Interstitial cystitis/bladder pain syndrome (IC/BPS), which is characterized by bladder pain and irritative voiding symptoms, is a frustrating disease without effective treatment. The cause is still largely not understood, although urothelium ischemia/hypoxia, apoptosis, denudation, and infiltration of inflammatory cells are common histopathological findings. The current uncertainty regarding the etiology and pathology of IC/BPS has a negative impact on its timely and successful treatment; therefore, the development of new treatment modalities is urgently needed. Herein, we present advances in our knowledge on this topic and review the potential application of regenerative medicine for the treatment of IC/BPS. This article provides information on the basic characteristics and clinical evidence of stem cells, platelet-rich plasma (PRP), and low-energy shock waves (LESWs) based on a literature review with a search strategy for articles related to IC/BPS, stem cells, PRP, and LESW published in MEDLINE and PubMed. Stem cells, PRP, and LESW, which modulate inflammatory processes and promote tissue repair, have been proven to improve bladder regeneration, relieve bladder pain, inhibit bladder inflammation, and increase bladder capacity in some preclinical studies. However, clinical studies are still in their infancy. Based on the mechanisms of action of stem cells, PRP, and LESW documented in many preclinical studies, the potential applications of regenerative medicine for the treatment of IC/BPS is an emerging frontier of interest. However, solid evidence from clinical studies remains to be obtained.

Background: Therapeutic interventions for diabetes are most effective when administered in the newly onset phase, yet determining the exact onset moment can be elusive in practice. Spontaneous autoimmune diabetes among NOD mice appears randomly between 12 and 32 weeks of age with an incidence range from 60 to 90%. Furthermore, the disease often progresses rapidly to severe diabetes within days, resulting in a very short window of newly onset phase, that poses significant challenge in early diagnosis. Conventionally, extensive blood glucose (BG) testing is typically required on large cohorts throughout several months to conduct prospective survey. We incorporated ultrasensitive urine glucose (UG) testing into an ordinary BG survey process, initially aiming to elucidate the lag period required for excessive glucose leaking from blood to urine during diabetes progression in the mouse model. Results: The observations unexpectedly revealed that small amounts of glucose detected in the urine often coincide with, sometimes even a couple days prior than elevated BG is diagnosed. Accordingly, we conducted the UG-based survey protocol in another cohort that was validated to accurately identified every individual near onset, who could then be confirmed by following few BG tests to fulfill the consecutive BG + criteria. This approach required fewer than 95 BG tests, compared to over 700 tests with traditional BG survey, to diagnose all the 37–38 diabetic mice out of total 60. The average BG level at diagnosis was slightly below 350 mg/dl, lower than the approximately 400 mg/dl observed with conventional BG monitoring. Conclusions We demonstrated a near perfect correlation between BG + and ultrasensitive UG + results in prospective survey with no lag period detected under twice weekly of testing frequency. This led to the refined protocol based on surveying with noninvasive UG testing, allowing for the early identification of newly onset diabetic mice with only a few BG tests required per mouse. This protocol significantly reduces the need for extensive blood sampling, lancet usage, labor, and animal distress, aligning with the 3Rs principle. It presents a convenient, accurate, and animal-friendly alternative for early diabetes diagnosis, facilitating research on diagnosis, pathogenesis, prevention, and treatment.

BACKGROUND/AIMS: Detailed characterization of the ultrastructural morphology of intercellular space in gastroesophageal reflux disease has not been fully studied. We aimed to investigate whether subtle alteration in intercellular space structure and tight junction proteins might differ among patients with gastroesophageal reflux disease. METHODS: Esophageal biopsies at 5 cm above the gastroesophageal junction were obtained from 6 asymptomatic controls, 10 patients with reflux symptoms but without erosions, and 18 patients with erosions. The biopsies were morphologically evaluated by transmission electron microscopy, and by using immunohistochemistry for tight junction proteins (claudin-1 and claudin-2 proteins). RESULTS: The expressions of tight junction proteins did not differ between asymptomatic controls and gastroesophageal reflux disease patients. In patients with gastroesophageal reflux disease, altered desmosomal junction morphology was only found in upper stratified squamous epithelium. Dilated intercellular space occurred only in upper stratified squamous epithelium and in patients with erosive esophagitis. CONCLUSIONS: This study suggests that dilated intercellular space may not be uniformly present inside the esophageal mucosa and predominantly it is located in upper squamous epithelium. Presence of desmosomal junction alterations is associated with increased severity of gastroesophageal reflux disease. Besides dilated intercellular space, subtle changes in ultrastructural morphology of intercellular space allow better identification of inflamed esophageal mucosa relevant to acid reflux.
Biopsy ; Claudin-2 ; Epithelium ; Esophagogastric Junction ; Esophagus ; Extracellular Space ; Gastroesophageal Reflux ; Humans ; Immunohistochemistry ; Intercellular Junctions ; Microscopy, Electron, Transmission ; Mucous Membrane ; Tight Junction Proteins ; Tight Junctions

