Feasibility of the Ultrasound-Guided Insertion of the Peripherally Inserted Central Catheter (PICC) by the Vascular Surgeon at the Bedside in the Trauma Intensive Care Unit.

BACKGROUND: This study analyzed the outcomes of the ultrasound-guided insertion of the peripherally inserted central venous catheter (PICC) by experienced vascular surgeons at the bedside of the trauma intensive care unit (ICU) and compared the outcomes with those of fluoroscopy-guided PICC performed by radiologists in the interventional suite. METHODS: Between May 1, 2016, and April 30, 2021, 97 patients who were hospitalized in the trauma ICU and underwent PICC insertion were enrolled in the study. Forty-two out of the 97 patients underwent PICC insertion by interventional radiologists in the interventional radiology suite under fluoroscopy guidance, while the remaining 55 cases underwent ultrasound-guided PICC insertion by the vascular surgeon at the trauma ICU bedside. RESULTS: The technical failure (P = 0.504) and malposition (P = 0.127) rates were not significantly different between the 2 groups. However, it took significantly less time for the vascular surgeon to complete the PICC insertion procedure (P < 0.001). Significantly more patients of the ultrasound-guided group required inotropes (P = 0.012) and mechanical ventilation (P = 0.003) at the time of the procedure. In addition, the ultrasound-guided group appeared to be in critical condition in terms of kidney function according to laboratory data (P = 0.014). Meanwhile, the ultrasound-guided group maintained the central line catheter for a shorter time (P < 0.001). CONCLUSIONS: In trauma patients, ultrasound-guided PICC insertion at the bedside by experienced vascular surgeons at the trauma ICU was feasible compared to fluoroscopy-guided insertion performed by interventional radiologists.

Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products.

RATIONALE: Oxidative stress is an important contributing factor in several human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid docosahexaenoic acid, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have proangiogenic and proinflammatory functions. Although CEP is continuously accumulated during chronic processes, such as tumor progression and atherosclerosis, its level during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism. OBJECTIVE: To identify the cellular and molecular mechanism for CEP clearance. METHODS AND RESULTS: Here, we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80(hi) and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared with F4/80(lo) and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on 2 receptors expressed by macrophages, CD36 and toll-like receptor 2. Although knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages' ability to scavenge CEP derivatives of proteins. CONCLUSIONS: Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.

Oxidative stress in angiogenesis and vascular disease.

Despite the damaging effect on tissues at a high concentration, it has been gradually established that oxidative stress plays a positive role during angiogenesis. In adults, physiological or pathological angiogenesis is initiated by tissue demands for oxygen and nutrients, resulting in a hypoxia/reoxygenation cycle, which, in turn promotes the formation of reactive oxygen species (ROS). The ROS can be generated either endogenously, through mitochondrial electron transport chain reactions and nicotinamide adenine dinucleotide phosphate oxidase, or exogenously, resulting from exposure to environmental agents, such as ultraviolet or ionizing radiation. In many conditions, ROS promotes angiogenesis, either directly or via the generation of active oxidation products, including peroxidized lipids. The latter lipid metabolites are generated in excess during atherosclerosis, thereby linking atherogenic processes and pathological angiogenesis. Although the main mechanism of oxidative stress-induced angiogenesis involves hypoxia-inducible factor/vascular endothelial growth factor (VEGF) signaling, recent studies have identified several pathways that are VEGF-independent. This review aims to provide a summary of the past and present views on the role of oxidative stress as a mediator and modulator of angiogenesis, and to highlight newly identified mechanisms.

Gamma-ray radiation response at 1550 nm of fluorine-doped radiation hard single-mode optical fiber.

We have investigated gamma-ray radiation response at 1550 nm of fluorine-doped radiation hard single-mode optical fiber. Radiation-induced attenuation (RIA) of the optical fiber was measured under intermittent gamma-ray irradiations with dose rate of ~10 kGy/h. No radiation hardening effect on the RIA by the gamma-ray pre-dose was found when the exposed fiber was bleached for long periods of time (27~47 days) at room-temperature. Photo-bleaching scheme upon 980 nm LD pumping has proven to be an effective deterrent to the RIA, particularly by suppressing the incipient RIA due to room-temperature unstable self-trapped hole defects (STHs). Large temperature dependence of the RIA of the optical fiber together with the photo-bleaching effect are worthy of note for reinforcing its radiation hard characteristics.

