Obstructive sleep apnoea is associated with diabetes in sleepy subjects.

BACKGROUND: Although obstructive sleep apnoea (OSA) has been linked to insulin resistance and glucose intolerance, it is unclear whether there is an independent association between OSA and diabetes mellitus (DM) and whether all patients with OSA are at risk. The objective of this study was to determine the association between OSA and DM in a large cohort of patients referred for sleep diagnostic testing. METHODS: A cross-sectional analysis of participants in a clinic-based study was conducted between July 2005 and August 2007. DM was defined by self-report and concurrent use of diabetic medications (oral hypoglycaemics and/or insulin). Sensitivity analysis was performed using a validated administrative definition of diabetes. OSA was defined by the respiratory disturbance index (RDI) using polysomnography or ambulatory monitoring. Severe OSA was defined as an RDI > or = 30/h. Subjective sleepiness was defined as an Epworth Sleepiness Scale score > or = 10. RESULTS: Complete data were available for 2149 patients. The prevalence of DM increased with increasing OSA severity (p<0.001). Severe OSA was associated with DM following adjustment for patient demographics, weight and neck circumference (odds ratio (OR) 2.18; 95% CI 1.22 to 3.89; p<0.01). Following a stratified analysis, this relationship was observed exclusively in sleepy patients (OR 2.59 (95% CI 1.35 to 4.97) vs 1.16 (95% CI 0.31 to 4.37) in non-sleepy patients). CONCLUSIONS: Severe OSA is independently associated with DM in patients who report excessive sleepiness. Future studies investigating the impact of OSA treatment on DM may wish to focus on this patient population.

Multitarget therapy of malignant cancers by the head-to-tail tandem array multiple shRNAs expression system.

Coexpression of multiple shRNAs can simultaneously inhibit multiple genes or target multiple sites on a single gene. These approaches can be used for dissecting complex signaling pathways and even be applied to targeting multiple genes in cancer therapy. Here we established a simple and efficient multiple shRNAs expression system based on pSUPER, the most popular expression vector in mammalian cells. A series of head-to-tail tandem array multiple shRNAs expression vectors were constructed containing different combinations of six shRNA expression cassettes targeting genes involved in cell proliferation and survival pathways: Bcl-2, Survivin, Akt1, Erk2, CyclinE and NFkappaB. In HeLa and HEK293 cells, the multiple shRNAs expression constructs could efficiently and simultaneously induce inhibition of all six genes. We further evaluated the inhibition effects of the multiple shRNAs expression vectors on the human prostate cancer cell line PC3, which contains different cell variants with distinct oncogenic signaling alterations. The results revealed that the multiple shRNAs expression system could inhibit all six genes and was much more efficient in inducing apoptosis in the PC3 cells. Our results suggest that the multitarget shRNAs expression system could be an effective strategy in cancer therapy and be applied to any other DNA vector-based shRNA expression system.

Interferon-alpha-induced serotonin uptake in Jurkat T cells via mitogen-activated protein kinase and transcriptional regulation of the serotonin transporter.

Interferon (IFN)-alpha upregulates serotonin (5-HT) uptake and serotonin transporter (5-HTT) messenger ribonucleic acid (mRNA) expression in immune cells, which implies the mechanism underlying IFN-alpha-induced depression. However, the signal transduction of this effect remains unclear. We investigated whether the effects of IFN-alpha on the functions of 5-HTT were related to mitogen-activated protein kinase (MAPK). By performing Western blotting, real-time reverse transcriptase-polymerase chain reaction and [3H]5-HT labelling, we examined MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake in Jurkat T cells. The cells had been cultured for different time periods (1) with IFN-alpha alone and (2) preincubated with either MAPK inhibitors or with the selective serotonin reuptake inhibitor, fluoxetine, and subsequently cultured along with IFN-alpha. The levels of MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake all increased in the IFN-alpha-treated cells but were blocked in those that were pretreated with MAPK inhibitors and fluoxetine. These results appear to clarify the association of depression with IFN-alpha-induced 5-HT uptake that reduces the 5-HT levels and IFN-alpha-regulated transcription of 5-HTT; further, the results suggest the involvement of MAPK in this process.

Prevalence of the JAK2-V617F mutation in Taiwanese patients with chronic myeloproliferative disorders.

