SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process.

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.

Catalytic Enantioselective Synthesis of N-C Axially Chiral Sulfonamides through Chiral Palladium-Catalyzed N-Allylation.

In the presence of ( S,S)-Trost ligand and (allyl-Pd-Cl)2 catalyst, the reaction of allyl acetate with the anionic species prepared from various N-(2- tert-butylphenyl)sulfonamides and NaH proceeded in an enantioselective manner (up to 95% ee) to give optically active N-allylated sulfonamide derivatives possessing an N-C axially chiral structure in high yields.

Volar locking plates not touching the flexor pollicis longus tendon appear as prominences on radiographs: a cadaver study.

BACKGROUND: Plate protrusion is a risk factor for flexor pollicis longus (FPL) rupture following volar locking plate (VLP) surgery. However, plate prominence on follow-up radiographs is common. We hypothesised that a VLP that does not touch the FPL tendon can appear as a plate prominence projected over the volar ridge on lateral radiographs. MATERIALS AND METHODS: We studied six current designs of widely used plates in formalin-fixed cadavers. Each plate was placed in six cadavers. We analysed 36 different plate-cadaver combinations. The main aim of plate fixation was to position the plate in the most distal position without FPL tendon contact. Radiographs were obtained using fluoroscopy. We evaluated plate prominence from the volar ridge according to the Soong grading system. RESULTS: Soong grades 0 (plate did not extend beyond volar ridge), 1 (plate protruded beyond volar ridge) and 2 (plate directly on or located beyond the volar ridge) were observed in 23 (63.9%), 9 (25.0%) and 4 (11.1%) cadavers, respectively. VariAx, DVR and VALCP showed grade 1 prominence, whereas Acu-Loc2, HYBRIX and MODE showed grade 2 prominence. CONCLUSIONS: Implant protrusion was observed in 36% of plate-cadaver combinations, even if the plate did not touch the FPL. Estimating the risk of FPL rupture using lateral radiographs alone is likely insufficient. Our findings can be applied to accurately identify the presence of implant prominence following VLP surgery.

[Infectivity Titers of Each Component of the Influenza Virus in the Live Vaccine Purchased from a Parallel Import Distributing System].

Currently in Japan, the only approved influenza vaccine is the inactivated vaccine which is injected subcutaneously. On the other hand, there is a live vaccine available elsewhere in the world. Flumist, an intranasal influenza live vaccine which contains four strains of infectious viruses, has been used in the United States for more than 10 years; the vaccine has been found effective in clinical trials, while it has some limitations such as those on subjects for the administration, strict storage conditions, relatively short expiration date etc. It is not yet approved in Japan, but available through personal import by some medical institutions, and prescribed based on the decision of the doctor. However, in Japan, there is no checking system whether the vaccine contains appropriate amounts of infectious viruses or not. In the present study, we purchased 2013-14 and 2014-15 years' lots of Flumist from a parallel importer and measured the amount of infectious viruses of each component of them using the focus assay. Consequently, for type A influenza viruses, the titers of both of H1N1pdm09 and H3N2 viruses in the 2013-14's lot were 1/30 of the lower limit of those shown in the package insert and 1/10 in 2014-15's lot, while those of type B viruses, both of B/Massachusetts and B/Brisbane viruses marginally cleared the lower limit. The digital PCR analysis showed that the absolute genome copy numbers of type A viruses were 1/10 of those of type B viruses. The relatively higher titer of B/Massachusetts also gradually decreased over time during its storage at 4°C and finally reached the lower limit at about one week before the expiration date. In case it is approved officially in the future to be used in Japan, some studies will be required to elucidate the minimum viral titers of the components necessary for effective live vaccine. In addition, there should be a system to check the titer during the distribution process in Japan.

AI-based Apoptosis Cell Classification Using Phase-contrast Images of K562 Cells.

