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A primary intraventricular haemorrhage (PIVH) usually presents with non-localised neurological symptoms since the haematoma is limited to the ventricles. However, it is sometimes associated with focal neurological signs, whose pathophysiologies are not confirmed. Here, we report on a case of PIVH who showed rare manifestations in the acute stage: upward gaze palsy and convergence insufficiency. The CT and MRI showed intraventricular haematoma without evidence of parenchymal haemorrhage, local mass effect around midbrain or hydrocephalus. There had been bilateral papilloedema, and it resolved along with improvement of the ophthalmic symptoms, suggesting a possible causal relation to increased intracranial pressure. The ophthalmic abnormalities suggested injury of the rostral part of the midbrain, especially the region around the dorsal midbrain tectum. It should be known that PIVH is one of the causes of acutely developing upward gaze palsy and convergence insufficiency.

Aging is a significant risk factor for disease in several tissues, including the prostate. Defining the kinetics of age-related changes in these tissues is critical for identifying regulators of aging and evaluating interventions to slow the aging process and reduce disease risk. An altered immune microenvironment is characteristic of prostatic aging in mice, but whether features of aging in the prostate emerge predominantly in old age or earlier in adulthood has not previously been established. Using highly multiplexed immune profiling and time-course analysis, we tracked the abundance of 29 immune cell clusters in the aging mouse prostate. Early in adulthood, myeloid cells comprise the vast majority of immune cells in the 3-month-old mouse prostate. Between 6 and 12 months of age, there is a profound shift towards a T and B lymphocyte-dominant mouse prostate immune microenvironment. Comparing the prostate to other urogenital tissues, we found similar features of age-related inflammation in the mouse bladder but not the kidney. In summary, our study offers new insight into the kinetics of prostatic inflammaging and the window when interventions to slow down age-related changes may be most effective.

Preoperative embolization for intracranial meningiomas can cause tumor necrosis, reduce intraoperative blood loss, and facilitate surgery. This study aimed to evaluate the efficacy of tumor embolization using Embosphere microspheres for skull base meningiomas and analyze postembolization plain computed tomography (CT) and magnetic resonance imaging (MRI) scans to identify findings that could potentially predict treatment response.Between April 2014 and April 2020, 80 patients with skull base meningiomas presenting at our medical center underwent embolization with Embosphere microspheres. The effects of tumor embolization were evaluated through a comparison of postembolization plain CT and contrast-enhanced MRI.A total of 143 vessels (102 of 108 external carotid artery branches and 41 of 65 internal carotid artery branches) from 80 skull base meningiomas were embolized with Embosphere microspheres. Microspheres 100-300 μm in size were used in 2 cases, microspheres 300-500 μm in size were used in 12 cases, and microspheres 500-700 μm in size were used in 66 cases. Postembolization contrast-enhanced MRI showed reductions in enhancing lesions within the tumor in 55 of 80 cases. Postembolization plain CT scans showed high-density lesions within the tumor in 41 of 55 cases. Thus, reductions in enhancing lesions on postembolization contrast-enhanced MRI were statistically significantly associated with the presence of high-density lesions on postembolization plain CT (P0.001). Embolization-related neurological complications occurred in 3 cases.Embosphere microspheres are user friendly and effective embolic materials for the embolization of skull base meningiomas. Postembolization contrast-enhanced MRI and plain CT findings may be useful for evaluating the effects of tumor embolization.

We investigated the pathogenic relationship between cerebral microbleeds and lacunar strokes. Two cases of lacunar strokes in the region of the basal ganglia, a 72-year-old man and a 67-year-old man, were studied; both cases showed cerebral microbleeds in the stroke areas. The cerebral microbleeds were surrounded by oedema, and the oedema faded out over time, suggesting the cerebral microbleeds had developed acutely. The cerebral microbleeds were located at the ventrolateral edge of the lacunar infarctions, and the locations appeared to be at or near the sites of occlusion of the lenticulostriatal branches. Although a cerebral microbleed and a lacunar infarction may be two unrelated events on juxtapositioned vessels, or a cerebral microbleed may be haemorrhagic conversion of an infarction, a cerebral microbleed could cause an occlusion of the arterial branch, leading to lacunar infarction of its supplying territories.