BACKGROUND: The Janus kinase-2 (JAK-2) V617F mutation has been recently reported in patients with myeloproliferative disorders (MPD), which is believed to underlie growth factor hypersensitivity displayed by haematopoietic progenitors in these disorders. However, its frequency has been rarely determined in Taiwanese patients. METHODS: The frequency of JAK2-V617F mutation in patients with polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis (IMF) was determined in the DNA from the peripheral blood leucocytes of 108 patients by genomic polymerase chain reaction and restriction enzyme-based assay. RESULTS: The JAK2-V617F mutation could be detected in 28 of 33 polycythaemia vera patients (85%), 29 of 49 essential thrombocythaemia patients (59%) and 2 of 6 IMF patients (33%), but was not detected in 11 patients with myelodysplastic syndrome or another 10 with other haematological diseases. The presence of the JAK2 mutation was associated with specific MPD disease subtypes (P = 0.007), longer disease duration (P = 0.005), splenomegaly (P = 0.019), a higher white blood cell count (P = 0.002) and a higher haemoglobin level (P = 0.036). However, the overall risk of thrombosis or bleeding was not affected by the presence of the JAK2 mutation (32 vs 17%; P = 0.22). CONCLUSION: The JAK2-V617F mutation can be frequently detected in the Taiwanese patients with MPD disorders and therefore should be incorporated into the initial evaluation of patients suspected of MPD.

Monocyte chemotactic protein-1 in the migration of differentiated leukaemic cells toward alveolar epithelial cells.

All-trans retinoic acid (ATRA) can induce acute respiratory distress syndrome in patients with acute promyelocytic leukaemia (APL). The current study investigated the role of monocyte chemotactic protein (MCP)-1 in the chemotactic transmigration of ATRA-treated NB4 (ATRA-NB4) APL cells toward A549 alveolar epithelial cells. NB4 and A549 cells were separately cultured with ATRA and/or dexamethasone (DEX). ATRA-NB4 cells were then placed in an upper insert and co-incubated with A549 cells or their conditioned medium (CM) located in a lower plate to test their transmigration activity. ATRA stimulated NB4 cells to transmigrate toward the A549 cells. The secretion of MCP-1 was enhanced by ATRA treatment in both A549 and NB4 cells. The binding assay demonstrated that ATRA-NB4 cells bound MCP-1. Pre-treatment of both CM-A549 cells with antibodies against MCP-1 and of ATRA-NB4 cells with antibodies against MCP-1 receptors reduced ATRA-NB4 cell transmigration. DEX did not suppress MCP-1 secretion and transmigration in ATRA-NB4 cells, although when applied to A549 cells, MCP-1 secretion was suppressed and ATRA-NB4 cell transmigration was attenuated. Monocyte chemotactic protein-1 secreted from alveolar epithelial cells plays an important role in the cell-cell interaction involved in the chemotactic transmigration of all-trans retinoic acid-treated acute promyelocytic leukaemia cells toward alveolar epithelial cells.

The effects of early postnatal dexamethasone therapy on pulmonary outcome in premature infants with respiratory distress syndrome: a two-year follow-up study.

AIM: To evaluate the pulmonary outcome at corrected age of 2 y on preterm infants who participated in a double-blind trial of early postnatal dexamethasone therapy (< 12 h after birth) for the prevention of chronic lung disease. METHODS: Clinical respiratory status, blood gases, acid-base balance and pulmonary function were evaluated at corrected age of 2 y in 116 preterm infants (59 infants in the control group; 57 in the dexamethasone-treated group). In the dexamethasone-treated group, dexamethasone was administered intravenously every 12 h in tapering doses: 0.25 mg/kg on days 1 through 7, 0.12 mg/kg on days 8 through 14, 0.05 mg/kg on days 15 through 21, and 0.02 mg/kg on days 21 through 28. RESULTS: The clinical and laboratory characteristics in the perinatal period were comparable between the groups. At the time of follow-up (mean +/- SD corrected age was 25.1 +/- 4.8 mo for the control group and 24.6 +/- 5.1 mo for the dexamethasone-treated group), there was a slightly lower mean body weight and body length, and a lower psychomotor developmental index in the dexamethasone-treated group than in the control group (10.9 +/- 2.1 vs 11.5 +/- 1.9 kg, 84.4 +/- 6.1 vs 85.9 +/- 5.8 cm, and 82 +/- 24 vs 89 +/- 26, respectively); however, these differences were not statistically significant. There were no significant differences between the control and dexamethasone-treated groups in clinical respiratory status, blood gases, acid-base balance or in lung mechanics (V(T): 9.5 +/- 2.0 vs 9.4 +/- 1.9 ml/kg; V(min): 0.23 +/- 0.04 vs 0.23 +/- 0.03 l/min/kg; C(RS): 13.1 +/- 3.9 vs 12.6 +/- 3.6 ml/kPa/kg; R(RS): 1.56 +/- 0.64 vs 1.62 +/- 0.58 kPa/l/s, respectively). CONCLUSION: There was no apparent adverse respiratory outcome associated with early postnatal dexamethasone therapy.