BACKGROUND/AIM: This study aimed to automate the classification of cells, particularly in identifying apoptosis, using artificial intelligence (AI) in conjunction with phase-contrast microscopy. The objective was to reduce reliance on manual observation, which is often time-consuming and subject to human error. MATERIALS AND METHODS: K562 cells were used as a model system and apoptosis was induced following administration of gamma-secretase inhibitors. Fluorescence staining was applied to detect DNA fragmentation and caspase activity. Cell images were obtained using both phase-contrast and fluorescence microscopy. Two AI models, Lobe(R) and a server-based ResNet50, were trained using these images and evaluated using F-values through five-fold cross-validation. RESULTS: Both AI models demonstrated effectively categorized individual cells into three groups: caspase-negative/no DNA fragmentation, caspase-positive/no DNA fragmentation, and caspase-positive/DNA fragmentation. Notably, the AI models' ability to differentiate cells relied on subtle variations in phase-contrast images, potentially linked to changes in refractive indices during apoptosis progression. Both AI models exhibited high accuracy, with the server-based ResNet50 model showing improved performance through repeated training. CONCLUSION: This study demonstrates the potential of AI-assisted phase-contrast microscopy as a powerful tool for automating cell classification, especially in the context of apoptosis research and the discovery of anticancer substances. By reducing the need for manual labor and enhancing classification accuracy, this approach holds promise for expediting high-throughput cell screening, significantly contributing to advancements in medical diagnostics and drug development.

Central Sensitization-Related Symptoms and Influencing Factors on Health-Related Quality of Life among Frail Older Adults in Senior Day Care Centers: A Cross-Sectional Study.

The recent increase in the number of frail older adults has led to increased attention being paid to care services in communities such as senior day care centers. Maintaining health-related quality of life (HRQOL) in frail older adults is important for managing long-term care. The purpose of this study was to comprehensively explore the impact of physical, mental, and cognitive factors, particularly central sensitization-related symptoms (CSSs), on the HRQOL among frail older adults in senior day care centers. HRQOL, physical, mental, and cognitive factors, and severity of CSSs were comprehensively measured using validated methods. Correlation and multiple regression analyses were used to examine factors affecting HRQOL among frail older adults in senior day care centers. The results showed that the timed up and go test significantly affected the HRQOL among frail older adults at senior day care centers. Additionally, knee extension muscle strength, number of pain sites, depressive tendencies, and CSS severity showed a significant negative correlation with HRQOL but were not significant influencing factors. This suggests that functional mobility assessments and approaches are important for maintaining and improving the HRQOL in frail older adults at senior day care centers.

The Influence of Physical, Mental, and Cognitive Factors on Health-Related Quality of Life among Community-Dwelling Older Adults: A Focus on Central Sensitization-Related Symptoms.

Most older adults wish to maintain independence in their familiar communities. However, many experience pain and pain-related disabilities which reduce their health-related quality of life (HRQOL), leading to increased hospitalizations and mortality. This study aimed to determine the impact of physical, mental, and cognitive factors, particularly central sensitization-related symptoms (CSS), on the HRQOL of community-dwelling older adults. A total of 206 participants were included in the analysis, which measured HRQOL, basic attributes, physical functions and body pain, mental factors, cognitive factors, and CSS severity using validated tools. A correlation analysis was used to examine the association between HRQOL and each measure. Furthermore, multiple regression analysis (forced entry method) was performed to identify the factors influencing the HRQOL. The study found that pain intensity and CSS severity significantly influenced the HRQOL among community-dwelling older adults. The higher the pain intensity and CSS severity, the lower their HRQOL. The participants had mild pain and CSS, demonstrating the need to monitor, address, and treat even non-severe issues in community-dwelling older adults. This association, revealed for the first time in this study, suggests that approaches to reduce pain and CSS are important for maintaining and improving the HRQOL of community-dwelling older adults.

Relationship between Subjective Grip Strength and Physical Functioning among Community-Dwelling Older Women.

