Autoimmune Encephalitis Associated with Anti-N-methyl-D-aspartate Receptor and Anti-Hu Antibodies Successfully Treated with Carboplatin and Etoposide for Small-cell Lung Cancer.

The coexistence of multiple autoantibodies associated with autoimmune encephalitis (AE) is rare. A 63-year-old woman developed psychosis and consciousness disorder. Her cerebrospinal fluid was positive for anti-N-methyl-D-aspartate receptor antibodies, and her serum was positive for anti-Hu antibodies. Enhanced computed tomography revealed a mass in the right pulmonary hilum. AE complicated with small-cell lung cancer was diagnosed. Immunotherapy (steroid therapy and intravenous immunoglobulin) and four courses of carboplatin-etoposide chemotherapy were required to improve her neurological symptoms. When the coexistence of multiple antibodies is detected, despite its rarity, aggressive detection and treatment of any underlying malignancy may be recommended.

Possible Role of Phosphatidylcholine and Sphingomyelin on Fumonisin B1-mediated Toxicity.

A major corn-related mycotoxin, fumonisin B1 (FB1), continues to attract attention of researchers as well as risk-assessors due to the diverse toxicological characteristics, including distinct target tissues in different animal species and opposite susceptibility in males and females in mice and rats. More than thirty years passed since the structure identification as a sphingoid-like chemical, but the causal mechanism of the toxicity remains obscure in spites of extensive studies. Considerable amounts of knowledge have been accumulated on the biochemical/toxicological actions of FB1, but the influence on lipid dynamics and mobilization in the body has not been focused well in relation to the FB1-mediated toxicity. Considerable influences of this toxin on mobilization of sphingolipids and phospholipids and also on adaptive changes in their compositions in tissues are implicated from recent studies on FB1-interacting ceramide synthases. Accumulated patho-physiological data also suggest a possible role of hepatic phospholipid on FB1-mediated toxicity. Thus, a mechanism of FB1-mediated toxicity is discussed in relation to the mobilization of phospholipids and sphingolipids in the body in this context.

Variability of breathing during wakefulness while using CPAP predicts adherence.

BACKGROUND AND OBJECTIVE: The standard therapy for obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP) therapy. However, long-term adherence remains at ~50% despite improvements in behavioural and educational interventions. Based on prior work, we explored whether regularity of breathing during wakefulness might be a physiologic predictor of CPAP adherence. METHODS: Of the 117 consecutive patients who were diagnosed with OSA and prescribed CPAP, 79 CPAP naïve patients were enrolled in this prospective study. During CPAP initiation, respiratory signals were collected using respiratory inductance plethysmography while wearing CPAP during wakefulness in a seated position. Breathing regularity was assessed by the coefficient of variation (CV) for breath-by-breath estimated tidal volume (VT ) and total duration of respiratory cycle (Ttot). In a derivation group (n = 36), we determined the cut-off CV value which predicted poor CPAP adherence at the first month of therapy, and verified the validity of this predetermined cut-off value in the remaining participants (validation group; n = 43). RESULTS: In the derivation group, the CV for estimated VT was significantly higher in patients with poor adherence than with good adherence (median (interquartile range): 44.2 (33.4-57.4) vs 26.0 (20.4-33.2), P < 0.001). The CV cut-off value for estimated VT for poor CPAP adherence was 34.0, according to a receiver-operating characteristic (ROC) curve. In the validation group, the CV value for estimated VT >34.0 confirmed to be predicting poor CPAP adherence (sensitivity, 0.78; specificity, 0.83). CONCLUSION: At the initiation of therapy, breathing regularity during wakefulness while wearing CPAP is an objective predictor of short-term CPAP adherence.

Acute Bilateral Renal and Splenic Infarctions Occurring during Chemotherapy for Lung Cancer.

We herein report a rare case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer. A 60-year-old man presented with acute and intensive upper abdominal and back pain during chemotherapy with cisplatin and etoposide for lung cancer. Contrast-enhanced computed tomography (CT) revealed bilateral renal and splenic infarctions. After the administration of unfractionated heparin his pain was relieved with a clearance of the infarctions in the CT findings and a recovery of renal dysfunction. Enhanced coagulation by lung cancer and arterial ischemia by chemotherapy may therefore contribute to the development of these infarctions.