Prostate cancer cells that survive clinical androgen receptor (AR) blockade mediate disease progression and lethality. Reprogrammed metabolic signaling is one mechanism by which tumor cells can survive treatment. However, how AR inhibition reprograms metabolism, and whether altered metabolism can be exploited to eradicate cells that survive AR blockade, remains unclear. Here, we comprehensively characterized the effect of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. AR inhibition maintains oxidative mitochondrial metabolism and reduces glycolytic signaling, through hexokinase II downregulation and decreased MYC activity. Robust elongation of mitochondria via reduced DRP1 activity supports cell fitness after AR blockade. In addition, AR inhibition enhances sensitivity to complex I inhibitors in several models, suggesting that AR blockade increases reliance on oxidative mitochondrial metabolism. Our study provides an enhanced understanding of how AR inhibition alters metabolic signaling and highlights the potential of therapies that target metabolic vulnerabilities in AR-inhibited cells.

3D cancer spheroids represent a highly promising model for study of cancer progression and therapeutic development. Wide-scale adoption of cancer spheroids, however, remains a challenge due to the lack of control over hypoxic gradients that may cloud the assessment of cell morphology and drug response. Here, we present a Microwell Flow Device (MFD) that generates in-well laminar flow around 3D tissues via repetitive tissue sedimentation. Using a prostate cancer cell line, we demonstrate the spheroids in the MFD exhibit improved cell growth, reduced necrotic core formation, enhanced structural integrity, and down-regulated expression of cell stress genes. The flow-cultured spheroids also exhibit an improved sensitivity to chemotherapy with greater transcriptional response. These results demonstrate how fluidic stimuli reveal the cellular phenotype previously masked by severe necrosis. Our platform advances 3D cellular models and enables study into hypoxia modulation, cancer metabolism, and drug screening within pathophysiological conditions.

To investigate the patient demographics, survival after diagnosis, and prognostic factors among patients with multiple-territory cerebral infarctions due to cancer-associated ischemic stroke (multiple CAIS).We performed a retrospective review of the medical records from a 10-year period of consecutive patients with multiple CAIS, defined as (1) newly developed multiple cerebral infarctions involving two or more cerebrovascular territories, (2) association with active cancer diagnosed or treated6 months before or after stroke, and (3) exclusion of obvious etiologies other than cancer-associated coagulopathy in routine screening. We extracted demographic features, stroke severity and characteristics, cancer characteristics, comorbidities, and laboratory data. Univariable Cox proportional hazards regression was used to idenify the prognostic factors.The median age was 74 years (interquartile range, 68.3-80.5), and the median survival after diagnosis was 44.5 (27.3-76.8) days in 26 patients with complete follow-up. The median National Institutes of Health Stroke Scale was 5.5 (2.0-9.0). Twenty (76.9%) patients had received a cancer diagnosis prior to the diagnosis of multiple CAIS, and most patients (25 patients, 96.2%) had stage IV cancer. Univariate analysis showed that high serum albumin (hazard ratio, 0.31; 95% confidence interval, 0.11-0.88) was significantly associated with prolonged survival, whereas stroke severity and comorbidities were not associated with survival.Multiple CAIS predominantly occurred in elderly patients with advanced cancer, and their survival was short. Serum albumin levels were significantly associated with prognosis, indicating the poor general condition associated with cancers may affect prognosis.

