Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis.

In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(ß-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

Acute irradiation causes a long-term disturbance in the heterogeneity and gene expression profile of medullary thymic epithelial cells.

The thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, a detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and a high level of TSAs was severely decreased by irradiation. In sum, we propose that the effects of acute irradiation disrupt the heterogeneity and properties of mTECs over an extended period, which potentially leads to an impairment of thymic T cell selection.

Subclavian Artery-Carotid Artery Bypass for Subclavian Artery or Common Carotid Artery Severe Stenosis or Occlusion.

Various surgical treatments are available for occlusive subclavian and common carotid artery diseases. Nevertheless, to date, when cerebral endovascular treatment is utilized, revascularization via direct surgery may be required. This study reported five symptomatic cases of revascularization for CCA and SCA occlusive and stenotic lesions that were expected to be challenging to treat with endovascular treatment. We performed subclavian artery-common carotid artery or internal carotid artery bypass using artificial blood vessels or saphenous vein grafts in five patients with subclavian steal syndrome, symptomatic common carotid artery occlusion, and severe proximal common carotid artery stenosis. In this study, good bypass patency was achieved in all five cases. Although there were no intraoperative complications, one patient had a postoperative lymphatic leak. Moreover, there was no recurrence of stroke during postoperative follow-up for an average of 2 years. Conclusively, subclavian artery-common carotid artery bypass can be an effective surgical treatment for common carotid artery occlusion, proximal common carotid artery stenosis, and subclavian artery occlusion.

Fentanyl-induced muscle rigidity in a dog during weaning from mechanical ventilation after emergency abdominal surgery: A case report.

A 22.5-kg, 8.4-year-old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl- and sevoflurane-based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco-abdominal muscle rigidity. To rule out fentanyl-induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl-induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 µg kg-1 ).

Integrative analysis of scRNA-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regulator.

Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit-amplifying Aire+mTEC precursors during the Aire+mTEC differentiation process of the postnatal thymus.

Hedgehog signaling plays a crucial role in hyperalgesia associated with neuropathic pain in mice.

Neuropathic pain is a debilitating chronic syndrome of the nervous system caused by nerve injury. In Drosophila, the Hedgehog (Hh) signaling pathway is related to increased pain sensitivity (hyperalgesia) but does not affect the baseline nociceptive threshold. In general, the contribution of the Hh signaling pathway to neuropathic pain in vertebrates is a highly debated issue. Alternatively, we investigated the potential role of Hh signaling in mechanical allodynia using a mouse model of neuropathic pain. Seven days after spinal nerve-transection (SNT) surgery, microglial activation increased in the ipsilateral spinal dorsal horn compared with that in the sham group; however, 21 days after surgery, microglial activation decreased. Contrastingly, astrocyte activation in the spinal cord did not differ between the groups. On day 21 of postsurgery, the SNT group showed marked upregulation of sonic hedgehog expression in peripheral glial cells but not in dorsal root ganglion (DRG) neurons. Intrathecal administration of the Hh signaling inhibitor vismodegib attenuated the mechanical allodynia observed on day 21 postsurgery. Conversely, intrathecal treatment with the Hh signaling activator smoothened agonist in naive mice induced mechanical allodynia, which was abolished by the ATP transporter inhibitor clodronate. Moreover, inhibition of Hh signaling by pretreatment with vismodegib significantly reduced ATP secretion and the frequency/number of spontaneous elevations of intracellular calcium ion levels in cultured DRG cells. Thus, the Hh signaling pathway appears to modulate the neural activity of DRG neurons via ATP release, and it plays an important role in sustaining mechanical allodynia and hypersensitivity in a mouse model of neuropathic pain.

Prediction of Cross-Clamp-Induced Cerebral Ischemia During Carotid Endarterectomy Using Arterial Blood Flow Assessment.

