Essentials for early diagnosis of primary intramedullary spinal cord lymphoma. How to suspect primary intramedullary spinal cord lymphoma early and proceed to invasive biopsy? A case report and literature review.

Background: Primary intramedullary spinal cord lymphoma (PISCL) is an extremely rare condition. Early diagnosis is very difficult due to the nonspecific clinical and imaging findings. A biopsy is essential for a definitive diagnosis, but courage is required to perform the surgery. Here, we present a case of PISCL and suggest useful indicators for accurate diagnosis of this pathological entity. Case Description: A 70-year-old woman presented with subacute bilateral lower-limb paralysis, disturbance of warm and pain sensations, and vesicorectal disturbance. Magnetic resonance imaging showed a contrast-enhanced mass from C7 to Th2 and large, edematous lesions from the upper cervical to lower thoracic spinal cord. Elevated uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) was identified in the enhanced regions on FDG-positron emission tomography (PET). Cerebrospinal fluid (CSF) analysis revealed highly elevated levels of ß2-microglobulin (ß2-MG). Steroid pulse therapy and therapeutic plasma exchange were performed for suspected myelitis, but symptoms did not improve. Spinal cord biopsy was, therefore, performed for treatment-resistant myelopathy. Histopathological examination revealed diffuse large B-cell lymphoma, which was diagnosed as PISCL because systemic examination showed no other findings suggestive of malignant lymphoma. Conclusion: In cases with poor response to treatment and a progressive course, PISCL should be considered, and spinal cord biopsy should be performed if PET shows increased 18F-FDG uptake and ß2-MG is elevated in CSF.

A far-ultraviolet-driven photoevaporation flow observed in a protoplanetary disk.

Most low-mass stars form in stellar clusters that also contain massive stars, which are sources of far-ultraviolet (FUV) radiation. Theoretical models predict that this FUV radiation produces photodissociation regions (PDRs) on the surfaces of protoplanetary disks around low-mass stars, which affects planet formation within the disks. We report James Webb Space Telescope and Atacama Large Millimeter Array observations of a FUV-irradiated protoplanetary disk in the Orion Nebula. Emission lines are detected from the PDR; modeling their kinematics and excitation allowed us to constrain the physical conditions within the gas. We quantified the mass-loss rate induced by the FUV irradiation and found that it is sufficient to remove gas from the disk in less than a million years. This is rapid enough to affect giant planet formation in the disk.

One-leg standing time is a simple measure for loss of skeletal muscle mass and fat deposition in muscle: the J-SHIPP study.

BACKGROUNDS: One-leg standing time (OLST) has been frequently used physical performance measure; however, what muscular characteristics OLST represents remains uncertain. AIM: This cross-sectional study aimed to investigate the association between OLST and muscle characteristics to clarify the possibility of using OLST as a physical performance measure. METHODS: Study participants comprised 1144 older adults aged 65 years or older. Computed tomography images provided mid-thigh skeletal muscle cross-sectional area and mean attenuation value. OLST was measured for a maximum of 60 s. Static postural instability was assessed using a posturography. RESULTS: A frequency of OLST < 20 s was increased by quartiles of muscle cross-sectional area (Q1: 33.6, Q2: 12.8, Q3: 13.6, Q4: 11.9%, P < 0.001) and mean attenuation value (Q1: 32.3, Q2: 21.7, Q3: 14.3, Q4: 7.7%, P < 0.001). Results of the multinomial regression analysis indicated that muscle cross-sectional area and mean attenuation value were independently associated with an OLST of less than 20 s. The crude odds ratio of OLST less than 20 s for the lowest quartiles of both cross-sectional area and mean attenuation value was 4.19 (95% CI: 3.01 - 5.84). The cross-sectional area of muscles with greater fat deposition was inversely associated with OLST, while that with smaller fat deposition showed a positive association with OLST, indicating why mean attenuation value and cross-sectional area were independently associated with OLST. No clear relationship was observed with static postural instability. CONCLUSION: OLST was a simply measurable quantifiable physical measure representing the loss of muscle mass and quality in older adults.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Preservation Efficacy of a Quercetin and Sucrose Solution for Warm Ischemically Damaged Porcine Liver Grafts.