Radial-firing optical fiber tip containing conical-shaped air-pocket for biomedical applications.

We report a novel radial-firing optical fiber tip containing a conical-shaped air-pocket fabricated by deforming a hollow optical fiber using electric arc-discharge process. The hollow optical fiber was fusion spliced with a conventional optical fiber, simultaneously deforming into the intagliated conical-shaped region along the longitudinal fiber-axis of the fiber due to the gradual collapse of the cavity of the hollow optical fiber. Then the distal-end of the hollow optical fiber was sealed by the additional arc-discharge in order to obstruct the inflow of an external bio-substance or liquid to the inner air surface during the surgical operations, resulting in the formation of encased air-pocket in the silica glass fiber. Due to the total internal reflection of the laser beam at the conical-shaped air surface, the laser beam (λ = 632.8 nm) was deflected to the circumferential direction up to 87 degree with respect to the fiber-axis.

Near-Field Sound Localization Based on the Small Profile Monaural Structure.

The acoustic wave around a sound source in the near-field area presents unconventional properties in the temporal, spectral, and spatial domains due to the propagation mechanism. This paper investigates a near-field sound localizer in a small profile structure with a single microphone. The asymmetric structure around the microphone provides a distinctive spectral variation that can be recognized by the dedicated algorithm for directional localization. The physical structure consists of ten pipes of different lengths in a vertical fashion and rectangular wings positioned between the pipes in radial directions. The sound from an individual direction travels through the nearest open pipe, which generates the particular fundamental frequency according to the acoustic resonance. The Cepstral parameter is modified to evaluate the fundamental frequency. Once the system estimates the fundamental frequency of the received signal, the length of arrival and angle of arrival (AoA) are derived by the designed model. From an azimuthal distance of 3-15 cm from the outer body of the pipes, the extensive acoustic experiments with a 3D-printed structure show that the direct and side directions deliver average hit rates of 89% and 73%, respectively. The closer positions to the system demonstrate higher accuracy, and the overall hit rate performance is 78% up to 15 cm away from the structure body.

Monaural sound localization based on structure-induced acoustic resonance.

A physical structure such as a cylindrical pipe controls the propagated sound spectrum in a predictable way that can be used to localize the sound source. This paper designs a monaural sound localization system based on multiple pyramidal horns around a single microphone. The acoustic resonance within the horn provides a periodicity in the spectral domain known as the fundamental frequency which is inversely proportional to the radial horn length. Once the system accurately estimates the fundamental frequency, the horn length and corresponding angle can be derived by the relationship. The modified Cepstrum algorithm is employed to evaluate the fundamental frequency. In an anechoic chamber, localization experiments over azimuthal configuration show that up to 61% of the proper signal is recognized correctly with 30% misfire. With a speculated detection threshold, the system estimates direction 52% in positive-to-positive and 34% in negative-to-positive decision rate, on average.

Cysteine as an Innovative Biomarker for Kidney Injury.

BACKGROUND: Kidney transplantation is a widely used treatment for end-stage kidney disease. Nevertheless, the incidence of acute kidney injury (AKI) in deceased donors poses a potential hazard because it significantly increases the risk of delayed graft function and potentially exerts an influence on the kidney allograft outcome. It is crucial to develop a diagnostic model capable of assessing the existence and severity of AKI in renal grafts. However, no suitable kidney injury markers have been developed thus far. METHODS: We evaluated the efficacy of the molecular probe NPO-B, which selectively responds to cysteine, as a new diagnostic tool for kidney injury. We used an in vitro model using ischemia/reperfusion injury human kidney-2 cells and an in vivo ischemia/reperfusion injury mouse model. Additionally, cysteine was investigated using urine samples from deceased donors and living donors to assess the applicability of detection techniques to humans. RESULTS: This study confirmed that the NPO-B probe effectively identified and visualized the severity of kidney injury by detecting cysteine in both in vitro and in vivo models. We observed that the fluorescence intensity of urine samples measured using NPO-B from the deceased donors who are at a high risk of renal injury was significantly stronger than that of the living donors. CONCLUSIONS: If implemented in clinical practice, this new diagnostic tool using NPO-B can potentially enhance the success rate of kidney transplantation by accurately determining the extent of AKI in renal grafts.