Although exercise is beneficial for chronic musculoskeletal pain (CMP), the optimal type and amount of exercise are unclear. This study aimed to determine the impact of circuit training that combines aerobic and resistance exercises on adult women with CMP. A total of 139 women with CMP underwent circuit training for 3 months and were asked to complete the following questionnaires at baseline and 3 months later: Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Roland-Morris Disability Questionnaire (RDQ), Shoulder36, and Knee injury and Osteoarthritis Outcome Score (KOOS). Significant improvements were observed in NRS, PCS, RDQ, and KOOS activities of daily living (ADL) scores after the intervention relative to baseline (p

We report a 52-year-old man with progressive disturbance of visual acuity following a head injury. Magnetic resonance imaging (MRI) showed an aneurysm of the internal carotid artery. Digital subtraction angiography (DSA) 57 days after onset found that the aneurysm originated in the proximal ophthalmic artery. We treated the patient with an intravascular coil embolization, partially filling the aneurysm. Follow-up DSA indicated that the aneurysm did not recur.

Oral mucositis is one of the most common adverse effects of radiation and chemotherapy in treatments of cancers. Some clinical guidelines have focused on the prevention and treatment of oral mucositis, and thus, a mouthwash containing drugs is often recommended. In this study, we aimed to evaluate the disappearance time and palatability in the oral cavities of healthy volunteers in foams prepared from different concentrations of the three viscosity grades of methylcellulose (SM-4, -100, -400). In addition, we prepared foam formulations of drugs (benzydamine, dexamethasone, allopurinol and rebamipide) for use as a prevention and treatment of oral mucositis. There was a significant relationship between the foam drainage ratios at 5-15 min and the disappearance time in the oral cavities. The significant relationship of foam densities to the foam disappearance time and overall palatability in a clinical study were observed. Thus, the foam density is considered an important parameter and reflects these clinically important properties. The foam from SM-4 has the longest disappearance time and the best palatability followed by foams from the 4 and 1% SM-4. Drug contents in drug-containing foam formulations which were prepared with 1-4% SM-4 represented 101-112% of the loaded drug contents, and the relative standard deviations of drug contents were

Background Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been reported to improve gait disturbances in Parkinson's disease (PD); however, there are controversies on the radiological and electrophysiological techniques for intraoperative and postoperative confirmation of the target and determination of optimal stimulation parameters. Objectives We investigated the correlation between the location of the estimated PPN (ePPN) and neuronal activity collected during intraoperative electrophysiological mapping to evaluate the role of microelectrode recording (MER) in identifying the effective stimulation site in two PD patients. Materials and methods Bilateral PPN DBS was performed in two patients who had suffered from levodopa refractory gait disturbance. They had been implanted previously with DBS in the internal globus pallidus and the subthalamic nucleus, respectively. The PPN was determined on MRI and identified by intraoperative MER. Neuronal activity recorded was analyzed for mean discharge rate, bursting, and oscillatory activity. The effects were assessed by clinical ratings for motor signs before and after surgery. Results The PPN location was detected by MER. Groups of neurons characterized by tonic discharges were found 9-10 mm below the thalamus. The mean discharge rate in the ePPN was 19.1 ± 15.1 Hz, and 33% of the neurons of the ePPN responded with increased discharge rate during passive manipulation of the limbs and orofacial structures. PPN DBS with bipolar stimulation at a frequency range 10-30 Hz improved gait disturbances in both patients. Although PPN DBS provided therapeutic effects post-surgery in both cases, the effects waned after a year in case 1 and three years in case 2. Conclusions Estimation of stimulation site within the PPN is possible by combining physiological guidance using MER and MRI findings. The PPN is a potential target for gait disturbances, although the efficacy of PPN DBS may depend on the location of the electrode and the stimulation parameters.

We present a case of a patient who survived carotid blowout syndrome(CBS)due to covered stent placement, but bled again 34 days later. A 67-year-old man with laryngeal cancer experienced cardiac arrest due to carotid blowout a day after he underwent the balloon occlusion test and abnormal feeder embolization of the tumor. After quick resuscitation, he was treated with endovascular therapy using a covered stent, since he had insufficient cerebral ischemic tolerance. We succeeded in stent placement and the bleeding stopped without any procedural complications. The patient survived after the procedure. However, bleeding recurred when a nasal endoscope was inserted 34 days later. The rupture point was immediately distal of the stent. We performed carotid artery occlusion with coils and n-butyl-cyanoacrylate. The patient survived, but his condition gradually weakened and died 97 days after stenting. Emergency hemostasis for carotid blowout using a covered stent is the only available treatment for patients who do not have sufficient cerebral ischemic tolerance. However, this procedure has a higher rate of re-bleeding than carotid artery occlusion. Moreover, it is an off-label treatment in Japan. Therefore, possible treatments for CBS including use of covered stent or treatments for non-ruptured CBS should be analyzed in the future.