BACKGROUND: The University of Wisconsin (UW) solution is the gold standard for preserving the liver, kidneys, and pancreas. For renal preservation, the addition of the flavonoid, quercetin (QE), to the preservation solution reduces damage to renal tubular cells, and the addition of sucrose (Suc) is also beneficial for preservation. The aim of this study was to investigate the protective effects of QE and Suc on porcine livers in terms of warm and cold injury and to evaluate whether their use improves ischemia-reperfusion (I/R) injury after simple cold storage (CS). METHODS: We tested porcine livers procured after 30 minutes of warm ischemia followed by preservation for 6 hours under the following 2 conditions: group 1, preserved with the CS/UW solution (n = 4); group 2, preserved with the CS/UW solution containing Que 33.1 µM and Suc 0.1 M (n = 6). All livers were evaluated using an ex vivo isolated liver reperfusion model with saline-diluted autologous blood. RESULTS: Aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels in group 2 were significantly lower at 30 minutes of reperfusion than in group 1. Furthermore, histologic evaluation by hematoxylin and eosin staining showed significantly fewer morphologic changes in group 2 than in group 1, as indicated by the total Suzuki score. Group 2 also had significantly better scores for sinusoidal congestion and hepatocyte cytoplasmic vacuolization. CONCLUSION: Adding Que and Suc to the UW solution can effectively prevent cold injury in livers donated after circulatory death.

Case report: Frontotemporal dementia and amyotrophic lateral sclerosis caused by a missense variant (p.Arg89Trp) in the valosin-containing protein gene.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

Formation of the methyl cation by photochemistry in a protoplanetary disk.

Forty years ago, it was proposed that gas-phase organic chemistry in the interstellar medium can be initiated by the methyl cation CH3+ (refs. 1-3), but so far it has not been observed outside the Solar System4,5. Alternative routes involving processes on grain surfaces have been invoked6,7. Here we report James Webb Space Telescope observations of CH3+ in a protoplanetary disk in the Orion star-forming region. We find that gas-phase organic chemistry is activated by ultraviolet irradiation.

Hepatocyte-specific damage in acute toxicity of sodium ferrous citrate: Presentation of a human autopsy case and experimental results in mice.

Acute iron overload is known to exert deleterious effects in the liver, but detailed pathology has yet to be documented. Here, we report pathological findings in an autopsy case of acute iron toxicity and validation of the findings in mouse experiments. In a 39-year-old woman who intentionally ingested a large amount of sodium ferrous citrate (equivalent to 7.5 g of iron), severe disturbance of consciousness and fulminant hepatic failure rapidly developed. Liver failure was refractory to treatment and the patient died on Day 13. Autopsy revealed almost complete loss of hepatocytes, while bile ducts were spared. To examine the detailed pathologic processes induced by excessive iron, mice were orally administered equivalent doses of ferrous citrate. Plasma aminotransferase levels markedly increased after 6 h, which was preceded by increased plasma iron levels. Hepatocytes were selectively damaged, with more prominent damage in the periportal area. Phosphorylated c-Jun was detected in hepatocyte nuclei after 3 h, which was followed by the appearance of γ-H2AX expression. Hepatocyte injury in mice was associated with the expression of Myc and p53 after 12 and 24 h, respectively. Even at lethal doses, the bile ducts were morphologically intact and fully viable. Our findings indicate that acute iron overload induces hepatocyte-specific liver injury, most likely through hydroxyl radical-mediated DNA damage and subsequent stress responses.

