A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Imeglimin Exhibits Novel Anti-Inflammatory Effects on High-Glucose-Stimulated Mouse Microglia through ULK1-Mediated Suppression of the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1ß) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.

Reference guide for the diagnosis of adult primary immune thrombocytopenia, 2023 edition.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose a new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%); 1) isolated thrombocytopenia with no morphological evidence of dysplasia in any blood cell type in a blood smear, 2) normal or slightly increased plasma TPO level (< cutoff), 3) elevated RP% or IPF% (> upper limit of normal), and 4) absence of other conditions that potentially cause thrombocytopenia including secondary ITP. A diagnosis of ITP is made if conditions 1-4 are all met. Cases in which criterion 2 or 3 is not met or unavailable are defined as "possible ITP," and diagnosis of ITP can be made mainly by typical clinical course. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments.

A Case of Phlebolith in the Tip of Tongue.

The differential diagnosis of a tongue mass containing calcified bodies includes a phlebolith associated with vascular lesions, such as hemangioma and vascular malformation, and diseases such as neoplasm, osseous choristoma and hypercalcemic states, including hyperparathyroidism. The appearance of the calcified bodies on plain radiographs may help to differentiate these entities. Computed tomography, magnetic resonance imaging, and ultrasonography are also useful for differentiating these soft tissue lesions. We report a 40-year-old man with a small mass containing a calcified body in the tip of tongue. The mass was surgically resected and histologically evaluated, confirming the diagnosis of phlebolith. Our case was a rare phlebolith that did not involve a vascular lesion.

[Recent progress in immune thrombocytopenia pathophysiology and treatment].

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased platelet destruction and impaired platelet production from bone marrow megakaryocytes. The details of different platelet destruction mechanisms resulting from differences in autoantibodies and autoantibody-independent direct platelet destruction remain unclear although antiplatelet autoantibodies directed against platelet glycoproteins, such as GPIIb/IIIa and GPIb, play a central role in ITP pathogenesis. ITP is diagnosed by excluding other causes of thrombocytopenia due to the lack of standard tests or biomarkers for its confirmation. Plasma thrombopoietin level measurement and reticulated platelet ratio are useful in distinguishing the cause of thrombocytopenia and will be included in the new "Diagnostic reference guide of adult immune thrombocytopenia." Currently, the treatment of refractory chronic ITP is mainly based on thrombopoietin receptor agonists, but ITP drugs with novel mechanisms of action are actively developed. New therapeutic agents are expected to be selected based on an accurate diagnosis and tailored to the pathophysiology of each case in ITP treatment.

Novel pathological implications of serum uric acid with cardiovascular disease risk in obesity.

AIMS: This cohort study intended to elucidate the association between serum uric acid (SUA) levels and cardiovascular disease events in Japanese patients with obesity. METHODS: Altogether, 450 obese Japanese outpatients were enrolled in a multicenter prospective cohort Japan, the Japan Obesity and Metabolic Syndrome Study. Primary analysis regarding the measurements of cardiovascular risk factors, including SUA levels, and the occurrence of macrovascular complications was based on following the participants over a 5-year period. RESULTS: Of the eligible patients, 335 (74.4%) were followed into the fifth year. During the study period, 15 coronary heart disease, 7 stroke, and 6 arteriosclerosis obliterans events occurred in 39 patients. The CVD incidence rate was 15.8 per 1000 person-years. In the analysis of adjusted models for traditional risk factors, hyperuricemia was a significant factor for the incidence of CVD events, especially in female obese patients. Additionally, we estimated the association between SUA levels and CVD events using cubic spline models, which showed a U-shaped association in both male and female patients. CONCLUSIONS: SUA is an effective predictor of CVD events in female obese patients and a risk factor for CVD incident in obese patients.

Taxifolin Suppresses Inflammatory Responses of High-Glucose-Stimulated Mouse Microglia by Attenuating the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus is associated with an increased risk of dementia, potentially through multifactorial pathologies, including neuroinflammation. Therefore, there is a need to identify novel agents that can suppress neuroinflammation and prevent cognitive impairment in diabetes. In the present study, we demonstrated that a high-glucose (HG) environment elevates the intracellular reactive oxygen species (ROS) levels and triggers inflammatory responses in the mouse microglial cell line BV-2. We further found that thioredoxin-interacting protein (TXNIP), a ROS-responsive positive regulator of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, was also upregulated, followed by NLRP3 inflammasome activation and subsequent interleukin-1beta (IL-1ß) production in these cells. Conversely, caspase-1 was not significantly activated, suggesting the involvement of noncanonical pathways in these inflammatory responses. Moreover, our results demonstrated that taxifolin, a natural flavonoid with antioxidant and radical scavenging activities, suppressed IL-1ß production by reducing the intracellular ROS levels and inhibiting the activation of the TXNIP-NLRP3 axis. These findings suggest the novel anti-inflammatory effects of taxifolin on microglia in an HG environment, which could help develop novel strategies for suppressing neuroinflammation in diabetes.

