GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis.

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

Identification of activity-based biomarkers for early-stage pancreatic tumors in blood using single-molecule enzyme activity screening.

Single-molecule enzyme activity-based enzyme profiling (SEAP) is a methodology to globally analyze protein functions in living samples at the single-molecule level. It has been previously applied to detect functional alterations in phosphatases and glycosidases. Here, we expand the potential for activity-based biomarker discovery by developing a semi-automated synthesis platform for fluorogenic probes that can detect various peptidases and protease activities at the single-molecule level. The peptidase/protease probes were prepared on the basis of a 7-amino-4-methylcoumarin fluorophore. The introduction of a phosphonic acid to the core scaffold made the probe suitable for use in a microdevice-based assay, while phosphonic acid served as the handle for the affinity separation of the probe using Phos-tag. Using this semi-automated scheme, 48 fluorogenic probes for the single-molecule peptidase/protease activity analysis were prepared. Activity-based screening using blood samples revealed altered single-molecule activity profiles of CD13 and DPP4 in blood samples of patients with early-stage pancreatic tumors. The study shows the power of single-molecule enzyme activity screening to discover biomarkers on the basis of the functional alterations of proteins.

Arterial Stiffness, Assessed Using the Cardio-Ankle Vascular Index, before and 2 Years after Total Knee Arthroplasty in Patients with Knee Osteoarthritis.

Purpose: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and such comorbidities increase the risk of postoperative complications following total knee arthroplasty (TKA). Arteriosclerosis plays a major role in hemodynamic dysfunction and CVD; however, the postoperative changes in arteriosclerosis following TKA have not been evaluated. Therefore, we assessed the postoperative changes in arteriosclerosis using the cardio-ankle vascular index (CAVI) in patients undergoing TKA, and its relationships with preoperative patient characteristics. Methods: Arteriosclerosis was prospectively evaluated in 119 consecutive patients (140 knees) (15 males (17), 104 females (123); median age 73 years) with knee osteoarthritis who underwent TKA. CAVI was measured before and 2 years after TKA, and the relationships between CAVI and preoperative age, sex, BMI, physical activity status, comorbidities, clinical score, triglyceride concentration, cholesterol concentration, and smoking history were analyzed. Results: CAVI remained stable or improved in 54 joints (39%) and worsened in 86 joints (61%) 2 years post-operation. The median difference between pre- and postoperative CAVI was 0.2 (-0.3, 0.8), and the only preoperative factor associated with this change was preoperative CAVI (r = -0.469, p < 0.001). No other preoperative factor had a significant effect on postoperative arteriosclerosis. Conclusions: The results suggest that patients who undergo TKA subsequently show less severe arteriosclerosis, and the protective effect of TKA on arterial stiffness is greater in those with a higher preoperative CAVI. TKA may be an effective means of reducing the deterioration of arteriosclerosis associated with knee osteoarthritis, at least in the relatively short term.

Growth Hormone Injection Log Analysis with Electronic Injection Device for Qualifying Adherence to Low-Irritant Formulation and Exploring Influential Factors on Adherence.

Introduction: Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients' adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7-71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence. Methods: This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12-48 weeks) were read by smartphones and collected into the data center through a cloud server. Results: Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (<85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029). Discussion: Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.

Characteristics of Preoperative Arteriosclerosis Evaluated by Cardio-Ankle Vascular Index in Patients with Osteoarthritis before Total Knee Arthroplasty.

PURPOSE: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and comorbidities increase postoperative complications after total knee arthroplasty (TKA). Arteriosclerosis plays a main role in hemodynamic dysfunction and CVD; however, arteriosclerosis has not been preoperatively evaluated before TKA using the cardio-ankle vascular index (CAVI). In this study, we evaluated the degree of preoperative arteriosclerosis using the CAVI in patients undergoing TKA, as well as its correlations with several preoperative patient factors. METHODS: Arteriosclerosis was evaluated in 209 consecutive patients (251 knees) with osteoarthritis who underwent TKA at our institution between May 2011 and June 2022. The CAVI was measured in the supine position 1 day before TKA, and the correlations between the CAVI and several clinical factors were analyzed. RESULTS: The CAVI was normal in 62 knees (25%), borderline in 71 knees (28%), and abnormal in 118 knees (47%). Univariate analysis revealed a moderate positive correlation between preoperative CAVI and age (r = 0.451, p < 0.001) and a weak negative correlation between preoperative CAVI and body weight (r = -0.306, p < 0.001) and body mass index (BMI) (r = -0.319, p < 0.001). Multivariate analysis showed that age (ß = 0.349, p < 0.001) and BMI (ß = -0.235, p < 0.001) were significantly correlated with preoperative CAVI. CONCLUSION: Arteriosclerosis should be carefully managed intraoperatively and postoperatively in patients with osteoarthritis undergoing TKA, particularly in older patients and patients with a low BMI.