This study aimed to evaluate genotype-phenotype correlations of Parkinson’s disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Age is a significant risk factor for disease of the prostate. However, the mechanisms by which age increases disease risk have not been well described. We previously reported age-related changes within the inflammatory and luminal compartments of the mouse prostate. Old mouse prostates exhibit an expansion of the population of Trop2+ luminal progenitor cells and a reduction in the frequency and functional capacity of Trop2- luminal cells, indicating that different cell-types have distinct responses to aging. Whether distinct cell-types in the prostate share a common signature of aging has not been established. We transcriptionally profiled four distinct cell-types in young adult and old mouse prostates: stromal, basal, Trop2+ luminal progenitor and Trop2- luminal cells. Motif analysis of genes upregulated in old prostate cell-types pointed to transcriptional regulators of inflammatory and hypoxia-related signaling. Glutathione metabolism and the antioxidant response emerged as a common signature of aging across prostatic lineages. Expression of genes implicated in mouse prostate aging, including the antioxidant response gene Hmox1, correlates with age of diagnosis in primary prostate tumors from the TCGA cohort. These findings reveal a common signature shared by distinct cell-types in the old prostate reflective of age-associated metabolic reprogramming.

Intravascular lymphoma (IVL) is a rare and clinically devastating subtype of extranodal diffuse large B-cell lymphoma with a distinct presentation. Diagnostic difficulty derives from marked variability in clinical presentations and nonspecific laboratory and radiological findings, especially when central nervous system (CNS) symptoms are the only manifestation. Establishing the diagnosis premortem thus remains a major challenge. We describe a 70-year-old male with CNS IVL. He presented with acute onset of neurocognitive impairments. Diffusion-weighted magnetic resonance imaging (MRI) showed multiple high-intensity areas suggesting occlusive cerebrovascular disease due to emboli, but extensive investigations detected no embolic sources. Intracranial neoplasm was included in a differential diagnosis based on elevated serum lactate dehydrogenase and interleukin 2 receptor levels. Gadolinium-enhanced MRI or 18-fluorodeoxyglucose positron emission tomography (PET) failed to demonstrate specific findings leading to a definite diagnosis, while 11C-methionine PET (MET-PET) distinctively demonstrated an area of focally increased MET uptake in the frontal cortex, suggesting the extent of tumor infiltration. Stereotactic biopsy was conducted under MET-PET imaging guidance and immunohistological examinations confirmed the proliferation and aggregation of CD20-positive lymphoma cells within the lumina of small blood vessels. The findings of the present case first suggest that MET-PET may provide important information on the diagnosis of CNS IVL and on the selection of the optimal site for brain biopsy. Further investigation is necessary to clarify whether positive findings on MET-PET are truly specific and pathognomonic for CNS IVL.

