Organelle communication maintains mitochondrial and endosomal homeostasis during podocyte lipotoxicity.

Organelle stress exacerbates podocyte injury, contributing to perturbed lipid metabolism. Simultaneous organelle stresses can occur in the kidney in the diseased state; therefore, a thorough analysis of organelle communication is crucial for understanding the progression of kidney diseases. Although organelles closely interact with one another at membrane contact sites, limited studies have explored their involvement in kidney homeostasis. The endoplasmic reticulum (ER) protein, PDZ domain-containing 8 (PDZD8), is implicated in multiple-organelle-tethering processes and cellular lipid homeostasis. In this study, we aimed to elucidate the role of organelle communication in podocyte injury using podocyte-specific Pdzd8-knockout mice. Our findings demonstrated that Pdzd8 deletion exacerbated podocyte injury in an accelerated obesity-related kidney disease model. Proteomic analysis of isolated glomeruli revealed that Pdzd8 deletion exacerbated mitochondrial and endosomal dysfunction during podocyte lipotoxicity. Additionally, electron microscopy revealed the accumulation of abnormal, fatty endosomes in Pdzd8-deficient podocytes during obesity-related kidney diseases. Lipidomic analysis indicated that glucosylceramide accumulated in Pdzd8-deficient podocytes, owing to accelerated production and decelerated degradation. Thus, the organelle-tethering factor, PDZD8, plays a crucial role in maintaining mitochondrial and endosomal homeostasis during podocyte lipotoxicity. Collectively, our findings highlight the importance of organelle communication at the 3-way junction among the ER, mitochondria, and endosomes in preserving podocyte homeostasis.

Factors necessary for a community pharmacist to achieve interprofessional collaboration in home-based care in Japan.

AIM: Interprofessional collaboration between medical professionals is an essential aspect of caring for Japan's super-aging population, but studies on the subject have been geographically limited in scope. Therefore, we aimed to determine the factors necessary for pharmacists to achieve interprofessional collaboration in home-based care in Japan. METHODS: Our online questionnaire survey was conducted from February 1, 2023 to February 15, 2023. The Japan Pharmaceutical Association introduced this survey to their membership, and survey letters were sent to hospitals and community pharmacies that were not included in this association. RESULTS: The study involved 1156 and 36 participants working in a community pharmacy and a hospital, respectively. These participants were divided into the collaboration group and the non-collaboration group. Enough time for visiting patients and for preparing the first visiting plan was important to achieve interprofessional collaboration in home-based care for a hospital pharmacist. More than 5 years of experience working in home-based care and participation in pre-visit conferences, discharge conferences, meetings with persons in charge of services were independent factors in collaborating with other medical staff for a community pharmacist. CONCLUSION: Hospital pharmacists with enough time to prepare and visit for home-based care and community pharmacists working in home-based care for more than 5 years and who share information on home-based care with medical staff achieved interprofessional collaboration in home-based care. Geriatr Gerontol Int 2024; 24: 1008-1014.

Sarcopenia shortens overall survival of patients with platinum-resistant recurrent ovarian cancer: inverse probability of treatment-weighting analysis.

OBJECTIVE: The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer. METHODS: A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests. RESULTS: The median patient age was 63 years (IQR: 53-71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm2/m2, which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06-3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045). CONCLUSION: Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

A Handheld Ultrasound Device Can Predict Constipation with Rectal Fecal Retention in a Palliative Care Setting.

Although handheld ultrasound devices (HUDs) are commonplace, their ability to diagnose fecal retention (FR) remains unclear. This prospective observational study examined HUDs' usefulness in diagnosing FR in patients with constipation in a palliative care setting. Between 10 December 2020 and 30 June 2022, we compared rectal ultrasonographic findings obtained using HUDs with clinical manifestations in 64 males and 70 females (48%, 52%, 68 ± 11 years old) with constipation who had undergone computed tomography (CT). FR was diagnosed using a HUD and compared with CT and digital rectal examination (DRE) results. In total, 42 (31%), 42 (31%), and 41 (31%) patients were diagnosed using HUDs, CT, and DRE, respectively. Thirty-nine (93%) patients in the CT group were also diagnosed with FR using HUDs. A total of 89 of 92 patients with a negative CT diagnosis also had a negative HUD diagnosis. Among the 41 patients in the DRE group, 37 were also diagnosed with FR using HUDs. Among 93 patients with a negative DRE diagnosis, 86 had a negative HUD diagnosis. The sensitivity, specificity, positive predictive value, and negative predictive value of HUDs for CT were 93%, 97%, 93%, and 97%, respectively. Those of HUDs for DRE were 88%, 94%, 86%, and 95%, respectively. The concordance rates for FR diagnosis were 128/134 for CT and HUDs and 123/134 for DRE and HUDs. HUD was useful for diagnosing FR in this setting. HUDs could provide valuable support for appropriate treatment selection. Developing a constipation treatment algorithm based on rectal ultrasonographic findings is warranted in the future.