Disclosure of Spousal Death to Patients with Dementia: Attitude and Actual Behavior of Care Managers.

As the number of dementia patients increases, there is a need to protect patients' right to know. However, in reality, there are cases in Japan where spouses' deaths are concealed from patients. We conducted a questionnaire survey of care managers (CMs) to obtain their attitude and actual behavior regarding the disclosure of a spouse's death to patients with dementia. A self-administered, anonymous questionnaire survey was implemented at academic meetings attended by CMs from March to December 2019, inquiring about experiences with spousal deaths of patients with dementia, disclosure rates, behavioral and psychological symptoms of dementia, and depression. Over 80% had experienced the spousal death of a patient with dementia; the percentage of CMs who had implemented the disclosures varied widely. About 18% had experienced worsening behavioral and psychological symptoms of dementia (BPSD), and 26% had worsening depression as a result of the disclosure. About 83% of respondents were positive about disclosure, but about 44% did so less than 50% of the time. This study is the first to reveal the current state of CMs' policies and behaviors regarding the disclosure of spousal death to patients with dementia in Japan. Family members' wishes and the possibility of BPSD put a relatively large number of caregivers in a dilemma regarding disclosure.

FNAIT pathogenesis determined by serial analysis of three subsequent pregnancies of a woman with severe fetal and neonatal alloimmune thrombocytopenia (FNAIT) with anti-HPA-4b and anti-HPA-5b alloantibodies in the first sibling.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by anti-HPA alloantibody, and anti-HPA-4b is the most common cause in Japanese. Anti-HPA-5b is frequently detected in pregnant women, but it is still controversial whether anti-HPA-5b causes severe FNAIT. CASE PRESENTATION: A Japanese woman with anti-HPA-4b and anti-HPA-5b alloantibodies delivered a baby with severe FNAIT who was both HPA-4b and HPA-5b incompatible. We carefully monitored the patient's following three pregnancies (the second and the fourth siblings were HPA-4b incompatible and HPA-5b compatible; the third sibling was both HPA-4b and HPA-5b compatible). FNAIT was not observed in all three siblings, although a modest decrease in cord blood platelet count was observed in the HPA-4b incompatible siblings compared to the HPA-4b compatible sibling. Serial monitoring of anti-HPA titer showed that anti-HPA-4b markedly decreased in late pregnancy and recovered after delivery of the HPA-4b incompatible siblings, but these decreases were not observed during the mother's pregnancy with the HPA-4b compatible sibling. In contrast, anti-HPA-5b remained at a high titer during pregnancy with all three siblings. CONCLUSION: Our data indicate that dynamic changes of anti-HPA-4b occur during pregnancy and strongly suggest that anti-HPA-5b was mainly responsible for severe FNAIT in this case.

Novel Therapeutic Potentials of Taxifolin for Obesity-Induced Hepatic Steatosis, Fibrogenesis, and Tumorigenesis.

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia.

Primary hyperchylomicronemia is characterized by marked hypertriglyceridemia exceeding 1,000 mg/dL. It is caused by dysfunctional mutations in specific genes, namely those for lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), apolipoprotein C2 (ApoC-II), lipase maturation factor 1 (LMF1), or apolipoprotein A5 (ApoA-V). Importantly, antibodies against LPL or GPIHBP1 have also been reported to induce autoimmune hyperchylomicronemia. The patient was a 46-year-old man diagnosed with immune thrombocytopenia (ITP) at 41 years. At the time, he was administered prednisolone (PSL) and eltrombopag, a thrombopoietin receptor agonist. At 44 years, he suffered from acute myocardial infarction, and PSL was discontinued to avoid enhancing atherogenic risks. He was maintained on eltrombopag monotherapy. After discontinuing PSL, marked hypertriglyceridemia (＞3,000 mg/dL) was observed, which did not improve even after a few years of pemafibrate therapy. Upon referral to our clinic, the triglyceride (TG) level was 2,251 mg/dL, ApoC-II was 19.8 mg/dL, LPL was 11.1 ng/mL (0.02-1.5 ng/mL), GPIHBP1 was 47.7 pg/mL (740.0-1,014.0 pg/mL), and anti-GPIHBP1 antibody was detected. The patient was diagnosed to have anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia. He was administered PSL 15 mg/day, and TG levels were controlled at approximately 200 mg/dL. Recent studies have reported that patients with anti-GPIHBP1 antibody-induced autoimmune hyperchylomicronemia had concomitant rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's disease, and Graves' disease. We report a rare case of anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia with concomitant ITP, which became apparent when PSL was discontinued due to the onset of steroid-induced acute myocardial infarction.

