0.30, 95%CI: 0.13-0.75), cardiac surgery (hazard ratio 2.40, 95%CI:,1.03-5.55), and digestive surgery (hazard ratio 1.20, 95%CI: 1.25-3.90) were related to the rate of achieving homecare. CONCLUSION: Aggressive surgical interventions contribute not to the long-term survival but to achieve homecare among individuals with trisomy 18. EVIDENCE LEVEL: Level 3 (Prognostic study, Case-Control study).

Cardiovascular complications associated with chronic active Epstein-Barr virus infection.

This study aimed to assess the outcome of cardiovascular diseases for patients with chronic active Epstein-Barr virus infection (CAEBV). The study enrolled 15 patients (7 boys and 8 girls) who fulfilled the diagnostic criteria for CAEBV, including 10 patients with T-cell type and 3 patients with natural killer (NK)-cell type. The median age at the CAEBV onset was 6.3 years (range, 1.2-17.8 years). Regular cardiologic studies were performed during the median follow-up period of 8 years (range, 2-20 years). Nine patients (60%) had cardiac diseases including coronary artery lesion (CAL) (n = 4, 44%), decreased left ventricular ejection fraction and pericardial effusion in (n = 3, 33%), complete atrioventricular block (n = 1), and sudden arrest (n = 1). The frequency of fever (78%, p = 0.04) or cytopenias (100%, p = 0.01), as the major symptom among patients with cardiac complications, was higher than among those without complications. The median time from disease onset to detection of CAL was 3.4 years (range, 1.8-8.6 years). The mean z-score increased to 3.98. Seven patients (78%) with cardiac complications died of disease progression, hematopoietic stem cell transplantation-related events, or both. In two patients, CAL regressed after allogeneic cord blood transplantation. Among CAEBV patients, CAL was the most common cardiac complication and could not be controlled without the eradication of EBV-infected T- and NK-cells.

Seasonality in clinical courses of Kawasaki disease.

OBJECTIVE: Epidemics of Kawasaki disease (KD) are well known; however, the seasonal variation in the clinical course of KD is uncertain. The aim of this study was to investigate the seasonality in the clinical course of KD. METHODS: This study included 744 patients who were admitted to six hospitals in Kitakyushu City for KD from 2010 to 2014. We divided the patients into two groups according to the average monthly temperature (warm and cold periods) and compared the clinical courses of KD. RESULTS: The clinical courses of 715 patients who were initially treated with intravenous immunoglobulin (IVIG) were investigated. The proportion of patients with resistance to the initial IVIG therapy was significantly higher during the warm period than during the cold period (p=0.016). There was no seasonality in the proportion of patients with coronary artery abnormalities. CONCLUSION: Seasonality was observed in the response to IVIG therapy of patients with KD.

A low perfusion-metabolic mismatch in 99m Tl and 123 I-BMIPP scintigraphy predicts poor prognosis in systemic sclerosis patients with asymptomatic cardiac involvement.

AIM: This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients. METHODS: We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using 99m thallium (99m Tl) and 123 I-ß-methyl-P-iodophenyl-pentadecanoic acid (123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of 123 I-BMIPP from that of 99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing 99m Tl and 123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis. RESULTS: Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases. CONCLUSIONS: Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients.

Multiseptate gallbladder: report of a case.

A 53-year-old Japanese female was referred to Miyazaki University hospital for the surgical treatment of gastric cancer. She had no symptoms and the presence of the complex cystic gallbladder with multiple and linear hyperechogenic septa was incidentally found by ultrasonography. Multicystic lesion of gallbladder was also observed on DIC-CT and MRCP. Neither the bile duct nor the pancreatic duct was dilated. The papilla of the Vater was of normal appearance endoscopically. Pathological study of the biopsy specimen from the type 3 tumor of the stomach showed poorly differentiated adenocarcinoma. Distal partial gastrectomy and cholecystectomy were performed. The gross examination of the gallbladder confirmed the presence of multiple thin septa with honeycomb appearance. Cancer cells were not observed histologically and final diagnosis was the multiseptate gallbladder. The postoperative course was uneventful. We herein report a rare case of multiseptate gallbladder showing the findings on DIC-CT and MRCP.

MR virtual endoscopy for biliary tract and pancreatic duct.