BACKGROUND: Cross-clamping during carotid endarterectomy (CEA) is associated with the risk of cerebral ischemia. Various studies have evaluated different criteria for detecting cerebral ischemia, but difficulties arise when ischemic changes appear after the carotid artery is cross-clamped and incised. Here, we explored a parameter that can predict cerebral ischemia prior to cross-clamping during CEA using a blood-flow meter. METHODS: The carotid arterial blood flow was measured directly (direct ABF) in the common carotid artery prior to cross-clamping. The anatomical information in preoperative magnetic resonance imaging, cerebral blood flow in xenon-enhanced computed tomography, and carotid peak systolic flow velocity by carotid echo from the skin surface were also evaluated. A decrease in the short-latency somatosensory evoked potentials (SSEP) during cross-clamping to insert a shunt was assessed, and a decrease in amplitude of ≥ 50% was considered an indicator for cerebral ischemia. Surgery was performed under general anesthesia, and a shunt was inserted in all cases. RESULTS: Of 156 CEA patients between April 2013 and March 2020, 30 had decreased SSEP during cross-clamping. The baseline characteristics and intra- and postoperative findings were not significantly different between patients with and without a decrease in SSEP. Among the evaluated parameters, only the direct-ABF ratio (ABF-internal carotid artery/ABF-common carotid artery) differed significantly between the 2 groups (P = 0.011). The direct-ABF ratio ≤ 0.58 was predictive of cerebral ischemia during CEA. CONCLUSIONS: Direct-ABF measurement with an ultrasonic blood-flow meter can be useful for predicting cerebral ischemia prior to carotid artery cross-clamping during CEA.

Aspergillus sphenoiditis growth on long cut ends of a non-absorbable sellar floor dura closure suture.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhea is a common complication after transsphenoidal surgery (TSS). Suturing of sellar dura is effective in the prevention of postoperative CSF rhinorrhea, but it may cause rare postoperative infections. Herein, we report a case of Aspergillus sphenoiditis with the growth noted on cut ends of a polyvinylidene fluoride (PVDF) suture used for dural closure. CASE DESCRIPTION: A previously healthy 51-year-old woman complained of abnormal odor 5 years after TSS for null cell adenoma. A white mass in the sphenoidal sinus was detected on rhinoscopy. Fungal balls were found clustered around the ends of a PVDF suture used for dural closure at the initial surgery. She underwent removal of both the fungal ball and dural suture. The pathological diagnosis was Aspergillus hyphae. It is thought that a dural suture protruding out of the sphenoid sinus mucosa can cause Aspergillus infection even in immunocompetent patients. A rapid and accurate diagnosis followed by surgical removal of the fungal ball and follow-up with oral antimycotic drugs result in good clinical outcomes. CONCLUSION: It is crucial to cut short the suture end and cover it with sphenoid sinus mucosa to avoid such complications.

Role of magnetic resonance vessel wall imaging in detecting and managing ruptured aneurysms among multiple intracranial aneurysms.

BACKGROUND: Wall enhancement of intracranial saccular aneurysms in high-resolution magnetic resonance vessel wall imaging (MR-VWI) might indicate a ruptured aneurysm. Therefore, this study aimed to determine the diagnostic ability of wall enhancement to detect the ruptured aneurysms among multiple aneurysms. METHODS: Patients with subarachnoid hemorrhage (SAH) and multiple intracranial aneurysms who underwent MR-VWI before craniotomy and clipping were included in the study. Three-dimensional T1-weighted fast spin-echo sequences were obtained before and after gadolinium injection. Aneurysm rupture was estimated based on the subarachnoid clot distribution, aneurysmal contours, and MR-VWI findings. We selectively performed surgical clipping and confirmed the rupture site intraoperatively. RESULTS: Thirteen patients with SAH with 13 ruptured and 17 unruptured aneurysms were treated at out facility. The accuracy rate of rupture site diagnosis using MR-VWI was 69.2% (9/13 cases). Each unruptured aneurysm was equally or more strongly enhanced in the other four cases than the ruptured aneurysms. In three of the four unruptured aneurysms with positive MR-VWI findings, atherosclerosis of the aneurysmal wall was observed during simultaneous or elective clipping surgery. Further, clipping surgery was performed without intraoperative rupture in two cases with the help of MR-VWI findings. CONCLUSION: Correct diagnosis of the rupture site using MR-VWI alone was unreliable due to false positives caused by the wall enhancement of unruptured aneurysms with atherosclerosis. Therefore, ruptured aneurysms should be detected using more information in addition to MR-VWI images. MR-VWI may be advantageous to determine surgical strategies when managing patients with SAH and multiple aneurysms.

In Pursuit of Adult Progenitors of Thymic Epithelial Cells.

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.

The heptamer sgRNA targeting the human OCT4 mRNA can upregulate the OCT4 expression.