Ingestion of a collagen peptide containing high concentrations of prolyl-hydroxyproline and hydroxyprolyl-glycine reduces advanced glycation end products levels in the skin and subcutaneous blood vessel walls: a randomized, double-blind, placebo-controlled study.

In this randomized, double-blind, placebo-controlled study, we investigated the effects of collagen peptides (CP) containing high concentrations of prolyl-hydroxyproline and hydroxyprolyl-glycine on advanced glycation end products (AGEs) levels in the skin and subcutaneous blood vessel walls. A total of 31 individuals aged 47-87 years were randomly assigned to receive either 5 g/day of fish-derived CP or a placebo for 12 weeks. Body and blood compositions and AGEs levels were measured at the beginning and end of the study. No adverse events were observed, and both groups' blood and body compositions did not change significantly. However, the CP group had significantly lower AGEs levels and a slightly lower insulin resistance index (homeostasis model assessment ratio [HOMA-R]) than the placebo group. In addition, the percentage changes in AGEs and HOMA-R levels were positively and strongly correlated in both groups. These findings suggest that fish-derived CP may be effective in reducing AGEs levels and improving insulin resistance.

Bioimpedance phase angle is independently associated with myosteatosis: The Shizuoka study.

BACKGROUND & AIMS: Phase angle (PhA) calculated from the resistance and reactance measured using a bioimpedance device was suggested to represent the degree of fat deposition in muscle (myosteatosis), though no direct evidence is available. We aimed to clarify the possible association between PhA and skeletal muscle myosteatosis in community-dwelling middle-aged to older adults. METHODS: Participants consisted of 424 Japanese (aged ≥50 years). Leg PhA and skeletal muscle mass index (SMI) were obtained by bioelectrical impedance analysis. The mean attenuation values and cross-sectional area of the mid-thigh skeletal muscle were calculated from computed tomography images and considered as indexes of myosteatosis and skeletal muscle mass, respectively. RESULTS: Leg PhA was positively associated with SMI, and cross-sectional area and mean attenuation value at mid-thigh. Multiple regression analysis adjusted for possible covariates identified leg PhA (ß = 0.214) and SMI (ß = 0.260) as independent factors of mid-thigh muscle cross-sectional area (P < 0.001), while leg PhA (ß = 0.349, P < 0.001) but not SMI (P = 0.645) was associated with mean attenuation value. Similar results were observed in the analysis in the older (≥65 years) subpopulation. The combination of low SMI and low leg PhA showed stepwise association with cross-sectional area, while only individuals with low leg PhA had lower mean attenuated value. CONCLUSIONS: Leg PhA was independently associated with mean attenuated value of the mid-thigh skeletal muscle, suggesting that the assessment of PhA in combination with SMI could provide additional information for the evaluation of muscle properties.

Combined Use of Subnormothermic Extracorporeal Support and Hypothermic Oxygenated Machine Perfusion for Liver Graft After Cardiac Death in Pigs.

BACKGROUND: The use of grafts from donors after cardiac death (DCD) would greatly contribute to the expansion of the donor organ pool. This study aims to determine the benefits of extracorporeal membrane oxygenation (ECMO) and hypothermic oxygenated machine perfusion (HOPE) in a large animal model of DCD liver. METHODS: After cardiac arrest, the abdominal aorta and the inferior vena cava were cannulated and connected to an ECMO circuit. Porcine livers were perfused in situ with ECMO at 22°C for 60 minutes after 45 minutes of cardiac death. Then, the livers were perfused for 4 hours by cold storage (CS) or HOPE. In group 1, non-in situ ECMO and grafts were preserved by HOPE. In group 2, in situ ECMO and grafts were preserved by HOPE. In group 3, in situ ECMO and grafts were preserved by CS. After preservation, all grafts were evaluated using an isolated reperfusion model (IRM) with autologous blood for 2 hours. RESULTS: During HOPE, aspartate aminotransferase (AST) levels and hepatic arterial pressure in group 2 tended to be lower than in group 1. Hematoxylin-eosin staining findings after HOPE showed more massive sinusoidal congestion and hepatocyte cytoplasmic vacuolization in group 1 than in group 2. The AST and LDH levels in group 2 at the start-up of IRM tended to be lower than in group 1. CONCLUSIONS: The combined use of in situ subnormothermic ECMO and HOPE is essential for the functional recovery of DCD liver grafts.