TGF-ß sensitivity is determined by N-linked glycosylation of the type II TGF-ß receptor.

N-linked glycosylation is a critical determinant of protein structure and function, regulating processes such as protein folding, stability and localization, ligand-receptor binding and intracellular signalling. TßRII [type II TGF-ß (transforming growth factor ß) receptor] plays a crucial role in the TGF-ß signalling pathway. Although N-linked glycosylation of TßRII was first demonstrated over a decade ago, it was unclear how this modification influenced TßRII biology. In the present study, we show that inhibiting the N-linked glycosylation process successfully hinders binding of TGF-ß1 to TßRII and subsequently renders cells resistant to TGF-ß signalling. The lung cancer cell line A549, the gastric carcinoma cell line MKN1 and the immortal cell line HEK (human embryonic kidney)-293 exhibit reduced TGF-ß signalling when either treated with two inhibitors, including tunicamycin (a potent N-linked glycosylation inhibitor) and kifunensine [an inhibitor of ER (endoplasmic reticulum) and Golgi mannosidase I family members], or introduced with a non-glycosylated mutant version of TßRII. We demonstrate that defective N-linked glycosylation prevents TßRII proteins from being transported to the cell surface. Moreover, we clearly show that not only the complex type, but also a high-mannose type, of TßRII can be localized on the cell surface. Collectively, these findings demonstrate that N-linked glycosylation is essentially required for the successful cell surface transportation of TßRII, suggesting a novel mechanism by which the TGF-ß sensitivity can be regulated by N-linked glycosylation levels of TßRII.

All-Nontoxic Fluorescent Probe for Biothiols and Its Clinical Applications for Real-Time Glioblastoma Visualization.

Fluorescence-guided surgery (FSG) is a surgical method to selectively visualize the tumor site using fluorescent materials with instrumental setups in the operation rooms. It has been widely used in the surgery of brain tumors, such as glioblastoma (GBM), which is difficult to distinguish from normal tissue. Although FSG is crucial for GBM surgery, the commercially available fluorescent materials for FSG have shown serious adverse effects. To satisfy the clinical demand, we recently reported reaction-based fluorescent probes based on a 4-chloro-7-nitrobenzofurazan (NBD) fluorophore that can detect cysteine (Cys) and homocysteine (Hcy), a biomarker of GBM, and their applications for the GBM diagnosis and FSG. However, our probes have cellular toxicity issues arising from the leaving group (LG) that is generated after the reaction of the fluorescent probe and the analytes. In this study, we disclosed a nontoxic fluorescent probe for sensing biothiols and their clinical applications for real-time human glioblastoma visualization. Systematic toxicity analysis of several LGs was conducted on several cell lines. Among the LGs, 2-hydroxy-pyridine showed negligible toxicity, and its fluorescent probe derivative (named NPO-o-Pyr) showed high specificity and sensitivity (LOD: 0.071 ppm for Cys; 0.189 ppm for Hcy), a fast response time (<5 min) to Cys and Hcy, and high biocompatibility. In addition, NPO-o-Pyr can significantly detect the GBM site both in actual clinical samples as well as in the GBM-xenografted mouse model. We are confident that NPO-o-Pyr will become a new substitute in FSG due to its capability to overcome the limitations of the current fluorescent probes.

Effect of Zn addition on non-resonant third-order optical nonlinearity of the Cu-doped germano-silicate optical glass fiber.

Cu/Zn-codoped germano-silicate optical glass fiber was manufactured by using the modified chemical vapor deposition (MCVD) process and solution doping process. To investigate the reduction effect of Zn addition on Cu metal formation in the core of the Cu/Zn-codoped germano-silicate optical glass fiber, the optical absorption property and the non-resonant third-order optical nonlinearity were measured. Absorption peaks at 435 nm and 469 nm in the Cu/Zn-codoped germano-silicate optical glass fiber were contributed to Cu metal particles and ZnO semiconductor particles, respectively. The effective non-resonant optical nonlinearity, gamma, of the Cu/Zn-codoped germano-silicate optical glass fiber was measured to be 1.5097 W(-1) x km(-1) by using the continuous-wave self-phase modulation method. The gamma of the Cu/Zn-codoped germano-silicate optical glass fiber was about four times larger than that of the reference germano-silicate optical glass fiber without any dopants. The increase of the effective non-resonant optical nonlinearity, gamma, of the Cu/Zn-codoped germano-silicate optical glass fiber, can be attributed to the enhanced nonlinear polarization due to incorporated ZnO semiconductor particles and Cu metal ions in the glass network. The Cu/Zn-codoped germano-silicate optical glass fiber showed high nonlinearity and low transmission loss at the optical communication wavelength, which makes it suitable for high-speed-high-capacity optical communication systems.