TRUE gene silencing is one of the gene suppression technologies. This technology exploits the enzymatic property of the tRNA 3' processing endoribonuclease tRNase ZL, which is that it can cleave a target RNA under the direction of a small guide RNA (sgRNA). We have been working on the development of therapeutic sgRNAs for hematological malignancies. In the course of an experiment to examine the ability of the heptamer-type sgRNA H15792 targeting the OCT4 mRNA to differentiate human amnion stem cells, we observed unexpectedly that the amnion cells exhibited a morphology resembling initialized cells. Here we investigated the effect of H15792 on human HL60 leukemia cells, and found that H15792 can upregulate the OCT4 expression and the expression of alkaline phosphatase in the cells.

[Intraoperative Rupture from Cerebral Aneurysm: Tactics for Management and Strategy for Prevention].

Rupture of a cerebral aneurysm during surgery carries risks that may lead to poor patient outcomes. Rupture often occurs during the separation procedure of the aneurysm from the surrounding structure. Knowledge regarding the basic principles of operation of surgical apparatus, for example suction devices, before and after the aneurysm rupture event is of paramount importance. It is desirable to deal with these complicated situations automatically in a non-heuristic manner, although some experience and learning are necessary to obtain this ability. When we necessarily apply temporary occlusion of the parent arteries, we need to consider the merits and demerits of temporary occlusion, as well as the limits of the occlusion time in order to prevent ischemic complications.

Results of surgical treatment after Gamma Knife radiosurgery for cerebral arteriovenous malformations: patient series.

BACKGROUND: Gamma Knife radiosurgery (GKRS) is a safe and effective treatment, but it has a risk of bleeding. Herein, the authors describe their experience with some patients who required surgical removal of cerebral arteriovenous malformations (AVMs) located mainly in eloquent areas of the brain after GKRS, and they consider the advantages of surgical removal after GKRS. OBSERVATIONS: Twelve patients who had undergone surgical removal of AVMs after GKRS at Tokyo Women's Medical University between April 2013 and July 2019 were selected for analysis. All participants underwent GKRS as first-line therapy for AVMs located in an eloquent region or if requested by the patient. Complete obliteration was achieved in 7 patients, and the size of the nidus decreased in 3 patients during the follow-up period. The Spetzler-Martin grade decreased in 11 patients. Three patients experienced symptomatic intracerebral hemorrhage before and after confirmation of complete obliteration of the nidus via GKRS, and 7 patients experienced some neurological deficits because of an encapsulated expanding hematoma. All patients underwent resection of the nidus without complications. The preoperative neurological deficits improved in 6 patients and remained unchanged in 6 patients. LESSONS: This report indicates that performing GKRS before surgery may be useful for future multimodal therapy.

High-flow bypass using saphenous vein grafts with trapping of ruptured blood blister-like aneurysms of the internal carotid artery: patient series.

BACKGROUND: Trapping an aneurysm after the establishment of an extracranial to intracranial high-flow bypass is considered the optimal surgical strategy for ruptured blood blister-like aneurysms (BBAs) of the internal carotid artery (ICA). For high-flow bypass surgeries, a radial artery graft is generally preferred over a saphenous vein graft (SVG). However, SVGs can be advantageous in acute-phase surgeries because of their greater length, easy manipulability, ability to act as high-flow conduits, and reduced risk of vasospasms. In this study, the authors presented five cases of ruptured BBAs treated with high-flow bypass using an SVG followed by BBA trapping, and they reported on surgical outcomes and operative nuances that may help avoid potential pitfalls. OBSERVATIONS: After the surgeries, there were no ischemic or hemorrhagic complications, including symptomatic vasospasms. In three of the five cases, postoperative modified Rankin scale scores were between 0 and 2 at the 3-month follow-up. In one case, the SVG spontaneously occluded after surgery while the protective superficial temporal artery (STA) to middle cerebral artery (MCA) bypass became dominant, and the patient experienced no ischemic symptoms. LESSONS: High-flow bypass using an SVG with a protective STA-MCA bypass followed by BBA trapping is a safe and effective treatment strategy.

Heptamer-type small guide RNA that can shift macrophages toward the M1 state.