Whole-Body and Whole-Organ 3D Imaging of Hypoxia Using an Activatable Covalent Fluorescent Probe Compatible with Tissue Clearing.

Elucidation of biological phenomena requires imaging of microenvironments in vivo. Although the seamless visualization of in vivo hypoxia from the level of whole-body to single-cell has great potential to discover unknown phenomena in biological and medical fields, no methodology for achieving it has been established thus far. Here, we report the whole-body and whole-organ imaging of hypoxia, an important microenvironment, at single-cell resolution using activatable covalent fluorescent probes compatible with tissue clearing. We initially focused on overcoming the incompatibility of fluorescent dyes and refractive index matching solutions (RIMSs), which has greatly hindered the development of fluorescent molecular probes in the field of tissue clearing. The fluorescent dyes compatible with RIMS were then incorporated into the development of activatable covalent fluorescent probes for hypoxia. We combined the probes with tissue clearing, achieving comprehensive single-cell-resolution imaging of hypoxia in a whole mouse body and whole organs.

Endoscopic papillectomy could be rewarding to patients with early stage duodenal ampullary carcinoma?

BACKGROUND/PURPOSE: There is currently no consensus on the use of endoscopic papillectomy (EP) for early stage duodenal ampullary adenocarcinoma. This study aimed to evaluate the feasibility of EP for patients with early stage duodenal ampullary adenocarcinoma. METHODS: Patients who underwent EP for ampullary adenocarcinomas were investigated. Complete and clinical complete resection rates were evaluated. Clinical complete resection was defined as either complete resection or resection with positive or unknown margins but no cancer in the surgically resected specimen, or no recurrence on endoscopy after at least a 1-year follow-up. RESULTS: Adenocarcinoma developed in 30 patients (carcinoma in situ [Tis]: 21, mucosal tumors [T1a(M)]: 4, tumors in the sphincter of Oddi [T1a(OD)]: 5). The complete resection rate was 60.0% (18/30) (Tis: 66.7% [14/21], T1a[M]: 50.0% [2/4], and T1a[OD]: 40.0% [2/5]). The mean follow-up period was 46.8 months. The recurrence rate for all patients was 6.7% (2/30). The clinical complete resection rates of adenocarcinoma were 89.2% (25/28); rates for Tis, T1a(M), and T1a(OD) were 89.4% (17/19), 100% (4/4), and 80% (4/5), respectively. CONCLUSIONS: EP may potentially achieve clinical complete resection of early stage (Tis and T1a) duodenal ampullary adenocarcinomas.

Investigation of geriatric syndromes associated with medication in Japan using insurance claims data.

AIM: Multiple risk factors are involved in geriatric syndrome (GS) occurring in older adults. Although drug therapy often contributes to GS, the specific causes among older adults in Japan remain unclear. In this study, we examined the possible prescribing cascade rate among older outpatients eligible for Late-stage Elderly Health Insurance and elucidated the differences between GS and GS associated with medication (GSAM) trends. METHODS: This retrospective study enrolled patients from health insurance claims data in Japan between October 2018 and March 2019; hospitalized patients were excluded. Two groups were identified among the participants with GS: GS (no use of GS-causing medications) and possible-GSAM (p-GSAM; use of GS-causing medications). The collected data were analyzed using the Bell Curve for Excel, and statistical significance was set at P < 0.05. RESULTS: In total, 137 781 outpatients were enrolled. Of the 32 259 outpatients who did not use GS-causing medications, 7342 were classified into the GS group. Among 105 522 outpatients who used GS-causing medications, 8347 were classified as having p-GSAM. The mean number of prescriptions was significantly higher in the p-GSAM group than in the GS group (P < 0.01). Furthermore, all GS symptoms showed significant differences, with impaired appetite being the most prevalent in the p-GSAM group than in the GS group (P < 0.01). A possible prescribing cascade was suspected in 2826 (33.9%) of 8347 outpatients in the p-GSAM group. CONCLUSION: Impaired appetite in patients taking GS-causing medications might lead to prescribing cascades. Further studies are needed to prevent such prescribing cascades. Geriatr Gerontol Int 2024; 24: 61-67.