Associations between adiponectin and leptin levels and skeletal muscle mass and myosteatosis in older adults: The Shimanami Health Promoting Program study.

AIM: Identifying plasma molecules associated with skeletal muscle properties can elucidate the pathophysiology of sarcopenia. Because adipocytokines are a promising candidate marker, the current study aimed to clarify the possible associations between adiponectin and leptin levels and mid-thigh muscle cross-sectional area and mean attenuation value, which are indices of muscle mass and fat deposition in muscle, respectively. METHODS: The current study included 1440 older Japanese adults (mean age 69.3 years). Mid-thigh skeletal muscle cross-sectional area and mean attenuation value were evaluated through computed tomography scan. A low attenuation value showed a greater fat deposition in muscle. Circulating adiponectin and leptin levels were assessed using blood specimens collected during the baseline investigation. RESULTS: Plasma leptin level was inversely correlated with muscle cross-sectional area, but not with attenuation value. The association with cross-sectional area was independent of possible confounding factors including body size (Q1: reference; Q2: ß = -0.032, P = 0.033; Q3: ß = -0.064, P < 0.001; Q4: ß = -0.111, P < 0.001). In contrast, adiponectin level was independently and inversely associated with attenuation value (Q1: reference; Q2: ß = -0.044, P = 0.122; Q3: ß = -0.080, P = 0.006; Q4: ß = -0.159, P < 0.001), but not with cross-sectional area. These associations between adipocytokine levels and muscle properties were independent of abdominal fat area and insulin resistance. CONCLUSIONS: There were adiposity- and insulin resistance-independent associations between adipocytokines levels and skeletal muscle mass and fat deposition in muscle, suggesting an involvement of adipocytokines in muscle properties. Geriatr Gerontol Int 2023; 23: 444-449.

High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation.

In contrast to the robust proliferation exhibited following acute liver injury, hepatocytes exhibit long-lasting proliferative activity in chronic liver injury. The mechanistic differences between these distinct modes of proliferation are unclear. Hepatocytes exhibited robust proliferation that peaked at 2 days following partial hepatectomy in mice, but this proliferation was completely inhibited by hepatocyte-specific expression of MadMyc, a Myc-suppressing chimeric protein. However, Myc suppression induced weak but continuous hepatocyte proliferation, thereby resulting in full restoration of liver mass despite an initial delay. Late-occurring proliferation was accompanied by prolonged suppression of proline dehydrogenase (PRODH) expression, and forced PRODH overexpression inhibited hepatocyte proliferation. In hepatocytes in chronic liver injury, Myc was not activated but PRODH expression was suppressed in regenerating hepatocytes. In liver tumors, PRODH expression was often suppressed, especially in the highly proliferative tumors with distinct Myc expression. Our results indicate that the robust proliferation of hepatocytes following acute liver injury requires high levels Myc expression and that there is a compensatory Myc-independent mode of hepatocyte proliferation with the regulation of proline metabolism, which might be relevant to liver regeneration in chronic injury.

Effects of Maca on Muscle Hypertrophy in C2C12 Skeletal Muscle Cells.