Multiple myeloma is a refractory cancer of plasma cells. Although treatment strategies for multiple myeloma are getting improved year by year, in most cases patients relapse due to the emergence of drug-resistant mutations in the myeloma cells. The interplay between myeloma cells and tumor-associated macrophages (TAM) is important for the pathology. We thought that some heptamer-type sgRNAs for TRUE gene silencing would be able to transform TAM toward the M1 state and might become therapeutic drugs for myeloma. Here, we searched for heptamer-type sgRNAs that can shift macrophages toward the M1 state. We screened a heptamer-type sgRNA library for the ability to up-regulate IL-12b gene expression in human macrophage-like cell lines, and found three such sgRNAs. One of the sgRNAs, H12960, which also showed such ability in human fresh macrophages and mouse macrophage-like cell lines, efficiently suppressed human myeloma cell growth in SCID/NOD mice.

Mastication Affects Transcriptomes of Mouse Microglia.

BACKGROUND/AIM: We investigated whether mastication affects microglia, whose activity is thought to be associated with cognition and brain tumor progression. MATERIALS AND METHODS: We kept mice by feeding either a hard or soft diet for 2, 4 or 8 months. After each period, we removed the whole brains and isolated microglia. The total RNA extracted from each brain's microglia was subjected to DNA microarray analysis. RESULTS: Many genes were found to be significantly differentially expressed between hard- and soft-diet-fed mice in each group of the same feeding period. The expression of several genes involved in the regulation of actin cytoskeleton was down-regulated in the soft-diet-fed mice. CONCLUSION: Mastication may affect microglia's roles in cognition as well as their neuroimmune activity through their activity of patrolling the brain.

Region- and neuronal-subtype-specific expression of Na,K-ATPase alpha and beta subunit isoforms in the mouse brain.

Na,K-ATPase is a ubiquitous molecule contributing to the asymmetrical distribution of Na+ and K+ ions across the plasma membrane and maintenance of the membrane potential, a prerequisite of neuronal activity. Na,K-ATPase comprises three subunits (α, ß, and FXYD). The α subunit has four isoforms in mice, with three of them (α1, α2, and α3) expressed in the brain. However, the functional and biological significances of the different brain isoforms remain to be fully elucidated. Recent studies have revealed the association of Atp1a3, a gene encoding α3 subunit, with neurological disorders. To map the cellular distributions of the α subunit isoforms and their coexpression patterns, we evaluated the mRNA expression of Atp1a1, Atp1a2, and Atp1a3 by in situ hybridization in the mouse brain. Atp1a1 and Atp1a3 were expressed in neurons, whereas Atp1a2 was almost exclusively expressed in glial cells. Most neurons coexpressed Atp1a1 and Atp1a3, with highly heterogeneous expression levels across the brain regions and neuronal subtypes. We identified parvalbumin (PV)-expressing GABAergic neurons in the hippocampus, somatosensory cortex, and retrosplenial cortex as an example of a neuronal subtype expressing low Atp1a1 and high Atp1a3. The expression of Atp1b isoforms was also heterogeneous across brain regions and cellular subtypes. The PV-expressing neurons expressed a high level of Atp1b1 and a low level of Atp1b2 and Atp1b3. These findings provide basic information on the region- and neuronal-subtype-dependent expression of Na,K-ATPase α and ß subunit isoforms, as well as a rationale for the selective involvement of neurons expressing high levels of Atp1a3 in neurological disorders.

The 31-nucleotide Y4-RNA fragment in plasma is a potential novel biomarker.

The 31- and 32-nt 5'-fragment of Y4-RNA (Y4RNAfr) exists abundantly in human peripheral blood plasma. Although physiological roles of the plasma Y4RNAfr are not well established, its potential utility as a diagnostic/prognostic marker for acute coronary syndrome was suggested. In this paper, to establish a normal range of the Y4RNAfr level in plasma, we measured plasma Y4RNAfr levels of 40 healthy persons using the method we have developed, and compared them with other blood test data. From the obtained data, we tentatively regarded <0.1 fmol/ng as normal for the Y4RNAfr level in peripheral blood plasma. And the white blood cell count (WBC) and the C-reactive protein (CRP) level showed moderate positive correlations with the Y4RNAfr level, suggesting that Y4RNAfr could be a potential novel inflammatory marker. We also measured the Y4RNAfr level in peripheral blood plasma from four multiple myeloma patients. The plasma Y4RNAfr level was abnormal in all four myeloma patients, and the levels for two patients were far beyond the normal level. The WBC for each patient was normal and the CRP levels for two patients were normal. These observations together suggest that a high level of Y4RNAfr in peripheral blood plasma and a normal WBC could be indicative of multiple myeloma.