IgG4-related pancreatobiliary diseases could be associated with onset of pancreatobiliary cancer: A multicenter cohort study.

BACKGROUND: The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4-SC. METHODS: Patients with AIP and IgG4-SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4-SC using standardized mortality ratio (SMR). RESULTS: This study included 201 patients with AIP and IgG4-SC. The mean follow-up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29-9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20-7.75). The SMR after the diagnosis of AIP and IgG4-SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83-6.99). CONCLUSIONS: Patients with autoimmune pancreatitis and IgG4-SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4-SC have a worse prognosis when they develop pancreatobiliary cancer.

Braided-type stent versus laser-cut-type stent for patients with unresectable distal malignant biliary obstruction: a randomized controlled trial.

BACKGROUND AND AIMS: Fully covered self-expandable metallic stents (SEMSs) are laser-cut (L) or braided (B); however, it remains unclear which approach is more effective for distal malignant biliary obstruction (DMBO). This study compared the clinical outcomes of using L-type and B-type stents because we believe that recurrent biliary obstruction (RBO) is less likely to occur with L-type stents. METHODS: Patients diagnosed with unresectable DMBO were randomly assigned to groups L and B in a stratified block fashion, and outcomes were compared. The primary outcome was the rate of RBO within 1 year; secondary outcomes were adverse events, clinical success rate, time to RBO (TRBO), and overall survival. RESULTS: Of the 60 enrolled participants, 56 (group L, n = 27; group B, n = 29) were included. The rates of RBO within 1 year were 44.4% and 17.2% in groups L and B, respectively (odds ratio, 2.57; 95% confidence interval [CI], 1.045-6.353). Early adverse events, which improved with conservative treatment, included pancreatitis (n = 4) in group L and pancreatitis (n = 3) and cholecystitis (n = 1) in group B (P = .913). The median TRBO (220 days [95% CI, 56-272] vs 418 days [95% CI, 232-454]) was significantly longer in group B than in group L (log-rank test, P = .0118). The median overall survival (group L, 158 days; group B, 204 days) after stenting was not significantly different between groups (P = .8544). CONCLUSIONS: In the setting of DMBO, B-type stents are associated with less recurrent obstruction than L-type stents, although there was no difference in safety. (UMIN Clinical Trials Registry number: UMIN000027239.).

Machine learning versus binomial logistic regression analysis for fall risk based on SPPB scores in older adult outpatients.

Objective: To compare the performance of the diagnostic model for fall risk based on the short physical performance battery (SPPB) developed using commercial machine learning software (MLS) and binomial logistic regression analysis (BLRA). Methods: We enrolled 797 out of 850 outpatients who visited the clinic between March 2016 and November 2021. Patients were categorized into the development (n = 642) and validation (n = 155) datasets. Age, sex, number of comorbidities, number of medications, body mass index (BMI), calf circumference (left-right average), handgrip strength (left-right average), total SPPB score, and history of falls were determined. We defined fall risk by an SPPB score of ≤6 in men and ≤9 in women. The main metrics used for evaluating the machine learning model and BLRA were the area under the curve (AUC), accuracy, precision, recall (sensitivity), specificity, and F-measure. The commercial MLS automatically calculates the parameter range of the highest contribution. Results: The participants included 797 outpatients (mean age, 76.3 years; interquartile range, 73.0-81.0; 288 men). The metrics of the current diagnostic model in the commercial MLS were as follows: AUC = 0.78, accuracy = 0.74, precision = 0.46, recall (sensitivity) = 0.81, specificity = 0.71, F-measure = 0.59. The metrics of the current diagnostic model in the BLRA were as follows: AUC = 0.77, accuracy = 0.75, precision = 0.47, recall (sensitivity) = 0.67, specificity = 0.77, F-measure = 0.55. The risk factors for falls in older adult outpatients were handgrip strength, female sex, experience of falls, BMI, and calf circumference in the commercial MLS. Conclusions: The diagnostic model for fall risk based on SPPB scores constructed using commercial MLS is noninferior to BLRA.