Identification of small-sized intrachromosomal segments at the ends of INV-DUP-DEL patterns.

The mechanism of chromosomal rearrangement associated with inverted-duplication-deletion (INV-DUP-DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV-DUP-DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV-DUP-DEL patterns in five patients using long-read whole-genome sequencing and detected 2.2-6.1 kb copy-neutral regions in all five patients. At the end of the INV-DUP-DEL, two patients exhibited chromosomal translocations, which are recognized as telomere capture, and one patient showed direct telomere healing. The remaining two patients had additional small-sized intrachromosomal segments at the end of the derivative chromosomes. These findings have not been previously reported but they may only be explained by the presence of telomere capture breakage. Further investigations are required to better understand the mechanisms underlying this finding.

Patient factors impacting localization of popliteal artery before total knee arthroplasty.

PURPOSE: Intraoperative injury to the popliteal artery (PA) should be avoided during total knee arthroplasty (TKA). This study was performed to clarify the preoperative localization of the PA and the patient factors that impact its localization as a preventive measure. METHODS: Ninety-seven patients (110 knees; 18 men, 79 women) with osteoarthritis who underwent primary TKA were retrospectively reviewed. Preoperative sagittal magnetic resonance imaging was used to measure the distance between the PA and the closest point at three levels: the femoral epicondyle (DPF), the tibial articular surface (DPAS), and the posterior tibial cortex (DPT). All variables are expressed in millimeters as median (interquartile range). RESULTS: The median distance was 10.35 (7.90-12.34) mm for DPF, 6.32 (5.12-8.57) mm for DPAS, and 3.76 (2.28-5.26) mm for DPT. Body height and weight showed weak correlations with DPF (r = 0.324, p < 0.001 and r = 0.207, p = 0.03, respectively). DPF was smaller in women [9.82 (7.64-12.23) mm] than in men [11.27 (10.26-12.75) mm] (p = 0.004). A larger flexion angle and range of motion showed a weak negative correlation with DPT (r = - 0.282, p = 0.003 and r = - 0.236, p = 0.016, respectively). Multiple regression analysis revealed that DPF was related to body height (ß = 0.341, p < 0.001) and that DPT was related to the flexion angle (ß = - 0.264, p = 0.005). CONCLUSIONS: Special attention should be paid to women with a small physique on the femoral side and/or patients with a large flexion angle on the tibial side as a strategy to prevent PA-related complications.

Knowns and unknowns about congenital hypothyroidism: 2022 update.

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH. 1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH? 2. What is the optimal method for monitoring treatment of severe CH? 3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function? 4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine? 5. Who qualifies for a genetic diagnosis? 6. What is the best index for distinguishing transient and permanent CH? 7. Is there any cancer risk associated with CH? The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.

Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and ßTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Positive effect of total knee arthroplasty on progression of arteriosclerosis evaluated by cardio-ankle vascular index.

INTRODUCTION: Physical function is expected to improve with an increase in physical activity owing to improvement in knee joint pain after total knee arthroplasty (TKA). This study was performed to evaluate the impact of TKA on arteriosclerosis by measuring the cardio-ankle vascular index (CAVI) before and after surgery. MATERIALS AND METHODS: In total, 206 consecutive patients undergoing unilateral TKA were investigated. The CAVI, an index of the overall stiffness of the artery from the origin of the aorta to the ankle, was used to evaluate the degree of arteriosclerosis. The CAVI of the TKA side and non-TKA side was compared before and 1 year after TKA. RESULTS: There were no differences in the CAVI before and after TKA on the TKA side and non-TKA side, although these values should have worsened at 1 year compared with preoperative values. The CAVI, which did not differ between the two sides preoperatively, differed significantly between the two sides postoperatively (p = 0.013). A generalized linear model showed no interaction between each time point and the measured sides in terms of the CAVI. The relationship between the preoperative CAVI and the difference between the preoperative and postoperative CAVI were examined, showing that R = - 0.428 (p < 0.001) for the TKA side and R = - 0.416 (p < 0.001) for the non-TKA side (significant negative correlation). CONCLUSIONS: The lack of significant age-related deterioration over time on both sides suggests that TKA may slow the progression of arteriosclerosis, especially on the operated side. The effect of TKA was found to be greater with a higher CAVI (i.e., more advanced arteriosclerosis).