This study investigated the relationship between subjective grip strength and physical function in community-dwelling older women. Subjective grip strength was assessed using a questionnaire, and physical function and body composition were compared between groups with strong and weak subjective grip strength. Additionally, the two groups were compared in those with mild cognitive impairment (MCI) and those with normal cognitive function, respectively. The results showed significant differences in grip strength (p < 0.001), 30 s chair-stand (CS-30) test (p = 0.039), timed up-and-go (TUG) test (p = 0.027), maximal gait speed (p = 0.029), and skeletal muscle mass (p < 0.001). Older adults with normal cognitive function showed significant differences in grip strength (p < 0.001), quadriceps muscle strength (p < 0.009), one-leg standing time (p = 0.041), CS-30 (p = 0.002), TUG (p = 0.014), gait speed (p = 0.006), and skeletal muscle mass (p = 0.003). Older adults with low subjective grip strength had lower physical function and skeletal muscle mass. However, no items showed significant differences between groups among older adults with MCI. Thus, subjective grip strength is an indicator of an overall decline in physical function and a reduction in skeletal muscle mass in older adults, and cognitive function should be considered when assessing subjective grip strength in older adults.

Effect of concomitant use of valproic acid during clozapine initiation on clozapine-induced inflammation among Japanese patients with schizophrenia.

During clozapine initiation, titration speed and concomitant valproate administration have been reported as risk factors for clozapine-induced fever and myocarditis. We tested the risk of concomitant valproate administration by stratifying patients according to titration rate. Concomitant valproate use was only associated with increased inflammatory adverse events in the slower titration group. The frequency of inflammatory adverse events was approximately 30 % during faster titration, regardless of concomitant valproate administration. However, the faster titration group with valproate had a higher frequency of severe adverse effects such as myocarditis. Clinicians should avoid concomitant valproate administration during clozapine initiation, regardless of titration rate.

Patterns of C-reactive protein trends during clozapine titration and the onset of clozapine-induced inflammation: a case series of weekly and daily C-reactive protein monitoring.

Background: International guidelines for clozapine titration recommend measuring C-reactive protein (CRP) weekly for 4 weeks after clozapine initiation to prevent fatal inflammatory adverse events, including myocarditis. However, limited evidence exists regarding whether weekly CRP monitoring can prevent clozapine-induced inflammation. Aims: We examined the relationship between CRP trends and the development of clozapine-induced inflammation. We also explored the usefulness and limitations of CRP monitoring during clozapine titration. Method: This study presents 17 and 4 cases of weekly and daily CRP monitoring during clozapine initiation, respectively. Results: Among 17 patients with weekly CRP measurements, 7 had fever. Elevated CRP levels were detected before the onset of fever in two of the seven patients. Of the five remaining patients, the CRP levels on a previous test had been low; however, the fever developed suddenly. Of the 10 patients with no fever under weekly CRP monitoring, three had elevated CRP levels >3.0 mg/dL. Refraining from increasing the clozapine dose may have prevented fever in these patients. Among four patients with daily CRP measurements, two became febrile. In both cases, CRP levels increased almost simultaneously with the onset of fever. Conclusion: Weekly and daily CRP monitoring during clozapine titration is valuable for preventing clozapine-induced inflammation, assessing its severity, and guiding clozapine dose adjustments. Weekly CRP monitoring may not adequately predict clozapine-induced inflammation in some cases. Consequently, clinicians should be aware of the sudden onset of clozapine-induced inflammation, even if CRP levels are low. Daily CRP monitoring is better for detecting clozapine-induced inflammation.

Finite element analysis predictions in the canine lumbar spine are useful and correlate with ex vivo biomechanical studies.

OBJECTIVE: To verify the validity of finite element analysis (FEA) predictions obtained from a canine lumbar segment model in comparison with experimental biomechanical testing results from the same subjects. ANIMALS: 6 healthy beagle dogs were euthanized for other purposes. METHODS: The L1-2 and L5-6 segments were harvested from euthanized animals and subjected to rotation tests and compression tests, respectively, using both ex vivo mechanical testing and FEA. For each method, we recorded the maximum torque value and angle of vertebral body rotation at rupture observed in rotation tests, as well as the maximum stress value and displacement of the vertebral body endplate at rupture measured from compression tests. We then calculated Pearson's correlation coefficient to determine correlations between the angle of gyration and displacement at rupture determined by mechanical testing and FEA. The study started on March 26, 2021, and ended on March 18, 2023. RESULTS: For the rotation test, correlation coefficients for the maximum torque and rotation angle of the vertebral body at rupture were r = 0.92 and 0.96, respectively. For the compression test, correlation coefficients for the maximum stress and displacement of the vertebral body endplate at rupture were r = 0.73 and 0.94, respectively. All results showed strong correlations between the FEA predictions and ex vivo mechanical test results. CLINICAL RELEVANCE: These findings suggest that FEA predictions are sufficiently reliable for ex vivo mechanical test results for biomechanical studies of canine lumbar segment models.