Shh/Ptch and EGF/ErbB cooperatively regulate branching morphogenesis of fetal mouse submandibular glands.

The hedgehog family includes Sonic hedgehog (Shh), Desert hedgehog, and Indian hedgehog, which are well known as a morphogens that play many important roles during development of numerous organs such as the tongue, pancreas, kidney, cartilage, teeth and salivary glands (SMG). In Shh null mice, abnormal development of the salivary gland is seen after embryonic day 14 (E14). Shh also induced lobule formation and lumen formation in acini-like structures in cultured E14 SMG. In this study, we investigated the relationship between Shh and epidermal growth factor (EGF)/ErbB signaling in developing fetal mouse SMG. Administration of Shh to cultured E13 SMG stimulated branching morphogenesis (BrM) and induced synthesis of mRNAs for EGF ligands and receptors of the ErbB family. Shh also stimulated activation of ErbB signaling system such as ERK1/2. AG1478, a specific inhibitor of ErbB receptors, completely suppressed BrM and activation of EGF/ErbB/ERK1/2 cascade in E13 SMGs cultured with Shh. The expressions of mRNA for Egf in mesenchyme and mRNA for Erbb1, Erbb2 and Erbb3 in epithelium of E13 SMG were specifically induced by administration of Shh. These results show that Shh stimulates BrM of fetal mouse SMG, at least in part, through activation of the EGF/ErbB/ERK1/2 signaling system.

Mini Nutritional Assessment Short-Form predicts exacerbation frequency in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity, mortality and reduced health status. Thus, to predict and prevent exacerbations is essential for the management of COPD. The aims of this study were to determine whether nutritional status as assessed by the Mini Nutritional Assessment Short-Form (MNA-SF) predicts COPD exacerbation and to compare the ability of the MNA-SF to predict COPD exacerbation with that of the COPD Assessment Test (CAT). METHODS: Pulmonary function, the modified Medical Research Council (mMRC) scale and body mass index (BMI) were evaluated in 60 stable patients with COPD (mean age, 72 years; mean forced expiratory volume in 1 s (FEV1 ), 51.1% predicted). The MNA-SF and CAT were also completed. Exacerbations were recorded prospectively for 1 year after the initial assessment. RESULTS: The mean MNA-SF score was 11.4 ± 2.4 (well nourished, 51%; at risk, 37%; and malnourished, 12%). The mean CAT score was 14.4 ± 7.5 (low impact, 37%; medium impact, 38%; high impact, 20%; and very high impact, 5%). The CAT scores were significantly associated with the mMRC scale and %FEV1, but were not associated with BMI and the MNA-SF score. The exacerbation frequency was associated with the MNA-SF score but not with the CAT score. CONCLUSIONS: The MNA-SF predicts COPD exacerbation independently of the CAT.

Branched-chain amino acid-rich diet improves skeletal muscle wasting caused by cigarette smoke in rats.

Cigarette smoke induces skeletal muscle wasting by a mechanism not yet fully elucidated. Branched-chain amino acids (BCAA) in the skeletal muscles are useful energy sources during exercise or systemic stresses. We investigated the relationship between skeletal muscle wasting caused by cigarette smoke and changes in BCAA levels in the plasma and skeletal muscles of rats. Furthermore, the effects of BCAA-rich diet on muscle wasting caused by cigarette smoke were also investigated. Wistar Kyoto (WKY) rats that were fed with a control or a BCAA-rich diet were exposed to cigarette smoke for four weeks. After the exposure, the skeletal muscle weight and BCAA levels in plasma and the skeletal muscles were measured. Cigarette smoke significantly decreased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles, while a BCAA-rich diet increased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles that had decreased by cigarette smoke exposure. In conclusion, skeletal muscle wasting caused by cigarette smoke was related to the decrease of BCAA levels in the skeletal muscles, while a BCAA-rich diet may improve cases of cigarette smoke-induced skeletal muscle wasting.