PURPOSE: Many studies supported that vegetarians have a lower risk of cardiac diseases and mortality, partly due to better blood pressure and serum cholesterol profiles. However, the inflammatory markers, especially lipoprotein-associated phospholipase A2 (Lp-PLA2), have not been well-studied. This study aimed to compare inflammatory markers and conventional risk factors between vegetarians and omnivores. MATERIALS AND METHODS: One hundred and seventy-three vegetarians and 190 omnivores were studied. Fasting blood samples were obtained to compare levels of glucose, total cholesterol, triacylglycerol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, homocysteine, Lp-PLA2 activity, and high-sensitivity C-reactive protein (hs-CRP). RESULTS: Vegetarians had higher serum levels of the following markers: hs-CRP (1.8 +/- 3.4 vs. 1.2 1.8 mg/L, respectively; p = 0.05), homocysteine (9.39 +/- 3.22 vs. 7.62 +/- 2.41 micromol/L, respectively; p < 0.01), and triacylglycerol (96.91 +/- 59.56 vs. 84.66 +/- 43.24 mg/dL, respectively; p < 0.05). Vegetarians also had lower levels of Lp-PLA2 (18.32 +/- 7.19 10-3 micromol/min/mL vs. 20.22 8.13 10-3 micromol/min/mL; p < 0.05), total cholesterol (180.62 +/- 36.55 mg/dL vs. 192.73 +/- 36.57 mg/dL; p < 0.01), LDL cholesterol (118.15 +/- 32.8 vs. 126.41 +/- 34.28 mg/dL; p < 0.05), and HDL cholesterol (55.59 +/- 13.30 vs. 62.09 +/- 14.52 mg/dL, p < 0.01). Multivariate analyses demonstrated that a vegetarian diet increases the chances for high serum hs-CRP and low Lp-PLA2 activity. CONCLUSION: In addition to lower total cholesterol, LDL-cholesterol, and HDL-cholesterol, Taiwanese female vegetarians have lower serum Lp-PLA2 activity but higher levels of hs-CRP, homocysteine, and triacylglyerol. It might be due to geographic differences of vegetarian diets, and further studies are needed.
1-Alkyl-2-acetylglycerophosphocholine Esterase/*blood ; Adult ; Asian Continental Ancestry Group ; C-Reactive Protein/metabolism ; Cholesterol/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; *Diet, Vegetarian ; Female ; Homocysteine/blood ; Humans ; Middle Aged ; Multivariate Analysis ; Risk Factors ; Taiwan ; Triglycerides/blood

Background: and Purpose Migraine is a condition that is often observed to run in families, but its complex genetic background remains unclear. This study aimed to identify the genetic factors influencing migraines and their potential association with the family medical history. Methods: We performed a comprehensive genome-wide association study of a cohort of 1,561 outpatients with migraine and 473 individuals without migraine in Taiwan, including Han Chinese individuals with or without a family history of migraine. By analyzing the detailed headache history of the patients and their relatives we aimed to isolate potential genetic markers associated with migraine while considering factors such as sex, episodic vs. chronic migraine, and the presence of aura. Results: We revealed novel genetic risk loci, including rs2287637 in DEAD-Box helicase 1 and long intergenic non-protein coding RNA 1804 and rs12055943 in engulfment and cell motility 1, that were correlated with the family history of migraine. We also found a genetic location downstream of mesoderm posterior BHLH transcription factor 2 associated with episodic migraine, whereas loci within the ubiquitin-specific peptidase 26 exonic region, dual specificity phosphatase 9 and pregnancy-upregulated non-ubiquitous CaM kinase intergenic regions, and poly (ADP-ribose) polymerase 1 and STUM were linked to chronic migraine. We additionally identified genetic regionsassociated with the presence or absence of aura. A locus between LINC02561 and urocortin 3 was predominantly observed in female patients. Moreover, three different single-nucleotide polymorphisms were associated with the family history of migraine in the control group. Conclusions This study has identified new genetic locations associated with migraine and its family history in a Han Chinese population, reinforcing the genetic background of migraine. The findings point to potential candidate genes that should be investigated further.

BACKGROUND: To date, there is no study comparing outcomes between post-total knee replacement genu recurvatum and fixed flexion. This study aims to provide data that will help in deciding which side to err on when neutral extension is not achieved. METHODS: A prospective cohort study of primary total knee arthroplasties was performed, which compared the 6-month and 2-year clinical outcomes between fixed flexion and genu recurvatum deformities at 6 months. RESULTS: At 6 months, knees in genu recurvatum did better than knees in fixed flexion deformity in terms of knee flexion. However, at 2 years, knees in fixed flexion deformity did better in terms of knee scores and showed better improvement in the degree of deformity. CONCLUSIONS: We conclude that it is better to err on the side of fixed flexion deformity if neutral alignment cannot be achieved.
Aged ; Arthroplasty, Replacement, Knee/*adverse effects/*statistics & numerical data ; Female ; Humans ; Knee Joint/*physiopathology/*surgery ; Male ; Middle Aged ; Prospective Studies ; Range of Motion, Articular ; Treatment Outcome