Head pleomorphic sarcoma showing murine double minute 2 amplification without a well-differentiated liposarcoma component in a pediatric patient.

BACKGROUND: Murine double minute 2 (MDM2) is an oncogene that inhibits p53, leading to decreased apoptosis. Sarcomas showing MDM2 amplification are rare among pediatric patients. CASE: A 14-year-old boy presented with pleomorphic sarcoma of the head showing MDM2 amplification without a well-differentiated liposarcoma component. Although chemotherapy was initially performed to reduce the tumor size before surgery, the tumor did not shrink. The patient underwent complete surgical resection. Microscopic examination revealed a positive surgical margin; thus, postoperative proton-beam radiotherapy was performed. 3 years after the therapy, no sign of recurrence was observed. CONCLUSION: Macroscopic surgical resection combined with adjuvant postoperative radiotherapy was effective against MDM2-amplified pleomorphic sarcoma refractory to neoadjuvant chemotherapy in a pediatric patient.

PlexinA1-deficient mice exhibit decreased cell density and augmented oxidative stress in parvalbumin-expressing interneurons in the medial prefrontal cortex.

PlexinA1 (PlxnA1) is a transmembrane receptor for semaphorins (Semas), a large family of axonal guidance cues vital during neural development. PlxnA1 is expressed in embryonic interneurons, and PlxnA1 deletion in mice leads to less interneurons in the developing cortex. In addition, PlxnA1 has been identified as a schizophrenia susceptibility gene. In our previous study, PlxnA1 knockout (KO) mice under a BALB/cAJ genetic background exhibited significantly increased self-grooming and reduced prepulse inhibition, a reliable phenotype for investigating the neurobiology of schizophrenia. However, the mechanism underlying the abnormal behavior of PlxnA1 KO mice remains unclear. We first confirmed PlxnA1 mRNA expression in parvalbumin-expressing interneurons (PV cells) in the medial prefrontal cortex (mPFC) of adult mice. Immunohistochemical analysis (IHC) showed significantly decreased densities of both GABAergic neurons and PV cells in the mPFC of PlxnA1 KO mice compared with wild type mice (WT). PV cells were found to express molecule interacting with CasL 1 (MICAL1), an effector involved in Sema-Plxn signaling for axon guidance, suggesting MICAL1 and PlxnA1 co-expression in PV cells. Furthermore, IHC analysis of 8-oxo-dG, an oxidative stress marker, revealed significantly increased oxidative stress in PlxnA1-deficient PV cells compared with WT. Thus, increased oxidative stress and decreased PV cell density in the mPFC may determine the onset of PlxnA1 KO mice's abnormal behavior. Accordingly, deficient PlxnA1-mediated signaling may increase oxidative stress in PV cells, thereby disrupting PV-cell networks in the mPFC and causing abnormal behavior related to neuropsychiatric diseases.

Comparison of the Tibial Posterior Slope Angle Between the Tibial Mechanical Axis and Various Diaphyseal Tibial Axes After Total Knee Arthroplasty.

Background: The posterior tibial slope angle (PTS) is crucial for sagittal alignment after total knee arthroplasty (TKA). This study aimed to determine which PTS based on the lateral view of standard knee radiographs (LSKRs; 36 × 43 cm) reflects the PTS based on a full-length lateral tibial radiograph (FLTR). Methods: A total of 290 patients (355 knees) who underwent primary TKA were retrospectively recruited. Cross-sectional views from the 3-dimensional digital model of the tibial prosthesis and bone complex in the sagittal plane were used as FLTRs and LSKRs. Considering the region 21.5 cm proximal to the site of FLTR as the spot for LSKR to determine the 5 tibial diaphyseal axes, the axis that simulates the PTS as determined by the tibial mechanical axis between the center of the tibial component and the ankle plafond in LSKR was determined and compared. Results: PTS (α5) defined by the line connecting the midpoints of tibial width between the region 10-cm distal to the knee joint and the distal end of the tibia based on LSKR revealed the least mean difference (0.13° ± 1.00°) and the strongest correlation (P < .001, r = 0.948) with PTS based on FLTR (α0). The number of knees in α5, indicating a difference of <2° from α0, was 333 of 355 (93.8%). The equivalence test results indicated that α0 and α5 were statistically equivalent within a difference of 2° (P < .001). Conclusions: PTS (α5) can be used as a clinically reliable substitution of the true PTS on an FLTR for evaluating sagittal alignment after TKA.