The impact of obstructive sleep apnea and nasal CPAP on circulating adiponectin levels.

PURPOSE: Although obstructive sleep apnea syndrome (OSAS) is known to be an important risk factor for cardiovascular diseases, the mechanism behind this association has not been fully elucidated. Transendothelial migration of monocytes mediated by adhesion molecules is a crucial step in the pathogenesis of atherosclerosis. We investigated the effect of hypoxic stress on plasma adiponectin and tumor necrosis factor-α (TNF-α) levels and whether adiponectin and TNF-α modulate adhesion molecules in patients with OSAS. METHODS: In 22 patients, plasma adiponectin and TNF-α levels and serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) were determined early in the morning after polysomnography and after nasal continuous positive airway pressure (nCPAP) treatment. RESULTS: Plasma adiponectin levels were inversely correlated with the apnea-hypopnea index (AHI) (r = -0.582, p < 0.005) and % time in SpO2 <90 % (r = -0.539, p < 0.01) but not with the body mass index (BMI). TNF-α levels were positively correlated with the AHI (r = 0.462, p < 0.05) and BMI (r = 0.452, p < 0.05). Serum sICAM-1 levels were inversely correlated with plasma adiponectin levels (r = -0.476, p < 0.05) but not with TNF-α levels. Although plasma TNF-α levels decreased after overnight nCPAP treatment (p < 0.05), plasma adiponectin levels increased after long-term nCPAP (3 months) treatment (p < 0.02) in ten patients. CONCLUSIONS: Our findings suggest that reduced adiponectin and elevated TNF-α levels in plasma are associated with OSAS-induced hypoxic stress. Decreased adiponectin levels are associated with sICAM-1 levels.

Distribution of bone mineral content is associated with body weight and exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although low bone mineral density is highly prevalent in patients with chronic obstructive pulmonary disease (COPD), the distribution of the reduced bone mass has not been fully elucidated. OBJECTIVES: To determine regional bone mass loss in patients with COPD and investigate whether the change in distribution may be associated with body weight loss and functional capacity. METHODS: Body mass index (BMI) was assessed, and height squared indices were derived for the bone mineral content index (BMCI) of the arms, legs and trunk by dual-energy X-ray absorptiometry in 45 male patients with COPD and 12 age- and sex-matched control subjects. Pulmonary function tests were performed, and maximal oxygen uptake (VO2max) was measured. RESULTS: The BMCI was lower in the total bone, legs and trunk of patients with COPD than in control subjects, although the BMCI in the arms was similar between the groups. BMI correlated significantly with the BMCI in all 3 segments. Bone mineral content (BMC) in the trunk, expressed as a percentage of total BMC (BMC trunk/total BMC), correlated significantly with BMI. The BMCI in the trunk was closely related with VO2max but not with airflow limitation. CONCLUSIONS: There was a regional difference in BMC reduction, but a predominant reduction of bone mass in the trunk was not associated with the severity of airflow limitation but rather with body weight loss and exercise intolerance. These data suggest that body weight loss and exercise intolerance are important risk factors for vertebral fracture in patients with COPD.

P2Y11 purinoceptor mediates the ATP-enhanced chemotactic response of rat neutrophils.

ATP and hydrolysis products of ATP like adenosine regulate the chemotaxis of neutrophils by activating purinoceptors and adenosine receptors. The present study was designed to examine exogenous ATP, activation of purinoceptors, and activation of A(3) adenosine receptor as key steps in the signal cascades that control cell orientation and migration of rat neutrophils. One or more of those steps might be potential therapeutic targets for treatment of inflammatory diseases. The chemotaxis of rat neutrophils was stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and measured with an EZ-TAXIScan apparatus. The effects of apyrase, exogenous ATP, suramin (P2X and P2Y blocker), PPADS (a P2X blocker), TNP-ATP (P2X(1) and P2X(3) antagonist), and Reactive Blue 2 (a P2Y blocker) on the chemotactic response were also investigated. Rat neutrophil chemotaxis was significantly suppressed by apyrase. fMLP induced rat neutrophil chemotaxis was potentiated by ATP, blocked by suramin, not affected by PPADS or TNP-ATP, and significantly inhibited by RB-2. Western blotting showed that A(3), P2Y(2), and P2Y(11) were expressed in rat neutrophils. The chemotactic response of rat neutrophils to fMLP stimulation is potentiated by ATP via P2Y(11) purinoceptors but not P2X purinoceptors or A(3) adenosine receptor, and that the response plays a critical role in host defense and pathogenicity.