AMPAR receptor inhibitors suppress proliferation of human small cell lung cancer cell lines.

BACKGROUND: Small cell lung cancer (SCLC) is a neuroendocrine tumor with poor prognosis. Neuroendocrine tumors possess characteristics of both nerve cells and hormone-secreting cells; therefore, targeting the neuronal properties of these tumors may lead to the development of new therapeutic options. Among the endogenous signaling pathways in the nervous system, targeting the glutamate pathway may be a useful strategy for glioblastoma treatment. Perampanel, an antagonist of the synaptic glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), has been reported to be effective in patients with glioblastoma. In this study, we aimed to investigate the antitumor effects of AMPAR antagonists in human SCLC cell lines. METHODS: We performed to examine the expression of AMPAR using Western blot and immunohistochemical analysis. The antitumor effects of AMPAR antagonists on human SCLC cell lines were investigated in vitro and in vivo. We also analyzed the signaling pathway of AMPAR antagonists in SCLC cell lines. Statistical analysis was performed by the GraphPad Prism 6 software. RESULTS: We first examined the expression of endogenous AMPAR in six human SCLC cell lines, detecting AMPAR proteins in all of them. Next, we tested the anti-proliferative effect of two AMPAR antagonists, talampanel and cyanquixaline, using SCLC cells in vitro and in vivo. Both AMPAR antagonists inhibited cell proliferation and mitogen-activated protein kinase (MAPK) phosphorylation in SCLC cells in vitro. Further, we observed reduced proliferation of implanted cell lines in an in vivo setting, assessed by Ki-67 immunohistochemistry. Additionally, using immunohistochemical analysis we confirmed AMPAR protein expression in human SCLC samples. CONCLUSION: AMPAR may be a potential therapeutic target for SCLC.

Suprapapillary placement of plastic versus metal stents for malignant biliary hilar obstructions: a multicenter, randomized trial.

BACKGROUND AND AIMS: The efficacy of the suprapapillary placement of inside plastic stents (iPSs) for unresectable malignant hilar biliary obstructions (MHOs) is unknown compared with that of uncovered inside metal stents (iMSs). This randomized controlled trial was designed to evaluate the outcomes of endoscopic placement of these stents for unresectable MHOs. METHODS: This open-label, randomized study was conducted at 12 Japanese institutions. The enrolled patients with unresectable MHOs were allocated to iPS and iMS groups. The primary outcome was defined as the time to recurrent biliary obstruction in patients for whom the intervention was both technically and clinically successful. RESULTS: Among 87 enrollments, 38 patients in the iPS group and 46 patients in the iMS group were analyzed. Technical success rates were 100% (38 of 38) and 96.6% (44 of 46), respectively (P = 1.00). After transferring 1 unsuccessful iMS-group patient to the iPS group (since iPSs were deployed), the clinical success rates were 90.0% (35 of 39) for the iPS group and 88.9% (40 of 45) for the iMS group from a per-protocol analysis (P = 1.00). Among the patients with clinical success, the median times to recurrent biliary obstruction were 250 (95% confidence interval, 85-415) and 361 (95% confidence interval, 107-615) days (log-rank test, P = .34). No differences were detected in rates of adverse events. CONCLUSIONS: This Phase II randomized trial did not show any statistically significant difference in stent patency between suprapapillary plastic versus metal stents. Considering the potential advantages of plastic stents for malignant hilar obstruction, these findings suggest that suprapapillary plastic stents could be a viable alternative to metal stents for this condition.

Low skeletal muscle mass predicts poor prognosis for patients with stage III cervical cancer on concurrent chemoradiotherapy.

