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.

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.

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.

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.

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.

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.

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.

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.

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.

Prevention of Shiga toxin 1-caused colon injury by plant-derived recombinant IgA.

Immunoglobulin A (IgA) is a candidate antibody for oral passive immunization against mucosal pathogens like Shiga toxin-producing Escherichia coli (STEC). We previously established a mouse IgG monoclonal antibody (mAb) neutralizing Shiga toxin 1 (Stx1), a bacterial toxin secreted by STEC. We designed cDNA encoding an anti-Stx1 antibody, in which variable regions were from the IgG mAb and all domains of the heavy chain constant region from a mouse IgA mAb. Considering oral administration, we expressed the cDNA in a plant expression system aiming at the production of enough IgA at low cost. The recombinant-IgA expressed in Arabidopsis thaliana formed the dimeric IgA, bound to the B subunit of Stx1, and neutralized Stx1 toxicity to Vero cells. Colon injury was examined by exposing BALB/c mice to Stx1 via the intrarectal route. Epithelial cell death, loss of crypt and goblet cells from the distal colon were observed by electron microscopy. A loss of secretory granules containing MUC2 mucin and activation of caspase-3 were observed by immunohistochemical methods. Pretreatment of Stx1 with the plant-based recombinant IgA completely suppressed caspase-3 activation and loss of secretory granules. The results indicate that a plant-based recombinant IgA prevented colon damage caused by Stx1 in vivo.

Gait Characteristics of Dynapenia, Sarcopenia, and Presarcopenia in Community-Dwelling Japanese Older Women: A Cross-Sectional Study.

Age-related decline in skeletal muscle mass and function are risk factors for reduced walking ability. This study aimed to understand the characteristic gait parameters of presarcopenia (low muscle mass only), dynapenia (low muscle function only), and sarcopenia (low muscle mass and function), which have differing skeletal muscle characteristics. Skeletal muscle mass, grip strength, and gait parameters (walking speed, cadence, step length, step width, gait angle, foot angle, stance time, swing time, and double stance time) were evaluated in 307 older Japanese women. Low muscle function was determined by grip strength and normal walking speed. Participants were assessed and divided into the normal (60.9%, n = 187), presarcopenia (25.7%, n = 79), dynapenia (5.2%, n = 16), and sarcopenia (8.1%, n = 25) groups. When compared to the normal group, the sarcopenia group had significantly slower walking speed and shorter step length (p < 0.05); the dynapenia group had significantly slower walking speed, smaller cadence, shorter step length, wider step width, and longer stance time (p < 0.05); and the presarcopenia group showed no differences. Skeletal muscle function may therefore be more strongly related to reduced walking function in older adults than body composition factors. The decrease in walking function was most pronounced in older women with dynapenia.

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.

Factors Influencing the Development of Mild Cognitive Impairment in Community-Dwelling People Aged 75 Years and Older.

In Asia, including Japan, dementia incidence peaks in older adults over ≥75 years; it is therefore important to detect mild cognitive impairment (MCI), and prevent its onset in this age group. Our study hypothesized that physical and psychological status would be associated with MCI incidence among community-dwelling people aged 75 years and older. The study population comprised 291 such individuals. Participants with a Mini-Mental State Examination score of 28 or more were considered non-MCI, and those with a score of less than 28 and greater than 24 were considered to have MCI. Several other measures were also evaluated, including information about their current medical visits due to diseases, depressive symptom severity, various physical functions (trunk function, 30 s chair-stand test, one-legged stance test, timed up and go test time, 5 m walking time, grip strength, knee-extension strength, and toe-grip strength), and body composition (body fat and skeletal muscle mass). Participants suspected of having MCI had significantly shorter educational histories, higher rates of medical visits due to hypertension, and poorer balance abilities. The results suggest that these indices can be considered screening indicators for detecting MCI in people aged 75 years and older, which may be useful for planning intervention programs for this population.

Geranylgeranyl acetone prevents glutamate-induced cell death in HT-22 cells by increasing mitochondrial membrane potential.

Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protects neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce heat shock proteins (Hsps). Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.

An anatomical study of flexor pollicis longus blood supply with specific reference to volar locking plate surgery.

The purpose of this study was to identify the vessels feeding the FPL to reduce the FPL tendon ruptures related to VLP surgery. The dissections identified the FPL, radial artery (RA) and anterior interosseous artery (AIA). The mean number of branches of the RA and AIA to the FPL was 2.0 and 4.0, respectively. The distance from volar prominence of the radius to the most distal branch of the RA and AIA was 43 mm and 57 mm, respectively. The most distal branch would be frequently injured during VLP surgery because of its proximity to the surgical field.

Extreme genetic signatures of local adaptation during Lotus japonicus colonization of Japan.

Colonization of new habitats is expected to require genetic adaptations to overcome environmental challenges. Here, we use full genome re-sequencing and extensive common garden experiments to investigate demographic and selective processes associated with colonization of Japan by Lotus japonicus over the past ~20,000 years. Based on patterns of genomic variation, we infer the details of the colonization process where L. japonicus gradually spread from subtropical conditions to much colder climates in northern Japan. We identify genomic regions with extreme genetic differentiation between northern and southern subpopulations and perform population structure-corrected association mapping of phenotypic traits measured in a common garden. Comparing the results of these analyses, we find that signatures of extreme subpopulation differentiation overlap strongly with phenotype association signals for overwintering and flowering time traits. Our results provide evidence that these traits were direct targets of selection during colonization and point to associated candidate genes.