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This report describes the first documented case of subcutaneous infection due to Cryptococcus flavescens in a dog. The chief symptoms of the patient dog were abscessed lesions on the dorsal muzzle, right eyelid, and lower jaw. Biopsy specimens from the lesions on the dorsal muzzle and lower jaw showed pyogranulomatous inflammation with numerous yeast cells. The patient dog was diagnosed with a subcutaneous fungal infection and orally received 5 mg/kg itraconazole once a day for 2 months, the abscesses disappeared. After 1 month at the end of treatment, the skin lesions did not redevelop. Isolates from the biopsy specimens were identified as C. flavescens by molecular analysis as well as morphologic and biochemical examination, indicating that C. flavescens is a potential canine pathogen.

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 106 iPSC within 7 weeks was 1.8‐4.0 × 109. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies. This translational study aimed to develop anti–GPC3 CAR‐expressing NK/ILC cells derived from HLA‐homozygous iPSC clone as an effective cell therapy against disseminated ovarian tumors and to assess the clinical cell manufacturing and pre–clinical aspects of the therapy, including safety and efficacy. Those aspects of the therapy clarified in the study provide perspective for the planned clinical trial.

D-Alanine, a rare enantiomer of alanine, can potentially alleviate the worsening of viral infections and maintain circadian rhythm. This study aimed to analyze the kinetics of D-Alanine upon oral intake. Five healthy volunteers were administered D-Alanine as a single oral dose at 11,236 or 33,708 µmoL (1–3 g). Upon intake of the lower dose, the plasma level of D-Alanine reached its peak concentration of 588.4 ± 40.9 µM with a peak time of 0.60 ± 0.06 h. The compartment model estimated the clearance of D-Alanine at 12.5 ± 0.3 L/h, or 208 ± 5 mL/min, distribution volume of 8.3 ± 0.7 L and half-life of 0.46 ± 0.04 h, suggesting a rapid clearance of D-Alanine. The peak concentration and area under the curve increased proportionally upon intake of the higher dose, while the clearance, distribution volume and half-life did not. The urinary ratio of D-Alanine per sum of D- and L-Alanine reached its peak of nearly 100%, followed by a slow decline. The peak time of the urinary ratio was 1.15 ± 0.15 h, showing a time lag of blood to urine excretion. Fractional excretion, a ratio of the clearance of a substance per a standard molecule in kidney, of D-Alanine increased from 14.0 ± 5.8% to 64.5 ± 10.3%; the latter corresponded to the urinary clearance of D-Alanine as about 77 mL/min for an adult, with a peak time of 1.90 ± 0.56 h. D-Alanine was quickly absorbed and appeared in blood, followed by urinary excretion. This kinetic analysis increases our fundamental knowledge of the oral intake of D-Alanine for the chronic dosing.Trial number: #UMIN000050865.Date of registration: 2023/6/30.

Imbalances between excitatory and inhibitory (E/I) neurotransmitters in the brain may contribute to the pathophysiology of bipolar disorder (BD). Proton magnetic resonance spectroscopy ( H-MRS) measures glutamatergic neurometabolites and gamma-aminobutyric acid (GABA) as indices of E/I neurotransmission. Previous meta-analyses reported higher glutamatergic neurometabolite levels in the medial prefrontal cortex of BD, but findings on GABA levels in the anterior cingulate cortex (ACC) of BD patients remain inconsistent. We conducted a cross-sectional study using H-MRS to compare GABA and glutamate plus glutamine (Glx) levels in the dorsal ACC (dACC) of 27 patients with BD and 27 age- and sex-matched healthy controls (HCs). We used the H-MRS (3 T MRI, MEGAPRESS, 256 averages, TR = 1500 ms, TE = 68 ms). Clinical symptoms were evaluated using standardized rating scales. Statistical analyses were conducted to assess group differences in neurometabolite levels and to explore the associations between these neurometabolite levels and clinical symptom severity within the BD group. No significant differences in dACC GABA levels, Glx levels, or Glx/GABA ratio were observed between the BD and HC groups. There were no significant differences within the BD group based on BD subtype (I or II) or clinical phase (depression or euthymic). Patients with lithium treatment had higher GABA levels compared to those without. Our results suggest that GABAergic function in the dACC may not play a pivotal role in the pathophysiology of BD. Given possible GABAergic dysregulation in BD, further research using alternative methodologies is warranted to elucidate the pathological basis.

ABSTRACT Background Imbalances between excitatory and inhibitory (E/I) neurotransmitters in the brain may contribute to the pathophysiology of bipolar disorder (BD). Proton magnetic resonance spectroscopy (1H‐MRS) measures glutamatergic neurometabolites and gamma‐aminobutyric acid (GABA) as indices of E/I neurotransmission. Previous meta‐analyses reported higher glutamatergic neurometabolite levels in the medial prefrontal cortex of BD, but findings on GABA levels in the anterior cingulate cortex (ACC) of BD patients remain inconsistent. Methods We conducted a cross‐sectional study using 1H‐MRS to compare GABA and glutamate plus glutamine (Glx) levels in the dorsal ACC (dACC) of 27 patients with BD and 27 age‐ and sex‐matched healthy controls (HCs). We used the 1H‐MRS (3 T MRI, MEGAPRESS, 256 averages, TR = 1500 ms, TE = 68 ms). Clinical symptoms were evaluated using standardized rating scales. Statistical analyses were conducted to assess group differences in neurometabolite levels and to explore the associations between these neurometabolite levels and clinical symptom severity within the BD group. Results No significant differences in dACC GABA levels, Glx levels, or Glx/GABA ratio were observed between the BD and HC groups. There were no significant differences within the BD group based on BD subtype (I or II) or clinical phase (depression or euthymic). Patients with lithium treatment had higher GABA levels compared to those without. Discussion Our results suggest that GABAergic function in the dACC may not play a pivotal role in the pathophysiology of BD. Given possible GABAergic dysregulation in BD, further research using alternative methodologies is warranted to elucidate the pathological basis.