Effective supercontinuum generation by using highly nonlinear dispersion-shifted fiber incorporated with Si nanocrystals.

The dispersion-shifted fiber (DSF) incorporated with Si nanocrystals (Si-NCs) having highly nonlinear optical property was fabricated to investigate the effective supercontinuum generation characteristics by using the MCVD process and the drawing process. Optical nonlinearity was enhanced by incorporating Si nanocrystals in the core of the fiber and the refractive index profile of a dispersion-shifted fiber was employed to match its zero-dispersion wavelength to that of the commercially available pumping source for generating effective supercontinuum. The non-resonant nonlinear refractive index, n2, of the Si-NCs doped DSF measured by the cw-SPM method was measured to be 7.03 x 10(-20) [m2/W] and the coefficient of non-resonant nonlinearity, gamma, was 7.14 [W(-1) km(-1)]. To examine supercontinuum generation of the Si-NCs doped DSF, the femtosecond fiber laser with the pulse width of 150 fs (at 1560 nm) was launched into the fiber core. The output spectrum of the Si-NCs doped DSF was found to broaden from 1300 nm to wavelength well beyond 1700 nm, which can be attributed to the enhanced optical nonlinearity by Si-NCs embedded in the fiber core. The short wavelength of the supercontinuum spectrum in the Si-NCs doped DSF showed shift from 1352 nm to 1220 nm for the fiber length of 2.5 m and 200 m, respectively.

Tumor regression grade combined with lymph node status in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.

INTRODUCTION: We aimed to elucidate the prognostic value of tumor regression grade (TRG) combined with lymph node status compared with the 8th edition of the ypTNM staging system in patients with advanced esophageal squamous cell cancer (ESCC) after neoadjuvant chemoradiotherapy (nCRT). METHODS: We enrolled 325 patients with ESCC who underwent nCRT followed by complete resection. We adopted the modified Schneider TRG system, with high (ypT0N0), mid (ypT0N+ or ypT + N0), and low (ypT + N+). After developing a multivariable Cox model, the discrimination ability of the ypStage and TRG systems was evaluated using the Akaike Information Criterion (AIC) and R2 measure. RESULTS: The mean duration of follow-up was 56.7 ± 43.3 months. The survival curves between the adjacent groups of TRG were significantly different for both overall survival (OS) and recurrence-free survival (RFS). However, there were no significant differences between ypStages II and III for OS (p = 0.683) or RFS (p = 0.760). The TRG system also had a discrimination ability in patients with ypStage I (p < 0.001 for both OS and RFS) and ypStage III (p = 0.045 for OS and 0.042 for RFS). Compared with the ypTNM staging system, the modified TRG had a lower AIC value (1835.99 vs. 1852.02) and a higher R2 (0.256 vs. 0.177), indicating better discrimination ability and prediction accuracy. CONCLUSIONS: For patients with ESCC who underwent esophagectomy following nCRT, the modified Schneider TRG system may complement the ypStage and help clinicians select the most appropriate postoperative treatment and surveillance.

Combined Intrathoracic and Abdominal Splenosis.