Vertebral fixation does not affect recovery or recurrence of cervical intervertebral disc herniation in small dogs (< 15 kg).

OBJECTIVE: To compare the prognosis of small dogs with cervical intervertebral disc herniation (C-IVDH) when treated with ventral slot decompression (VSD) alone or with concomitant vertebral fixation (VF). ANIMALS: Small dogs (n = 303) weighing < 15 kg diagnosed with C-IVDH and treated with VSD. PROCEDURES: We recorded signalment, cervical myelopathy grade, surgical site, use of VF, degree of adjacent disc degeneration, recovery, recurrence, recurrence site, and postoperative course, including the time elapsed from recovery to recurrence. We examined factors associated with recovery and recurrence during the 30-month postoperative period using multivariate logistic regression analysis. RESULTS: VF did not affect recovery (P = .79). However, nonchondrodystrophic breeds had poorer recovery (OR, 5.89; P = .023) than chondrodystrophic breeds, and a higher preoperative cervical myelopathy grade (grade 3 or 4) was associated with poorer recovery (OR, 7.09 or 3.46, respectively; P = .019 or .042, respectively), compared with grade 1. VF did not affect recurrence (P = .79); however, increasing age was associated with recurrence (OR, 1.79; P = .001). CLINICAL RELEVANCE: In small dogs weighing < 15 kg, there was no difference in postoperative recovery and recurrence rates after VSD with or without concomitant VF. Therefore, in small dogs with C-IVDH, even if the slot volume is increased to remove sufficient disc material during VSD, a good prognosis can be achieved with or without VF.

Slower clozapine titration than the official Japanese protocol led to fewer inflammatory adverse effects: A retrospective chart review of seven hospitals.

BACKGROUND: Higher frequencies of inflammatory adverse effects of clozapine have been reported in Japan. As the international titration protocol for Asians has set slower dose titration than the Japanese package insert, we hypothesized that a dose titration speed slower than the recommendation of the guideline would be associated with fewer inflammatory-related adverse events. METHODS: The medical records of all 272 patients who were first started on clozapine at seven hospitals between 2009 and 2023 were studied retrospectively. Of those, 241 were included in the analysis. The patients were divided into two groups regarding whether the titration speed was faster or slower than the guideline for Asians. The incidence of inflammatory adverse events with clozapine was compared between the groups. RESULTS: The frequency of inflammatory adverse events was 34 % (37/110) in the faster titration group and 13 % (17/131) in the slower titration group, and a significant difference was observed by Fisher exact test (odds ratio 3.38; 95 % confidence interval 1.71-6.91; p < 0.001). Serious adverse effects, fever for more than five days, and clozapine discontinuation were significantly more frequent in the faster titration group. Logistic regression analysis indicated significantly more inflammatory adverse events in the faster titration group (adjusted odds ratio 4.01; 95 % confidence interval 2.02-7.87; p < 0.001) considering age, sex, body mass index, concomitant valproic acid, and smoking as confounding factors. CONCLUSION: Clozapine-induced inflammatory adverse events were less frequent in Japanese individuals when a titration rate was more gradual than the protocol recommended in the Japanese package insert.

Slower clozapine titration is associated with delayed onset of clozapine-induced fever among Japanese patients with schizophrenia.

Clozapine-induced fever marks the beginning of its inflammatory and potentially life-threatening adverse effects, such as myocarditis. We retrospectively analyzed the correlation between clozapine titration rate and fever onset date in 254 Japanese patients, including 55 with treatment-resistant schizophrenia who developed clozapine-induced fever. Pearson's product-moment correlation indicated a significant delay in the fever onset date with slower titration. Most fever onset cases occurred within 4 weeks, even with slow titration. Therefore, clinicians should remain vigilant in monitoring clozapine-induced fever within 4 weeks of clozapine initiation, regardless of the titration rate.