A Survey of Genetic Counseling for Non-invasive Prenatal Testing Examinees in Akita.

Introduction: In recent years, there has been an increase in noninvasive prenatal testing (NIPT), where maternal blood samples are used to extract fetal cell-free DNA. Despite this being offered in several facilities in urban areas, NIPT remains to be scarcely unavailable in rural areas. Moreover, there is lacking information with regard to how pregnant women in rural areas perceive NIPT. Thus, in this study, we conducted a survey among pregnant women who came to our clinic for NIPT and examined their views on NIPT and genetic counseling. Methods: A questionnaire survey was administered to pregnant women who requested NIPT and underwent genetic counseling at our hospital between November 2016 and February 2020. The questionnaire was administered twice, once after completing the genetic counseling and once after explaining the NIPT results. The number of genetic counseling and NIPT sessions and positive test results, as well as anxiety about the test and evaluation of genetic counseling and NIPT, were assessed. Results: In total, 115 patients received genetic counseling, of which 109 underwent NIPT. The test results were found to be positive in six patients. As per our findings, 103 patients (93%) indicated they needed genetic counseling for NIPT, whereas 99 (93%) were satisfied with the counseling they received from a genetic medicine specialist. On the other hand, 82 patients (77%) requested for more testing facilities. Conclusions: The enhancement of genetic counseling systems is essential to expand the environment in which NIPT is performed. Therefore, we need to consider the need to make the NIPT testing environment more conducive and inform clients of the importance of genetic counseling in NIPT.

Comparison of Operative Times in Primary Bilateral Total Knee Arthroplasty Performed by a Single Surgeon.

Purpose: Prolonged operative time (OT) is associated with adverse complications after total knee arthroplasty (TKA). The purpose of this study was to determine whether preoperative factors, such as sex, age, body mass index, body weight (BW), body height, American Society of Anesthesiologists grade, tibiofemoral angle, hospital for special surgery scores, surgical side, surgical order, and calendar year of surgery, affect OT. Methods: One hundred and nineteen patients (238 knees) with osteoarthritis who underwent staged bilateral primary TKA performed by a single surgeon were evaluated. The medical records of 15 males and 104 females were retrospectively reviewed. All variables were expressed as median (interquartile range). Results: The OT for all TKAs was 57 min (51, 65). The OT on the left side (59 min (52−67)) was longer than that on the right side (55 min (50−62)) (p = 0.015). Multiple regression analysis revealed that longer OT was related to BW (ß = 0.488, p < 0.001), calendar year of surgery (ß = −0.218, p< 0.001), and operative side (ß = −0.151, p = 0.007). The Jonckheere−Terpstra test showed a trend toward decreasing OT with calendar year on the left side (p = 0.037) (surgeon's non-dominant side), but not on the right (p = 0.795). Body height, BW, and body mass index showed weak correlations (r = 0.212, p = 0.001; r = 0.352, p < 0.001; r = 0.290, p < 0.001, respectively) with OT. Conclusion: Patients with a large physique, and especially obesity, with an affected knee on the surgeon's non-dominant side may require a longer OT; OT decreased over time.

Precocious puberty in a case of Simpson-Golabi-Behmel syndrome with a de novo 240-kb deletion including GPC3.

Here, we report a Japanese patient with Simpson-Golabi-Behmel syndrome involving a de novo 240-kb deletion including a part of GPC3. The patient showed pre- and postnatal macrosomia associated with coarse face, macrocephaly, supernumerary nipples, and cryptorchidism and characteristically presented with precocious puberty, mostly evaluated as advanced pubertal age of 15 years at the chronological age of 11.5 years.

New mimic of relapse or regional lymph node metastasis in a cancer survivor: a case of mRNA COVID-19 vaccine-induced lymphadenitis with high FDG uptake.

Western countries that were first to administer the COVID-19 vaccination report cases of vaccine-induced axillary lymphadenitis with high FDG uptake. However, no such findings have been reported from any Asian countries. We report here a confusing case of a 31-year-old female cancer survivor with high FDG uptake in her axillary lymph nodes, suggesting recurrence, following mRNA COVID-19 vaccination. Although the value of SUVmax was elevated (12.7), additional imaging revealed that her lymphatic lesions were benign, and they resolved spontaneously. This case of a strong immune reaction to COVID-19 vaccination in regional lymph nodes is the first reported in a Japanese patient. We should be aware of this new mimic and optimize diagnostic imaging methods accordingly in the era of COVID-19.