Surgical removal of glomus jugulare tumors is challenging owing to the complex anatomy of the temporal bone and craniocervical region, aggressive tumor invasion into the nearby structures, and their hypervascularity. However, recent advances in skull base techniques, intraoperative neuromonitoring, and radiological interventions have enabled their relatively safe resection, while giving priority to functional preservation. This video demonstrates a case of a glomus jugulare tumor treated by the extradural transjugular transsigmoid approach with high-cervical exposure and tympamoplasty, after preoperative embolization. A 47-year-old woman presented with progressive hearing disturbance, pulsatile tinnitus, and hemifacial spasm. Neuroimaging displayed a hypervascular tumor occupying the temporal bone, extending to the cervical region through the jugular foramen, and to the external auditory canal. Preoperative feeder occlusion was successfully performed without any additional symptoms, while carefully evaluating the provocative test. Near-total resection of the tumor was achieved through the transjugular transsigmoid approach with high-cervical exposure under detailed neuromonitoring, including continuous facial nerve monitoring and auditory brainstem response. In this patient, in whom the tumor did not invade intradurally and the sigmoid sinus was already occluded preoperatively, the sinus was managed only by coagulation, to avoid unnecessary dural opening and the risk of cerebrospinal fluid leakage. Anterior facial nerve rerouting was not required since the tumor removal was accomplished through the corridor above and below the fallopian bridge. The patient had no new neurological deficits, and her pulsatile tinnitus and hemifacial spasm disappeared after the surgery. Her hearing disturbance improved postoperatively.The link to the video can be found at: https://youtu.be/gqf3dxHlv_0.

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient’s expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.

Objectives We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia. Methods Five patients with SCA with cortical atrophy (ages 60‐69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET. Results Postsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%). Interpretation Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello‐thalamo‐cortical network.

Background Our previous population-based study in 1982 – 2001, Nagano Prefecture, Japan, indicated increased numbers of patients with elderly-onset (≥ 65) myasthenia gravis (MG). Aim We performed a retrospective survey in 2002 – 2012 in the same area, and investigated the epidemiology, clinical picture, and treatments for MG. Methods Questionnaires were sent to 23 hospitals and patient records were reviewed. Patients were classified into the non-elderly-onset (15 – 64, n = 136) or elderly-onset (≥ 65, n = 78) group. The questionnaires included details of sex, age/date at onset, initial symptoms, disease severity, association with thymoma, and treatments. Post-intervention status and maximum/maintenance dose of prednisolone were investigated. Results The rate of elderly-onset MG patients increased in 2002 – 2012 despite correction for increases in the elderly population. The ratio of MGFA class I was higher, and that of class Πb was lower, and thymectomy rate in non-thymomatous generalized MG patients was lower in the elderly-onset group. There was no marked difference in the rate of intensive treatments (plasma exchange, intravenous immunoglobulin, etc.) between the groups. Immunosuppressive therapies (prednisolone, calcineurin inhibitors) were applied frequently in both groups, while calcineurin inhibitor use rate and mean maximal dose of prednisolone were lower, and the “minimum manifestation status with prednisolone ≤ 5 mg” rate was higher in the elderly-onset group. Conclusion This study suggested that a low or moderate dose of prednisolone can be fully effective in many elderly-onset MG patients, and some may not require calcineurin inhibitors or thymectomy to reduce prednisolone dose. This article is protected by copyright. All rights reserved.

Here we describe the research and development of a process for the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C–N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of (R)-1. Moreover, an epimerization process to obtain (R)-7 from the undesired (S)-7 was developed.

Macrophage autophagy has been shown to exert a protective role in atherosclerosis. Beclin 1 is an essential autophagic protein, and the Beclin-1-interacting complex promotes the formation of autophagosomes. However, the localization of Beclin 1 in human atherosclerotic lesions has not been clarified to date. We hence investigated the immunolocalization of Beclin 1 in atherosclerotic lesions of human carotid and major intracranial arteries. Furthermore, we investigated the colocalization of Beclin 1 with the 14-3-3 eta isoform and high mobility group box 1 (HMGB1). Beclin 1 was observed in the cytoplasm of many foamy macrophages located near to or in the periphery of lipid-rich necrotic cores. Beclin 1 colocalized with the 14-3-3 eta isoform in carotid plaques, and also colocalized with HMGB1 in carotid plaques. This is the first demonstration of Beclin 1 immunolocalization in human carotid and main cerebral artery plaques. We believe that our results will contribute towards understanding the role of autophagy in atherosclerosis and towards the prevention of stroke.