PURPOSE: This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). MATERIALS AND METHODS: Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. RESULTS: Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. CONCLUSION: TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.
Adenocarcinoma ; Adrenal Insufficiency ; Adult ; Anorexia ; Ascites ; Asian Continental Ancestry Group* ; Asthenia ; Disease Progression ; Esophagogastric Junction ; Gastrointestinal Neoplasms ; Guanylate Cyclase* ; Half-Life ; Hemorrhage ; Humans ; Hypertension ; Infusions, Intravenous ; Maximum Tolerated Dose ; Nausea ; Neutropenia ; Pharmacokinetics ; Stomach

Objective: Predicting disease relapse and early intervention could reduce symptom severity. We attempted to identify potential indicators that predict the duration to next admission for an acute affective episode in patients with bipolar I disorder. Methods: We mathematically defined the duration to next psychiatric admission and performed single-variate regressions using historical data of 101 patients with bipolar I disorder to screen for potential variables for further multivariate regressions. Results: Age of onset, total psychiatric admissions, length of lithium use, and carbamazepine use during the psychiatric hospitalization contributed to the next psychiatric admission duration positively. The all-in-one found that hyperlipidemia during the psychiatric hospitalization demonstrated a negative contribution to the duration to next psychiatric admission; the last duration to psychiatric admission, lithium and carbamazepine uses during the psychiatric hospitalization, and heart rate on the discharge day positively contributed to the duration to next admission. Conclusion We identified essential variables that may predict the duration of bipolar I patients’ next psychiatric admission. The correlation of a faster heartbeat and a normal lipid profile in delaying the next onset highlights the importance of managing these parameters when treating bipolar I disorder.

Objective: Problematic use of social media (PUSM) may affect sleep quality and self-stigma in people with schizophrenia and consequently reduce their quality of life (QoL). This longitudinal study investigated if sleep quality and self-stigma mediated relationships between PUSM and QoL. Methods: One-hundred-and-ninety-three outpatients with schizophrenia were recruited from a psychiatric center in Taiwan from April 2019 to August 2021 and participated in a longitudinal study at intervals of three months between measurements. QoL was assessed using the World Health Organization Quality of Life Questionnaire Brief Version; sleep quality using the Pittsburgh Sleep Quality Index; self-stigma using the Self-Stigma Scale-Short; and PUSM using the Bergen Social Media Addiction Scale. Via SPSS 20.0, general estimating equation models assessed temporal associations between variables. Via R software, mediating effects of self-stigma and sleep quality were examined through Monte Carlo simulations with 20,000 repetitions. Results: Mean scores of physical, psychological, social and environmental QoL ranged from 11.86 to 13.02. Mean scores of sleep quality and self-stigma were 9.1±4.5 and 2.2±0.8, respectively. Sleep quality and self-stigma were directly related to QoL (p<0.001) and mediated indirect relationships between PUSM and all components of QoL with a range of 95% confidence intervals spanning from -0.0591 to -0.0107 for physical QoL; -0.0564 to -0.0095 for psychological QoL; -0.0292 to -0.0035 for social QoL; and -0.0357 to -0.0052 for environmental QoL. Conclusion Sleep quality and self-stigma mediated relationships between PUSM and QoL in people with schizophrenia. Developing interventions targeting PUSM, sleep, and self-stigma may help improve QoL in people with schizophrenia.

Background: and Purpose This study aimed to investigate early changes in interstitial fluid (ISF) flow in patients with severe carotid stenosis after carotid angioplasty and stenting (CAS). Methods: We prospectively recruited participants with carotid stenosis ≥80% undergoing CAS at our institute between October 2019 and March 2023. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), and the Mini-Mental State Examination (MMSE) were performed 3 days before CAS. MRI with DTI and MMSE were conducted within 24 hours and 2 months after CAS, respectively. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated from the DTI data to determine the ISF status. Increments were defined as the ratio of the difference between post- and preprocedural values to preprocedural values. Results: In total, 102 participants (age: 67.1±8.9 years; stenosis: 89.5%±5.7%) with longitudinal data were evaluated. The DTI-ALPS index increased after CAS (0.85±0.15; 0.85 [0.22] vs. 0.86±0.14; 0.86 [0.21]; P=0.022), as did the MMSE score (25.9±3.7; 24.0 [4.0] vs. 26.9±3.4; 26.0 [3.0]; P<0.001). Positive correlations between increments in the DTI-ALPS index and MMSE score were found in all patients (rs=0.468; P<0.001). Conclusion An increased 24-hour post-CAS DTI-ALPS index suggests early improvement in ISF flow efficiency. The positive correlation between the 24-hour DTI-ALPS index and 2-month MMSE score increments suggests that early ISF flow improvement may contribute to long-term cognitive improvement after CAS.