Extracellular regulated kinase5 is expressed in fetal mouse submandibular glands and is phosphorylated in response to epidermal growth factor and other ligands of the ErbB family of receptors.

Growth factors and their receptors regulate development of many organs through activation of multiple intracellular signaling cascades including a mitogen-activated protein kinase (MAPK). Extracellular regulated kinases (ERK)1/2, classic MAPK family members, are expressed in fetal mouse submandibular glands (SMG), and stimulate branching morphogenesis. ERK5, also called big mitogen-activated protein kinase 1, was recently found as a new member of MAPK super family, and its biological roles are still largely unknown. In this study, we investigated the expression and function of ERK5 in developing fetal mouse SMGs. Western blotting analysis showed that the expression pattern of ERK5 was different from the pattern of ERK1/2 in developing fetal SMGs. Both ERK1/2 and ERK5 were phosphorylated after exposure to ligands of the ErbB family of receptor tyrosine kinases (RTKs). Phosphorylation of ERK1/2 was strongly induced by epidermal growth factor (EGF) in SMG rudiments at embryonic day 14 (E14), E16 and E18. However, ERK5 phosphorylation induced by EGF was clearly observed at E14 and E16, but not at E18. Branching morphogenesis of cultured E13 SMG rudiments was strongly suppressed by administration of U0126, an inhibitor for ERK1/2 activation, whereas the phosphorylation of ERK5 was not inhibited by U0126. BIX02188, a specific inhibitor for ERK5 activation, also inhibited branching morphogenesis in cultured SMG rudiments. These results show that EGF-responsive ERK5 is expressed in developing fetal mouse SMG, and suggest that both ERK1/2 and ERK5 signaling cascades might play an important role in the regulation of branching morphogenesis.

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes.

INTRODUCTION: Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis. METHODS: Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb). RESULTS: Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss. CONCLUSIONS: The differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.

Reduced larger von Willebrand factor multimers at dawn in OSA plasmas reflect severity of apnoeic episodes.

Plasma von Willebrand factor (VWF), produced in and released from vascular endothelial cells by various stimuli including hypoxia, induces platelet aggregation under high shear stress and plays dual pivotal roles in haemostasis and thrombosis within arterioles, which are regulated by the size of vWF multimers (VWFMs). Patients with obstructive sleep apnoea (OSA) have increased risk of thrombotic cardiovascular events, but the pathogenesis is unclear. We examined the relationship between VWF and OSA by measuring VWF antigen (VWF:Ag), VWFMs, VWF collagen binding activity (VWF:CB) and a disintegrin-like, metalloproteinase, and thrombospiondin type 1 motifs 13. A total of 58 OSA patients were enrolled. Blood samples were collected before sleep, after sleep, and after one night of nasal continuous positive airway pressure therapy. Based on VWFM analysis, OSA patients were classified into three groups; consistently normal VWFMs (group 1, n=29), increased high molecular weight (HMW)-VWFMs at 06:00 h (group 2, n=18), and decreased or absent HMW-VWFMs at 06:00 h (group 3, n=11). Patients in group 3 had significantly worse apnoea/hypopnoea index; VWF:CB followed a similar pattern. We observed a significant decrease in platelet count between 21:00 h and 06:00 h in OSA patients, potentially associated with reduced larger VWFMs together with decreased VWF:Ag levels. Severe OSA may contribute to an arterial pro-thrombotic state.

Regulation of experimental autoimmune uveoretinitis by anti-delta-like ligand 4 monoclonal antibody.