With aging, sarcopenia and the associated locomotor disorders, have become serious problems. The roots of maca contain active ingredients (triterpenes) that have a preventive effect on sarcopenia. However, the effect of maca on muscle hypertrophy has not yet been investigated. The aim of this study was to examine the effects and mechanism of maca on muscle hypertrophy by adding different concentrations of yellow maca (0.1 mg/mL and 0.2 mg/mL) to C2C12 skeletal muscle cell culture. Two days after differentiation, maca was added for two days of incubation. The muscle diameter, area, differentiation index, and multinucleation, were assessed by immunostaining, and the expression levels of the proteins related to muscle protein synthesis/degradation were examined by Western blotting. Compared with the control group, the muscle diameter and area of the myotubes in the maca groups were significantly increased, and the cell differentiation index and multinucleation were significantly higher in the maca groups. Phosphorylation of Akt and mTOR was elevated in the maca groups. Maca also promoted the phosphorylation of AMPK. These results suggest that maca may promote muscle hypertrophy, differentiation, and maturation, potentially via the muscle hypertrophic signaling pathways such as Akt and mTOR, while exploring other pathways are needed.

Dermal advanced glycation end-product accumulation is associated with sarcopenia-related measures in middle-aged and older men.

AIMS: Sarcopenia is the age-associated atrophy of muscles, and advanced glycation end-products (AGEs) accumulate in patients with age-associated diseases. We aimed to investigate the relationship between AGE accumulation in the skin and sarcopenia in middle-aged and older Japanese people. MATERIALS AND METHODS: We enrolled 240 participants in this cross-sectional study. The participants consisted of 120 men (mean age 68.8 ± 10.1 years) and 120 women (mean age 67.4 ± 9.0 years). The level of dermal AGE accumulation in the forearms was measured using skin autofluorescence (SAF) and many parameters associated with sarcopenia, including grip strength and thigh muscle cross-sectional area (CSA), were evaluated during medical check-ups at the Ehime University Hospital. RESULTS: Grip strength and thigh muscle CSA were significantly higher in men than women, but mean SAF did not significantly differ between them. There were significant correlations of age, height, C-reactive protein, glycated hemoglobin, grip strength, and thigh muscle CSA with SAF in men, but only age in women. Multivariate analysis showed that SAF was significantly independently associated with low grip strength in men (ß =-0.211, p =0.046). The men were then allocated to four groups according to their grip strength and thigh muscle CSA, and SAF was significantly higher in the lowgrip strength/low-thigh muscle CSA group than in the high-grip strength/high-thigh muscle CSA group (low/low group 2.25 ± 0.37 and high/high group 1.93 ± 0.36, p =0.001). CONCLUSIONS: SAF is associated with sarcopenia-related measures, especially grip strength, in middle-aged and older Japanese men, but not women.

Vascular endothelial dysfunction associated with severity in multiple sclerosis.

BACKGROUND: Impairment of cerebrovascular reactivity (CVR) has been reported in patients with multiple sclerosis (MS). Chronic inflammation and endothelial dysfunction are possible mechanisms underlying this hemodynamic impairment. This study aimed to evaluate CVR and endothelial function in patients with MS and explore their relationships with disease progression using functional sonographic procedures. METHODS: Patients with MS and age-/sex-matched healthy controls were assessed for endothelial function, determined by flow-mediated dilation (FMD), and CVR, measured using the breath-holding index (BHI). RESULTS: Twenty-seven patients with MS and 24 healthy controls were enrolled. FMD was significantly lower in MS subjects than in control subjects (6.0 ± 0.6 vs. 8.6 ± 0.7, p = 0.006); furthermore, BHI was similarly lower in MS than in controls, but insignificant. Remarkably, FMD was significantly lower in secondary progressive MS subjects than in relapse-remitting MS subjects (3.7 ± 1.3 vs. 6.7 ± 0.7, p = 0.045). In addition, FMD was inversely correlated with the disability score as per the expanded disability status scale (R2 = 0.170, p = 0.033) and modified Rankin scale (R2 = 0.187, p = 0.027). CONCLUSION: In patients with MS, endothelial dysfunction was more noticeable than CVR impairment, correlating with the severity and progression of MS.