BACKGROUND Splenosis refers to autotransplantation of splenic tissue after splenic injury or splenectomy, most frequently occurring in the abdominal and pelvic cavities. Thoracic splenosis is a rare condition associated with a history of simultaneous rupture of the spleen and diaphragm resulting from trauma. To the best of our knowledge, only a limited number of cases have been reported for combined intrathoracic and abdominal splenosis. CASE REPORT We present a case of a 50-year-old man with a history of splenectomy and left nephrectomy 15 years ago due to an accident, who had experienced chest pain for the past month. A 1-cm focal pleural thickening in the left posterior pleura was revealed on the chest computed tomography (CT) scan. We found this to be suspicious for a solitary fibrous tumor. Based on this information, surgery was performed for tumor removal, and the pathologic examination confirmed splenic tissues. The patient was then discharged without any complications. Further abdominopelvic CT showed several contrast-enhanced lesions, suggestive of intraperitoneal splenosis. CONCLUSIONS We would like to emphasize the importance of thorough history-taking to avoid misdiagnosis and unnecessary procedures with respect to the rarity of splenosis. Moreover, appropriate use of diagnostic tools, including radionuclide imaging studies, is recommended to establish an accurate diagnosis of thoracic splenosis.

Pyridine-NBD: A homocysteine-selective fluorescent probe for glioblastoma (GBM) diagnosis based on a blood test.

The precise in vitro diagnosis requires a high selectivity and sensitivity for a diagnostic agent. In this respect, fluorescent diagnostic probes have attracted attention in various clinical fields. Herein, we disclosed a tailor-made fluorescent homocysteine probe (NPO-Pyr) based on pyridine-thiol coordination and amine-addition. To date, Hcy has been recognized as an excellent biomarker for various diseases, but there still remain some limitations in detecting of Hcy due to its structural similarity to Cys. In this study, we developed a new fluorescent diagnostic probe for monitoring Hcy by incorporating 4-hydroxy-pyridine moiety into the skeleton of the NBD fluorophore. The incorporated pyridine moiety could coordinate with the thiol group at Hcy, followed by the amine-addition reaction (12 kJ/mol). Based on this rationale, NPO-Pyr responded to Hcy and exhibited turn-on properties with high selectivity and sensitivity (LOD: 0.084 ppm), and a fast-response time (<5 min). Furthermore, NPO-Pyr could predict the formation of glioblastoma (GBM) at an early stage through sensing Hcy in blood plasma (vs. healthy group, ∗∗∗∗P < 0.0001). Our findings have a significant importance across various fields from basic science to clinical translation, and we strongly believe that NPO-Pyr has the potential to fully replace the current complex GBM diagnostic process as a simpler in vitro agent.

Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium.

Heterogeneity of endothelial cell (EC) populations reflects their diverse functions in maintaining tissue's homeostasis. However, their phenotypic, molecular, and functional properties are not entirely mapped. We use the Tie2-CreERT2;Rosa26-tdTomato reporter mouse to trace, profile, and cultivate primary ECs from different organs. As paradigm platform, we use this strategy to study bone marrow endothelial cells (BMECs). Single-cell mRNA sequencing of primary BMECs reveals that their diversity and native molecular signatures is transitorily preserved in an ex vivo culture that conserves key cell-to-cell microenvironment interactions. Macrophages sustain BMEC cellular diversity and expansion and preserve sinusoidal-like BMECs ex vivo. Endomucin expression discriminates BMECs in populations exhibiting mutually exclusive properties and distinct sinusoidal/arterial and tip/stalk signatures. In contrast to arterial-like, sinusoidal-like BMECs are short-lived, form 2D-networks, contribute to in vivo angiogenesis, and support hematopoietic stem/progenitor cells in vitro. This platform can be extended to other organs' ECs to decode mechanistic information and explore therapeutics.

Red-Emitting SBBF (Single-Benzene-Based Fluorophore)-Silica Hybrid Material: One-Pot Synthesis, Characterization, and Biomedical Applications.

We report, for the first time, a new red-emitting hybrid material based on a single-benzene-based fluorophore (SBBF) and silica. This robust formulation shows several features, including bright emissions at a red wavelength (>600 nm), high scalability (>gram-scale), facile synthesis (one-pot reaction; SBBF formation, hydrolytic condensation, propagation), high stability (under different humidity, pH, light), bio-imaging applicability with low cellular toxicity, and an antibacterial effect within Gram-negative/Gram-positive strains. Based on our findings, we believe that these hybrid materials can pave the way for the further development of dye-hybrid materials and applications in various fields.

Prevalence of chronic post-thoracotomy pain in patients with traumatic multiple rib fractures in South Korea: a cross-sectional study.