PURPOSE: To investigate the involvement of δ-like ligand (Dll)4 in the development of experimental autoimmune uveoretinitis (EAU) in B10.RIII mice. METHODS: B10.RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) peptide 161-180 in complete Freund's adjuvant together with intraperitoneal injection of Bordetella pertussis toxin. mRNA expressions of Notch receptors and their ligands in the eye were evaluated. To investigate the involvement of Dll in EAU, anti-Dll1, anti-Dll4, or control antibody (Ab) was intraperitoneally injected during both the induction and the effector phases or only the effector phase. Alternatively, mice were intraperitoneally injected with γ-secretase inhibitor (GSI) or the control vehicle during the induction phase. Fourteen days after immunization, the eyes and spleens were harvested. The eyes were used for histologic and/or cytokine mRNA expression analysis, whereas the spleens were used for flow cytometric analysis, and antigen-recall proliferation and cytokine assays. RESULTS: Expression of Notch1, 2, 4, and Dll4 in the eye were upregulated by EAU induction. Anti-Dll4 Ab treatment during both the induction and effector phases, but not only the effector phase, significantly reduced the severity of EAU. IFN-γ, IL-12p35, IL-17A, and TGF-ß mRNA expression in the eye were significantly attenuated by treatment with anti-Dll4 Ab. Splenocytes from anti-Dll4 Ab-treated mice showed significantly less proliferation and IL-17 production on antigen stimulation. Also, the severity of EAU was significantly reduced by γ-secretase inhibitor treatment during the induction phase. CONCLUSIONS; Dll4-mediated Notch signaling during the sensitization is critical for the development of EAU. This can be a novel prophylactic target for autoimmune uveitis.

Mesenchymal miR-21 regulates branching morphogenesis in murine submandibular gland in vitro.

Branching morphogenesis in murine submandibular glands (SMG) is regulated by growth factors, extracellular matrix (ECM) and many biological processes through interactions between the epithelium and the mesenchyme. MicroRNAs (miRNAs) are a set of small, non-protein-coding RNAs that regulate gene expression at the post-transcriptional level. We hypothesized that branching morphogenesis is partly regulated by miRNAs. Forty-four miRNAs and novel miRNA candidates were detected in SMG at embryonic day 13 by a cloning method combined with Argonaute-2 immunoprecipitation. MicroRNA21 (miR-21) expression in the mesenchyme was up-regulated and accelerated by epidermal growth factor, which is known to enhance branching morphogenesis in vitro. Down-regulation of miR-21 in the mesenchyme by locked nucleic acids was associated with a decrease in the number of epithelial buds. Relative quantification of candidates for target genes of miR-21 indicated that two messenger RNAs (for Reck and Pdcd4) were down-regulated in the mesenchyme, where miR-21 expression levels were up-regulated. These results suggest that branching morphogenesis is regulated by miR-21 through gene expression related to ECM degradation in the mesenchyme.

[Clinical analysis of eight patients with pulmonary toxocariasis].

We encountered 8 adult cases of pulmonary toxocariasis. Five were asymptomatic, 1 had transient chest pain, 1 suffered from arthralgia and migrating skin pain, and 1 had chest discomfort due to pneumothorax. Infection was associated with the consumption of raw liver with paratenic hosts in 5 patients. The cause was suspected to be contact with infected young dogs in 1 case and was undetermined in 2 cases. All 8 cases showed some abnormalities in their laboratory examination results including eosinophilia (>500/microl) and elevated IgE (>100 IU), and all had positive results in serological examinations for the larval excretory-secretory product of Toxocara canis. In 7 patients, excluding the patient with pneumothorax, chest computed tomography demonstrated multiple small pulmonary lesions, most of which were either nodules with halos, or ground-glass opacities. One patient recovered without medication, while the other 7 were treated with albendazole (ABZ) with good responses. Although the optimal duration of ABZ therapy has not been established, 4 weeks or longer seemed necessary to obtain a complete cure in pulmonary toxocariasis.