Developments in magnetic resonance (MR) equipment and techniques have been remarkable. Especially, respiratory-triggered three-dimensional MR cholangiopancreatography (3D-MRCP) has been developed to provide images with high spatial resolution of the biliary tract and pancreatic duct. These 3D data can be employed in MR virtual endoscopy (MRVE) with volume rendering to visualize the lumina of the gallbladder, bile duct, and pancreatic duct. To observe the changes in the lumina with threshold settings on a workstation, we made an original phantom with tubes 2, 3, and 6 mm in internal diameter. We examined the changes in luminal diameter using several threshold settings by comparing the actual internal diameters to determine an appropriate threshold setting, which we then applied in 50 clinical cases, including pancreatic tumors, hepatic tumors, and biliary tract stones. We obtained MRVE images of the gallbladder, bile duct, and pancreatic duct to assess the clinical usefulness of this method. In the phantom study, a value identical to the actual luminal diameter could be obtained with a threshold of less than 20%. In all clinical cases, we obtained MRVE images of the gallbladder, bile duct, and pancreatic duct using the threshold we had determined appropriate and scored the diagnostic usefulness in each region. The MRVE images of the biliary tract provided much supplementary information, including the presence of stones and of duct invasion by the malignancy as wells as visualization of the post-stenotic portion. MRVE images of the gall bladder did not significantly improve diagnosis (P=0.311), but those of the bile and pancreatic ducts did (P<0.05). In addition, MRVE may aid navigation during cholangioscopy. Thus, MRVE is a clinically useful technique for examining lesions of the biliary tract and pancreas.

Successful surgical treatment for pulmonary crystal-storing histiocytosis following the onset of gastric non-hodgkin lymphoma.

Crystal-storing histiocytosis is a rare clinical entity characterized by an increase in the number of abnormal histiocytes accompanied by accumulation of crystallized immunoglobulins. We describe the case of an 80-year-old man who presented with crystal-storing histiocytosis of the lung 13 years after receiving a diagnosis of gastric non-Hodgkin lymphoma (NHL ; clinical stage, Lugano IA). After wedge resection of the left upper lobe, the histological findings showed crystal-storing histiocytosis with CD68(+), some small to medium lymphoid cells with CD79a(+) with κ(+(weekly)) and λ(-), and some plasma cells with CD138(+), and rearrangement of the immunoglobulin heavy chain. Based on the nonrecurrent gastric NHL, small B-cell population, and failure to detect the same clone by polymerase chain reaction analysis, our case was classified as pulmonary localized crystal-storing histiocytosis without underlying lymphoproliferative or plasma cell disorder. The findings of minor B-cell populations harboring a heavy chain rearrangement with slight light-chain restriction (κ > λ) may be related to the pathogenesis of crystallogenesis and crystal-storing histiocytosis. Moreover, surgical treatment may be an effective therapeutic option for solitary crystal-storing histiocytosis.

Genetic susceptibility to Kawasaki disease: analysis of pattern recognition receptor genes.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology occurring in infants and children. Several lines of evidence suggested the importance of genetic factors and infectious triggers for the pathogenesis of KD. We have reported that oral administration of a pure NOD1 ligand induces coronary arteritis in mice without fail. Since NOD1 is one of the pattern recognition receptors (PRRs) which play important roles in the innate immunity for the detection of microbial substances and induce inflammatory responses, we have investigated the association of PRR genes with the development of KD. Forty-six tagging-SNPs in 19 PRR genes were genotyped in Japanese KD patients (n=356, consisting of two groups) and controls (n=215). The genotypes and allele frequencies of each SNP or haplotype were compared between KD patients and controls. As a result, we did not find any genes with strongly contributed to the development of KD. A haplotype, G-T-C-C, in the NOD1 gene, was associated with lower risk for KD development (KD 1st group versus controls: 23.2% versus 35.3%, Pc=0.0385). The second-round case-control study in KD group 2 demonstrated that a haplotype, T-T-C-G-A-C, in the NLRP1 gene was associated with a higher risk for KD development (4.9% versus 1.2%, Pc=0.035). From the association analysis of SNPs and haplotypes of 19 PRR genes, NOD1 and NLRP1 seemed to partly contribute to the development of KD. Further analysis with larger samples of another independent set would be needed to find confirmative results.

Lack of association between E148Q MEFV variant and Kawasaki disease.

We investigated a possible association between Kawasaki disease (KD), a systemic vasculitis of unknown etiology, or its coronary artery lesions (CAL) and MEFV gene variants including E148Q, the most common and mild mutation in the MEFV gene for familial Mediterranean fever or vasculitis-related disorders. The study population comprised a total of 138 Japanese patients with KD, including 45 patients with CAL and 93 patients without CAL and 170 normal controls. Sequence variations for the MEFV gene were detected by direct sequencing, followed by the TaqMan SNP genotyping assay. The genotype and allele frequencies of MEFV gene variants (E148Q, L110P, R202Q, P369S, R408Q) were compared between KD patients with and without CAL or between KD patients with CAL and controls. E148Q heterozygotes and homozygotes were observed in 37.1 and 5.5% of healthy controls, 33.3 and 5.1% of KD patients, and 37.8 and 4.4% of KD patients with CAL. No significant differences were observed in the genotype and allele frequencies of other MEFV gene variants (L110P, R202Q, P369S, R408Q) between KD patients with and without CAL or between KD patients with CAL and controls. No associations were detected between the MEFV gene variants and the development of KD or CAL formation in KD.