A Case of Spindle Cell Squamous Cell Carcinoma Manifesting in the Mandible Following Resection of Buccal Mucosal Squamous Cell Carcinoma.

Spindle cell squamous cell carcinoma (SCSCC) represents a distinctive subtype of squamous cell carcinoma, characterized by a marked malignancy and sarcomatoid transformations predominantly comprising spindle-shaped cells. In this context, we executed a surgical resection of a buccal mucosal squamous cell carcinoma, encompassing the mandibular periosteum, for a case where buccal mucosal cancer had pervaded the mandibular gingival mucosa. Notably, in a period of one year and four months subsequent to this procedure, a spindle cell squamous cell carcinoma emerged as an intraosseous carcinoma, originating from the periosteum resection. This report delineates the occurrence of this rare pathology. The subject of this case is an 83-year-old female. She underwent a resection of a buccal mucosal squamous cell carcinoma, including the mandibular gingival periosteum, for cancer on the right buccal mucosa. The histopathological evaluation post-surgery confirmed the diagnosis of squamous cell carcinoma with clear margins. A computed tomography (CT) scan, conducted one year and four months postoperatively, disclosed a contrast-enhanced tumorous growth in the mandible. Owing to the considerable restriction in opening caused by scarring and the attendant challenges in biopsy acquisition, an expedited intraoperative diagnosis was rendered. This preliminary assessment indicated a spindle cell sarcoma, leading to a hemimandibular resection. The final histopathological diagnosis was spindle cell squamous cell carcinoma. Twelve months have elapsed since the surgical intervention, with no evidence of recurrence or metastasis observed to date.

Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2 pathway.

Currently, no mouse models manifest calcification and thrombus formation, which is frequently associated with human atherosclerosis. We demonstrated that lack of Favine/CCDC3 in apoE knockout mice accelerated atherosclerosis accompanied by large cholesterol crystals and calcification, and also promoted thrombus formation in the left ventricle and arteries. Circulating Favine was detectable in WT mouse plasma. RNA-sequencing analysis of aortae in DKO mice showed similar gene expression patterns of human atherosclerosis with unstable and vulnerable plaques. Importantly, human FAVINE mRNA expressions were lower in atheroma plaque than in adjacent intact aortic tissue and decreased with the progression of atherosclerosis. Pathway analysis of aortae in DKO mice suggested the decrease of the MEF2C-KLF2-mediated transcriptional pathway. Favine insufficiency and its attenuated downstream pathways may increase atherosclerosis progression with calcification and thrombus, which have not previously been fully modeled in experimental animals. Favine and its downstream pathways may have therapeutic potential for atherosclerosis.

Nivolumab-induced systemic lymphadenopathy occurring during treatment of malignant melanoma: a case report.

Nivolumab is an anti-programmed cell death protein 1 monoclonal antibody that exhibits significant efficacy in treating melanoma and other malignancies. However, various nivolumab-induced immune-related adverse events (irAEs) have been reported, and differentiating irAEs from tumor progression is sometimes difficult. Here, we report a case of reactive lymphadenopathy occurring after treatment with nivolumab. A 56-year-old man with stage IIIC melanoma received adjuvant therapy with nivolumab after wide local excision. He developed systemic lymphadenopathy and autoimmune hemolytic anemia 1 month after receiving seven cycles of nivolumab. Pathological analysis of a cervical lymph node biopsy specimen revealed no metastatic lesion or any other malignancy, including lymphoma. Thus, the patient was diagnosed with nivolumab-induced reactive lymphadenopathy. Systemic corticosteroids were administered to reduce hemolysis, which led to the resolution of lymphadenopathy. When progressive lymphadenopathy is observed in a patient who received immune checkpoint inhibitor therapy, reactive lymphadenopathy should be carefully distinguished from progression to lymphoid metastasis, and biopsy should be performed if needed.