Production of inflammatory mediators by monocytes in patients with obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is known to be a risk factor of cardiovascular events. However, the precise mechanism linking the two has not been fully elucidated. OBJECTIVE: The aim of this study was to investigate the effect of hypoxic stress on the production of tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9) by monocytes. METHODS: Thirty-three OSAS patients and 13 healthy control subjects were enrolled. The OSAS patients were classified as mild-to-moderate (13) and severe (20). Venous blood samples were collected before and after sleep as well as after long-term nasal continuous positive airway pressure (CPAP) treatment for the purpose of isolation of monocytes. Peripheral blood monocytes were isolated using standard methods. Monocytes were cultured under lipopolysaccharide stimulation for 24 hours, and TNF-alpha, MCP-1, and MMP-9 in the culture supernatants were determined by ELISA. RESULTS: In severe patients, the TNF-alpha production by monocytes was significantly elevated as compared to that before sleep (p<0.01). In all OSAS patients, the TNF-alpha production after sleep was significantly correlated with AHI (p<0.01), ODI (p<0.01) and % time in SpO(2)<90% (p<0.05), and inversely correlated with the lowest SpO(2) (p<0.01). The production of MCP-1 and MMP-9 by monocytes was significantly elevated compared to that before sleep in severe patients (p<0.05). The production of these mediators by monocytes was significantly decreased after long-term nasal CPAP treatment (p<0.05). CONCLUSION: These results indicate that OSAS-induced hypoxic stress activates the production of inflammatory mediators by monocytes.

Nocturnal hypoxic stress activates invasive ability of monocytes in patients with obstructive sleep apnoea syndrome.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea syndrome (OSAS) is known to be a risk factor for cardiovascular events. However, the precise mechanism has not been fully elucidated. OSAS-induced hypoxic stress may promote the production of inflammatory cytokines and chemokines by monocytes, which has a crucial role in the development of atherosclerosis. In addition, adhesion to the vascular endothelium and transendothelial migration of monocytes are considered to induce atherosclerosis. The aim of this study was to investigate the effects of hypoxic stress on the invasive ability of monocytes in OSAS. METHODS: Twenty-one male patients with OSAS and 17 healthy male control subjects, who were matched for age and BMI, were enrolled. Venous blood samples were collected before and after sleep, and also after CPAP titration, for the purpose of monocyte isolation. The invasive ability of monocytes was evaluated by counting the number of invading cells using a BD BioCoat Matrigel Invasion Chamber. RESULTS: The number of cells, which represents the invasive ability of monocytes, was significantly higher in patients with OSAS compared with control subjects, in the early morning (P < 0.001). In patients with OSAS, invasive ability in the early morning after sleep was significantly elevated as compared with that before sleep (P < 0.001), and was positively correlated with the oxygen desaturation index (P < 0.05). CPAP titration led to a decrease in the invasive ability (P < 0.001). CONCLUSIONS: These results indicate that OSAS-induced hypoxic stress activates the invasive ability of monocytes, and that the occurrence of this phenomenon during sleep may contribute to the development of atherosclerosis in OSAS.

Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15.

The development of NK cells from hematopoietic stem cells is thought to be dependent on IL-15. In this study, we demonstrate that stimulation of human cord blood CD34(+) cells by a Notch ligand, Delta4, along with IL-7, stem cell factor, and Fms-like tyrosine kinase 3 ligand, but no IL-15, in a stroma-free culture induced the generation of cells with characteristics of functional NK cells, including CD56 and CD161 Ag expression, IFN-gamma secretion, and cytotoxic activity against K562 and Jurkat cells. Addition of gamma-secretase inhibitor and anti-human Notch1 Ab to the culture medium almost completely blocked NK cell emergence. Addition of anti-human IL-15-neutralizing Ab did not affect NK cell development in these culture conditions. The presence of IL-15, however, augmented cytotoxicity and was required for a more mature NK cell phenotype. CD56(+) cells generated by culture with IL-15, but without Notch stimulation, were negative for CD7 and cytoplasmic CD3, whereas CD56(+) cells generated by culture with both Delta4 and IL-15 were CD7(+) and cytoplasmic CD3(+) from the beginning and therefore more similar to in vivo human NK cell progenitors. Together, these results suggest that Notch signaling is important for the physiologic development of NK cells at differentiation stages beyond those previously postulated.