OBJECTIVES: The aim of this study was to evaluate whether low skeletal muscle mass before initial treatment is an independent prognostic factor defining overall survival (OS) and progression-free survival (PFS) in patients diagnosed with stage III cervical cancer. METHODS: Body composition and clinicopathologic data were collected retrospectively. Information was extracted and analyzed from the medical records of 92 patients with stage III cervical cancer and undergoing concurrent chemoradiotherapy. Skeletal muscle mass in the L3 region was measured using cross-sectional computed tomography images and corrected for body surface area to calculate the skeletal muscle index (SMI). The primary outcome was OS, and the secondary outcome was PFS. Statistical analyses were performed using the Mann-Whitney U test. The Kaplan-Meier method was used to determine OS and PFS. Univariate and multivariate analyses were performed with Cox proportional hazard ratios. RESULTS: The optimal cutoff value for predicting 5-y survival was 35.6 cm2/m2, defined based on data derived from 24 patients with a low SMI and 68 patients without a low SMI. A low SMI was significantly associated with shorter OS (hazard ratio [HR], 2.470; 95% confidence interval [CI], 1.208-5.053; P = 0.013), with no significant difference in PFS (HR, 1.651; 95% CI, 0.876-3.110; P = 0.121). Multivariate analysis also identified a low SMI as an independent OS-defining prognostic factor (HR, 2.473; 95% CI, 1.151-5.314; P = 0.020). CONCLUSION: A low pretreatment SMI is an independent prognostic factor for OS in patients diagnosed with stage III cervical cancer and treated with concurrent chemoradiotherapy.

Good and evil, more reasons to study UPR.

The unfolded protein response (UPR) pathway, launched by endoplasmic reticulum, maintains endoplasmic reticulum homeostasis. Dysregulated UPR pathway links disease phenotypes, such as proteinuria, inflammation, and fibrosis, in kidney disease. Although accumulating evidence indicates the beneficial impact of the UPR pathway as a therapeutic target for various diseases, including kidney disease, the control of adaptive UPR status is still difficult for disease treatment. This article may give us a new insight into the strategy for sustaining the kidney protective UPR pathway.

Pre-emptive hydration with lactated Ringer's solution could reduce the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis in at-risk patients: Propensity score-matched analysis.

BACKGROUND/PURPOSE: This study aimed to investigate the efficacy of intensive fluid-loading therapy post-endoscopic retrograde cholangiopancreatography (ERCP) for the prevention of post-ERCP pancreatitis (PEP) in at-risk patients. METHODS: In this retrospective study, data of 1200 patients at risk for PEP were investigated. After propensity score matching, 404 patients were included in the normal (n = 202) and hydration (n = 202) groups. On the day of ERCP, patients in both groups were infused with 2000 ml/24 h of fluid before ERCP. Meanwhile, the hydration group received an additional 1000 ml/10 h of lactated Ringer's solution postoperatively. RESULTS: The incidence of PEP was lower in the hydration group (12.4%) than in the normal group (24.3%) (odds ratio [OR]: 0.44; 95% CI: 0.26-0.75, p = .003). The incidence of severe PEP was 2.0% and 6.9% in the hydration and normal groups (OR: 0.27; 95% CI: 0.09-0.84, p = .027), respectively. The incidence of fatal PEP was 0% and 2.0% in the hydration and normal groups (OR: N.A.: p = .123), respectively. CONCLUSIONS: Post-ERCP hydration may be an effective method of preventing PEP, including severe PEP, in at-risk patients.

Request for biliary drainage for IgG4-SC could be waived before steroid administration?

BACKGROUND: In IgG4-related sclerosing cholangitis (IgG4-SC), the necessity of biliary drainage (BD) is unclear. In this study, we aimed to retrospectively investigate the improvement of liver damage and jaundice in cases of IgG4-SC with and without BD, before starting steroids. METHODS: A total of 52 patients with IgG4-SC were investigated in the study. The study endpoints were the normalization rate of alkaline phosphatase (ALP)/total bilirubin (T-Bil) after 8 weeks of steroids, with and without BD. RESULTS: Propensity score matching was performed based on ALP and T-Bil, and 28 patients were included. There were 14 patients each in the BD and non-BD groups. Before initiation of steroids, the mean ALP in the BD group and the non-BD group was 378/461 (P = .541); the mean T-Bil was 2.5/1.8 (P = .401). Eight weeks after initiation of steroids, ALP improvement rate in the BD group/non-BD group was 69.2%/61.5% (P = 1.000), and T-Bil improvement rate was 100%/100% (P = Ns). CONCLUSIONS: Steroids for IgG4-SC could prove effective in improving liver damage and jaundice, regardless of the presence or absence of BD. BD for IgG4-SC aimed to improve jaundice may not be necessary.