Decreased Portal Circulation Augments Fibrosis and Ductular Reaction in Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease often progresses to cirrhosis and causes liver cancer, but mechanisms of its progression are yet to be elucidated. Although nonalcoholic fatty liver disease is often associated with abnormal portal circulation, there have not been any experimental studies to test its pathogenic role. Here, whether decreased portal circulation affected the pathology of nonalcoholic steatohepatitis (NASH) was examined using congenital portosystemic shunt (PSS) in C57BL/6J mice. Whereas PSS significantly attenuated free radical-mediated carbon tetrachloride injury, it augmented pericellular fibrosis in the centrilobular area induced by a 0.1% methionine choline-deficient l-amino acid-defined high-fat diet (CDAHFD). PSS aggravated ductular reaction and increased the expression of connective tissue growth factor. Pimonidazole immunohistochemistry of the liver revealed that the centrilobular area of PSS-harboring mice was more hypoxic than that of control mice. Although tissue hypoxia was observed in the fibrotic area in CDAHFD-induced NASH in both control and PSS-harboring mice, it was more profound in the latter, which was associated with higher carbonic anhydrase 9 and vascular endothelial growth factor expression and neovascularization in the fibrotic area. Furthermore, partial ligation of the portal vein also augmented pericellular fibrosis and ductular reaction induced by a CDAHFD. These results demonstrate that decreased portal circulation, which induces hypoxia due to disrupted intralobular perfusion, is an important aggravating factor of liver fibrosis in NASH.

Low Carotid Flow Pulsatility Index Correlates With the Presence of Unruptured Intracranial Aneurysms.

Background We assessed cases of incidental unruptured intracranial aneurysm (UIA) discovered on screening magnetic resonance angiography to identify hemodynamic and atherosclerotic risk factors. Methods and Results The data of 1376 healthy older subjects (age range, 31-91 years) without cerebro- or cardiovascular diseases who underwent brain magnetic resonance angiography as part of a medical checkup program at a health screening center were examined retrospectively. We looked for an increase in classical risk factors for UIAs (age, sex, hypertension, and smoking) and laboratory data related to lifestyle diseases among subjects with UIAs. Brachial-ankle pulse wave velocity, central systolic blood pressure, radial augmentation index, and carotid flow pulsatility index were also compared between those with and without UIAs. We found UIAs in 79 (5.7%) of the subjects. Mean age was 67.1±9.0 years, and 55 (70%) were women. Of the 79 aneurysms, 75 (95%) were in the anterior circulation, with a mean diameter of 3.1 mm (range, 2.0-8.0 mm). Subjects with UIAs were significantly older and had more severe hypertension. The carotid flow pulsatility index was significantly lower in subjects with UIAs and negatively and independently correlated with UIAs. Tertile analysis stratified by carotid flow pulsatility index revealed that subjects with lower indices had higher levels of low-density lipoprotein cholesterol. Conclusions The presence of UIAs correlated with lower carotid flow pulsatility index and elevated low-density lipoprotein cholesterol in the data from a population of healthy older volunteers. A reduced carotid flow pulsatility index may affect low-density lipoprotein cholesterol elevation by some molecular pathways and influence the development of cerebral aneurysms. This may guide aneurysm screening indications for institutions where magnetic resonance angiography is not routine.

Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice.

The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC-CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS- or HRAS/Myc-induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte-derived liver tumors were induced in heterozygous and homozygous p53-knockout (KO) mice by hydrodynamic tail vein injection of HRAS- or Myc-containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase-expressing plasmid. The HRAS-induced and HRAS/Myc-induced tumors in the wild-type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53-KO mice was consistent with cHCC-CCA. The expression of fetal/neonatal liver proteins, including delta-like 1, was detected in the HRAS/Myc-induced but not in the HRAS-induced cHCC-CCA tissues. The dedifferentiation in the HRAS/Myc-induced tumors was more marked in the homozygous p53-KO mice than in the heterozygous p53-KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte-derived tumor cells through either transdifferentiation or Myc-mediated dedifferentiation.