Autoimmune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation: significance of detecting reticulated platelets and glycoprotein-specific platelet autoantibodies.

Autoimmune hematological disorders are rare complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of immune thrombocytopenia (ITP) is challenging, especially after allo-HSCT, because various complications such as graft-versus-host disease, disease relapse, viral infection, thrombotic microangiopathy, and drug side effects can also cause thrombocytopenia. Assessment of reticulated platelets (RP) and plasma thrombopoietin (TPO) levels may be useful to distinguish between ITP and hypoplastic thrombocytopenia. ITP is generally characterized by an increased percentage of RP, and a normal or slightly increased plasma TPO level. We now report three cases of thrombocytopenia after allo-HSCT. RP% was elevated in these patients, as it is in primary ITP. However, in contrast to primary ITP, plasma TPO levels were high in two of three patients. Anti-αIIbß3 and anti-GPIb/IX-specific direct IgG antibodies were detected as well, suggesting occurrence of immune-mediated platelet destruction in addition to bone marrow suppression in two patients. All three patients were successfully treated with corticosteroids and/or thrombopoietin receptor agonists (TPO-RAs). These results suggest that increased RP% and detection of glycoprotein-specific platelet autoantibodies are useful for the diagnosis of ITP after HSCT.

Depression of Bone Density at the Weight-Bearing Joints in Wistar Hannover Rats by a Simulated Mechanical Stress Associated With Partial Gravity Environment.

The partial gravity environment in space can negatively affect bone health. This survey aimed to study the reaction of different parts of the lower limb bones of rats to partial gravity and the effects of different degrees of gravity on these bony parts. We used 15 8-week-old male Wistar Hannover rats were used at the beginning of the experiment. The degree of mechanical stress was modified, but the ankle joint was maintained at ∼30°, ∼120°, or ∼160° with or without plaster fixation during 10-day hindlimb suspension. Computed tomography was performed to measure the bone parameters [bone mineral density (BMD), trabecular BMD, cortical BMD, and cortical thickness] of each studied group of the whole, proximal, middle, and distal femur and distal tibia. BMD, trabecular BMD, and cortical thickness of the distal femur and proximal tibia of the simulated mechanical stress associated with partial gravity groups were significantly lower than those of the control group; the effect of different degrees of gravity on the same area of hindlimb bone had no significant difference. The simulated mechanical stress associated with partial gravity had the most significant effect on the bone close to the knee joint, with the largest weight-bearing response.

Metabolomic Profiles in Adipocytes Differentiated from Adipose-Derived Stem Cells Following Exercise Training or High-Fat Diet.

Controlling the differentiation potential of adipose-derived stem cells (ADSCs) is attracting attention as a new strategy for the prevention and treatment of obesity. Here, we aimed to observe the effect of exercise training (TR) and high-fat diet (HFD) on the metabolic profiles of ADSCs-derived adipocytes. The rats were divided into four groups: normal diet (ND)-fed control (ND-SED), ND-fed TR (ND-TR), HFD-fed control (HFD-SED), and HFD-fed TR (HFD-TR). After 9 weeks of intervention, ADSCs of epididymal and inguinal adipose tissues were differentiated into adipocytes. In the metabolome analysis of adipocytes after isoproterenol stimulation, 116 metabolites were detected. The principal component analysis demonstrated that ADSCs-derived adipocytes segregated into four clusters in each fat pad. Amino acid accumulation was greater in epididymal ADSCs-derived adipocytes of ND-TR and HFD-TR, but lower in inguinal ADSCs-derived adipocytes of ND-TR, than in the respective controls. HFD accumulated several metabolites including amino acids in inguinal ADSCs-derived adipocytes and more other metabolites in epididymal ones. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that TR mainly affected the pathways related to amino acid metabolism, except in inguinal ADSCs-derived adipocytes of HFD-TR rats. These findings provide a new way to understand the mechanisms underlying possible changes in the differentiation of ADSCs due to TR or HFD.

Homeobox A5 and C10 genes modulate adaptation of brown adipose tissue during exercise training in juvenile rats.