Chronic post-thoracotomy pain is a debilitating condition after traumatic multiple rib fractures and surgery. We aimed to estimate the prevalence of chronic post-thoracotomy pain after traumatic multiple rib fractures in South Korea and explore factors associated with it. From October 2017 to June 2019, a cross-sectional survey of 100 adults, who had undergone thoracotomy due to traumatic fractures of two or more ribs 2 years to 3 months prior to the survey, was conducted in the regional trauma center in South Korea. In total, 80% and 65% patients reported any level and above moderate chronic pain, respectively. Quality of life was mostly below the normative value of the US general population. Forty-six percent patients had restrictive respiratory dysfunction, and 47% and 59% patients were classified as being at risk of above mild-level anxiety and depression, respectively. More than 70% of patients had a current opioid prescription. Multivariable logistic regression analysis showed weak evidence of association between acute, severe postoperative pain and chronic postsurgical pain (adjusted odds ratio 2.4, 95% confidence intervals 0.9 to 6.4). Collectively, chronic post-thoracotomy pain and associated incomplete recovery regarding respiratory, functional, and psychological outcomes were prevalent in patients with traumatic multiple rib fractures in South Korea.

Acupuncture combined with multidisciplinary care for recovery after traumatic multiple rib fractures: a prospective feasibility cohort study.

INTRODUCTION: Acute pain significantly delays early physiological recovery and results in chronic functional disability in patients with traumatic multiple rib fractures (MRFs). This prospective cohort study aimed to investigate the feasibility of acupuncture combined with multidisciplinary care during recovery in patients with traumatic MRFs. METHODS: Twenty patients with traumatic MRFs who were admitted to a regional trauma centre in South Korea were enrolled. A combination of acupuncture and multidisciplinary inpatient ward management was provided at the trauma ward. Patients were permitted to continue acupuncture treatments at outpatient clinics for 3 months after the traumatic events. Clinical outcomes, including pain, acute physiological recovery, quality of life, patient satisfaction with the care provided, respiratory function and use of opioids, were evaluated up to 6 months after trauma. RESULTS: Seventeen (85%) participants completed the 6-month follow-up. One patient withdrew consent during admission due to discomfort after three sessions of acupuncture. The proportion of patients with above-moderate level of pain decreased from 95% at baseline to 41% at 6 months. Quality of life appeared to deteriorate consistently throughout the study period. Around 80% of respondents expressed satisfaction with the acupuncture treatments and stated that they found acupuncture to be acceptable. Over 94% of respondents reported slight or considerable improvement. CONCLUSION: The provision of acupuncture combined with multidisciplinary care for recovery in patients with traumatic MRFs was feasible in a regional trauma centre in South Korea. Randomised trials are needed to investigate the role of acupuncture combined with multidisciplinary care in the future. TRIAL REGISTRATION NUMBER: KCT0002911 (Clinical Research Information Service).

Defective Notch activation in microenvironment leads to myeloproliferative disease.

Despite the great importance of nonhematopoietic cells constituting the microenvironment for normal hematopoiesis, the cellular interactions between nonhematopoietic cells themselves are largely unknown. Using the Cre-loxP system in mice to inactivate Mind bomb-1 (Mib1), an essential component for Notch ligand endocytosis, here we show that the development of an MPD is dependent on defective Notch activation in the microenvironment. Our 2 independent Mib1 conditional knockout (CKO) mouse lines each developed a myeloproliferative disease (MPD), with gradual accumulations of immature granulocytes. The mutant mice showed hepatosplenomegaly, anemia, granulocytosis, and leukocyte infiltration in multiple organs and finally died at approximately 20 weeks of age. We were surprised to find that the transplantation of wild-type bone marrow cells into the Mib1-null microenvironment resulted in a de novo MPD. Moreover, by introducing the constitutively active intracellular domain of Notch1 in the Mib1-null background, we show that active Notch1 expression in the Mib1-null microenvironment significantly suppressed the disease progression, suggesting that the MPD development in the Mib1 CKO mice is due to defective Notch activation in the nonhematopoietic cells. These findings demonstrate that normal hematopoiesis absolutely requires Notch activation through the Notch ligand-receptor interaction between microenvironmental cells themselves and shed light on the microenvironment that fosters hematopoietic disorders.