The prostate epithelium is comprised predominantly of basal and luminal cells. In vivo lineage tracing has been utilized to define the differentiation capacity of mouse prostate basal and luminal cells during development, tissue-regeneration and transformation. However, evaluating cell-intrinsic and extrinsic regulators of prostate epithelial differentiation capacity using a lineage tracing approach often requires extensive breeding and can be cost-prohibitive. In the prostate organoid assay, basal and luminal cells generate prostatic epithelium ex vivo. Importantly, primary epithelial cells can be isolated from mice of any genetic background or mice treated with any number of small molecules prior to, or after, plating into three-dimensional (3D) culture. Sufficient material for evaluation of differentiation capacity is generated after 7-10 days. Collection of basal-derived and luminal-derived organoids for (1) protein analysis by Western blot and (2) immunohistochemical analysis of intact organoids by whole-mount confocal microscopy enables researchers to evaluate the ex vivo differentiation capacity of prostate epithelial cells. When used in combination, these two approaches provide complementary information about the differentiation capacity of prostate basal and luminal cells in response to genetic or pharmacological manipulation.

Hypervascular vestibular schwannomas (HVSs) are a type of the vestibular schwannomas (VSs) that are extremely difficult to remove. We examined whether HVSs can be predicted by using arterial spin labeling (ASL) imaging. A total of 103 patients with VSs underwent ASL imaging and digital subtraction angiography (DSA) before surgery. Regional cerebral blood flow (CBF) of gray matter and regional tumor blood flow (TBF) were calculated from ASL imaging, and we defined the ratio of TBF to CBF as the relative TBF (rTBF = TBF/CBF). Angiographic vascularity was evaluated by DSA, and clinical vascularity was evaluated by the degree of intraoperative tumor bleeding. Based on the angiographic and clinical vascularity, the VSs were divided into two categories: HVS and non-HVS. We compared rTBF with angiographic and clinical vascularities, retrospectively. The mean rTBFs of angiographic non-HVSs and HVSs were 1.29 and 2.58, respectively (p

The transactivation response DNA binding protein (TARDP) of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes. We investigated the immunolocalization of pTDP-43 in atherosclerotic lesions of human carotid and main cerebral arteries. Furthermore, we investigated the co-localization between pTDP-43 and 14-3-3 eta isoform or high mobility group box 1 (HMGB1). pTDP-43 localized in the cytoplasm of many foamy macrophages located in the periphery of lipid-rich necrotic cores, and in the cytoplasm of infiltrated smooth muscle cell-like cells. pTDP-43 co-localized the 14-3-3 eta isoform in carotid plaques. pTDP-43 also co-localized HMGB1. This is the first demonstration of pTDP-43 immunolocalization in human carotid and main cerebral artery plaques. We believe that demonstration of the localization of pTDP-43 in atherosclerotic lesions is important as this may contribute to the establishment of the clinical diagnostic imaging of FTLD and ALS using the pTDP-43 epitope. Moreover, this finding may be useful for further understanding the role of TDP in cell death.

Tubulointerstitial fibrosis is a progressive process affecting the kidneys, causing renal failure that can be life-threatening. Thus, renal fibrosis has become a serious concern in the ageing population; however, fibrotic development cannot be diagnosed early and assessed noninvasively in both patients and experimental animal models. Here, we found that serum amyloid A3 (Saa3) expression is a potent indicator of early renal fibrosis; we also established in vivo Saa3/C/EBPβ-promoter bioluminescence imaging as a sensitive and specific tool for early detection and visualization of tubulointerstitial fibrosis. Saa3 promoter activity is specifically upregulated in parallel with tumor necrosis factor α (TNF-α) and fibrotic marker collagen I in injured kidneys. C/EBPβ, upregulated in injured kidneys and expressed in tubular epithelial cells, is essential for the increased Saa3 promoter activity in response to TNF-α, suggesting that C/EBPβ plays a crucial role in renal fibrosis development. Our model successfully enabled visualization of the suppressive effects of a citrus flavonoid derivative, glucosyl-hesperidin, on inflammation and fibrosis in kidney disease, indicating that this model could be widely used in exploring therapeutic agents for fibrotic diseases., This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to No. Y).