NEW FINDINGS: What is the central question of this study? Exercise can stimulate brown adipose tissue (BAT) with subsequent increase in uncoupling protein 1 expression and mitochondrial biogenesis. In that case, do BAT-specific Hox genes modify BAT functioning and cause uncoupling protein expression changes due to exercise? What is the main finding and its importance? Exercise enhanced brown adipocyte markers, with significant upregulation of HoxA5 and downregulation of HoxC10 mRNA expression in rat BAT. HoxA5 and HoxC10 are thus likely to play distinct roles in exercise-induced changes in BAT markers during the early postnatal period. These findings provide new insight into the mechanisms underlying exercise-induced changes in BAT function. ABSTRACT: Brown adipose tissue (BAT) recruitment is involved in increased energy expenditure associated with cold exposure and exercise training. We explored whether exercise training induced changes in expression levels of brown adipocyte-selective factors and Homeobox (Hox) genes during the post-weaning growth period of male Wistar rats. Relative to total body weight, BAT weights alone were lower in exercise-trained (EX) rats compared to sedentary control (SED) rats. mRNA expression of HoxA5 was higher and that of HoxC10 was lower in EX rats than in SED rats, accompanied by both higher citrate synthase activity and protein expression levels for uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor (PPAR) α, and PPARγ-coactivator (PGC)-1α. HoxA5 knockdown with siRNA reduced the expression of PR-domain containing 16 (Prdm16), cell death-inducing DNA fragmentation factor-α-like effector A (Cidea) gene, type 2 deiodinase mRNA, and PRDM16 protein. Comparatively, HoxC10 knockdown with siRNA enhanced mRNA expression of Prdm16, Pparα and Pgc1α and protein expression of UCP1, PPARα and PGC1α in brown adipocytes. The stimulation of brown adipocytes with isoproterenol, a ß-adrenoceptor agonist, caused a phenomenon similar to the effect of exercise training on the genes tested: upregulation of HoxA5 mRNA, downregulation of HoxC10 mRNA, and increased protein expression for UCP1 and PGC1α. Collectively, HoxA5 and HoxC10 may have unique functions that contribute to modulating the expression of BAT-selective markers in BAT of juvenile rats during exercise training. The study findings regarding activation and recruitment of BAT during exercise training have implications for anti-obesity management.

A Case of Osteomyelitis of the Mandibular Condyle Secondary to Bisphosphonate-related Osteonecrosis of the Jaw.

We present a case of osteomyelitis of the condyle secondary to bisphosphonate-related osteonecrosis of the jaw. A 77-year-old female was referred to our clinic with complaints of swelling in the left mandibular molar regions. The patient had been suffering from myeloperoxidase anti-neutrophil cytoplasmic antibody (MPOANCA) associated vasculitis and had been treated with glucocorticoids for 8 years, and oral bisphosphonates had been prescribed to prevent osteopenia secondary to glucocorticoids. Imaging examinations showed radiolucency of the left mandibular body. Based on the diagnosis of osteomyelitis of the mandibular body secondary to bisphosphonate-related osteonecrosis, the patient received antimicrobial therapy and was well-healed. However, the patient returned 8 weeks later complaining of acute left preauricular swelling. Computed tomography showed the destructive changes in the mandibular condyle. We speculated that the infection was caused by the local spread from osteomyelitis of the left mandibular body. The risk of jaw necrosis related to antiresorptive therapy is well known. In recent years, the number of older patients being administered glucocorticoids with bisphosphonates has increased; therefore, we must be attentive to the signs of infectious diseases of the jawbone in the aging because it can easily shift to osteomyelitis or osteonecrosis and spread infection through the marrow.

Exercise Training-Enhanced Lipolytic Potency to Catecholamine Depends on the Time of the Day.

Exercise training is well known to enhance adipocyte lipolysis in response to hormone challenge. However, the existence of a relationship between the timing of exercise training and its effect on adipocyte lipolysis is unknown. To clarify this issue, Wistar rats were run on a treadmill for 9 weeks in either the early part (E-EX) or late part of the active phase (L-EX). L-EX rats exhibited greater isoproterenol-stimulated lipolysis expressed as fold induction over basal lipolysis, with greater protein expression levels of hormone-sensitive lipase (HSL) phosphorylated at Ser 660 compared to E-EX rats. Furthermore, we discovered that Brain and muscle Arnt-like (BMAL)1 protein can associate directly with several protein kinase A (PKA) regulatory units (RIα, RIß, and RIIß) of protein kinase, its anchoring protein (AKAP)150, and HSL, and that the association of BMAL1 with the regulatory subunits of PKA, AKAP150, and HSL was greater in L-EX than in E-EX rats. In contrast, comparison between E-EX and their counterpart sedentary control rats showed a greater co-immunoprecipitation only between BMAL1 and ATGL. Thus, both E-EX and L-EX showed an enhanced lipolytic response to isoproterenol, but the mechanisms underlying exercise training-enhanced lipolytic response to isoproterenol were different in each group.