Characterizing Granulocytopenia Associated with Thiamazole in Patients with Hyperthyroidism Based on Real-World Data from the MID-NET in Japan.

Despite the requirement of routine blood tests during thiamazole treatment in Japan, granulocytopenia among patients treated with thiamazole has been occasionally reported to the Pharmaceuticals and Medical Devices Agency (PMDA). To characterize granulocytopenia in patients with thiamazole in Japan, the effects of routine blood tests were examined in a cohort of new users of thiamazole or propylthiouracil utilizing the MID-NET. The occurrence of granulocytopenia (neutrophil count ≤ 1,500/µL) in a given period was compared between patients with and without blood test results prior to the period. The trend in neutrophil count during thiamazole treatment was also compared between patients with and without granulocytopenia. A nested case-control study based on the cohort was conducted to identify potential risk factors for granulocytopenia during thiamazole treatment. In the new user cohort including 4,371 patients treated with thiamazole, the occurrence of granulocytopenia in patients who had undergone blood tests at all previous periods was similar or higher than that among those who had not undergone blood test in all previous periods (e.g., adjusted odds ratio in period 2 was 1.63). The neutrophil count was relatively lower in the group of patients with granulocytopenia even before the occurrence of granulocytopenia. In a nested case-control study, an upward tendency of the risk was observed when a patient was co-prescribed anti-arrhythmic drugs or antiulcer drugs with thiamazole. The characteristics of granulocytopenia during thiamazole treatment elucidated in this study should be recognized in clinical practice for the proper use of thiamazole.

Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12.

Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with bone-producing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-kappaB ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common gamma chain or DNAX-activating protein (DAP)12 (also referred to as KARAP or TYROBP) that associates with the cognate immunoreceptors. Here, we show that a third adaptor, YINM costimulatory motif-harboring DAP10, triggers osteoclastogenesis and bone remodeling. DAP10-deficient (DAP10(-/-)) mice become osteopetrotic with age, concomitant with a reduction in osteoclasts. The DAP10-associating receptor was identified as myeloid DAP12-associating lectin-1 (MDL-1), whose physiologic function has not been found. MDL-1-mediated stimulation of osteoclast precursor cells resulted in augmented osteoclastogenesis in vitro. MDL-1 associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, where DAP10 association depends almost entirely on DAP12, suggesting a formation of MDL-1-DAP12/DAP10 trimolecular complexes harboring ITAM/YINM stimulatory/costimulatory motifs within a complex that could be a novel therapeutic target for skeletal and inflammatory diseases.

Successful rechallenge with clozapine after discontinuation due to drug-induced pneumonia: A case report.

Background: There have been a limited number of case reports of clozapine-induced pneumonia. Few have reported rechallenging of clozapine after discontinuation due to the side-effect. Case Presentation: A 43-year-old man was diagnosed with schizophrenia after developing auditory hallucinations and delusions of persecution and reference. After diagnosing him with treatment-resistant schizophrenia, clozapine was started. From a starting dose of 12.5 mg/day, we increased it by 25 mg every 2-3 days to reach 150 mg/day by Day 15. On Day 17, his body temperature suddenly rose to 39.6°C (103.3°F) without any other apparent physical symptoms. Blood biochemistry testing showed elevated C-reactive protein (CRP) and high counts of leukocytes and neutrophils, but not eosinophils. Chest computed tomography revealed ground-glass opacities in the lower lobes of both lungs. Suspecting bacterial pneumonia, we started him on levofloxacin 500 mg/day. However, pneumonia exacerbated, and eosinophilia became apparent 5 days after the onset of fever. We suspected acute eosinophilic pneumonia induced by clozapine and discontinued its administration the same day. The patient clinically recovered the next day after stopping clozapine. After stopping clozapine, his psychiatric symptoms, such as persecutory/referential delusions, irritability, and polydipsia, became worse. We decided to rechallenge with clozapine in incremental doses slower than the standard protocol, along with careful monitoring of CRP and eosinophil counts. Pneumonia has not recurred, and his psychiatric symptoms have been well managed. Conclusion: Our experience suggests that some patients with inflammatory reactions to clozapine can still take the drug if it is reintroduced with caution.