Chinese dialect identification using segmental and prosodic features.

Several approaches to Chinese dialect identification based on segmental and prosodic features of speech are described in this paper. When using segmental information only, the system performs phonotactic analysis after speech utterances have been tokenized into sequences of broad phonetic classes. The second scheme comprises prosodic models which are trained to capture tone sequence information for individual dialects. Also proposed is a novel approach that examines differences between Chinese dialects at broad phonetic and prosodic levels. These algorithms were evaluated via a multispeaker read-speech mode. Simulation results indicate that the combined use of segmental and prosodic features allows the proposed system to discriminate among three major Chinese dialects spoken in Taiwan with 93.0% accuracy.

Automated analysis of digital oximetry in the diagnosis of obstructive sleep apnoea.

BACKGROUND: The gold standard diagnostic test for obstructive sleep apnoea (OSA) is overnight polysomnography (PSG) which is costly in terms of time and money. Consequently, a number of alternatives to PSG have been proposed. Oximetry is appealing because of its widespread availability and ease of application. The diagnostic performance of an automated analysis algorithm based on falls and recovery of digitally recorded oxygen saturation was compared with PSG. METHODS: Two hundred and forty six patients with suspected OSA were randomly selected for PSG and automated off line analysis of the digitally recorded oximeter signal. RESULTS: The PSG derived apnoea hypopnea index (AHI) and oximeter derived respiratory disturbance index (RDI) were highly correlated (R = 0.97). The mean (2SD) of the differences between AHI and RDI was 2.18 (12.34)/h. The sensitivity and specificity of the algorithm depended on the AHI and RDI criteria selected for OSA case designation. Using case designation criteria of 15/h for AHI and RDI, the sensitivity and specificity were 98% and 88%, respectively. If the PSG derived AHI included EEG based arousals as part of the hypopnea definition, the mean (2SD) of the differences between RDI and AHI was -0.12 (15. 62)/h and the sensitivity and specificity profile did not change significantly. CONCLUSIONS: In a population of patients suspected of having OSA, off line automated analysis of the oximetry signal provides a close estimate of AHI as well as excellent diagnostic sensitivity and specificity for OSA.

Clinical and epidemiological implications of swine hepatitis E virus infection.

In nonendemic areas, most patients with acute hepatitis E were infected through traveling to endemic areas. However, some patients did not have a history of foreign travel before infection. Furthermore, high seroprevalence rates of antibody to hepatitis E virus (anti-HEV) were found in the general adult population in some countries without any recorded outbreak of hepatitis E. The significance of anti-HEV assay in these subjects remains obscure. To study if swine might be a source of HEV infection, HEV was tested in sera of 235 pigs in Taiwan, and from 5 patients with acute HEV infection who either denied or did not provide any foreign travel history. Three (1.3%) pigs had detectable swine HEV RNA. The swine and human HEV strains from Taiwan formed a monophyletic group, distinct from three previously reported groups: the United States human and swine HEV strains, the Mexico strain, and the largest group composed of the Asian and the African strains. The identity of nucleotide sequences was 84-95% between swine and human HEV strains in Taiwan, and 72-79% between Taiwan strains and those from different areas. The predicted amino acid sequence of a Taiwan swine HEV strain within the peptide 3-2 used in commercial anti-HEV assay showed a high identity (91-94%) with those of other human and swine HEV strains. Swine may be a reservoir of HEV and subclinical swine HEV infection may occur. Cross-reactivity of current anti-HEV assay may account for the high prevalence rate of anti-HEV in the general population in nonendemic areas.

Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocytosis.

The regulation of megakaryocytopoiesis and thrombopoiesis appears to be under the control of an array of hematopoietic growth factors. To determine the relationship between endogenous cytokine levels and circulating platelet counts, we measured the serum levels of both thrombopoietic and inflammatory cytokines in the peripheral blood and bone marrow samples from 70 patients with clonal thrombocytosis (CT) caused by myeloproliferative disorders, 28 patients with reactive thrombocytosis (RT), and 35 normal control subjects. The levels of thrombopoietin (TPO), interleukin-6 (IL-6), soluble IL-6 (sIL-6) receptor, IL-11, stem cell factor (SCF), IL-3, and IL-8 were determined by enzyme-linked immunosorbent assay (ELISA). Platelet counts were significantly higher in both CT and patients with RT (699+/-399x10(9)/L, P<.001; 642+/-200 x 10(9)/L, P<.001; respectively) as compared with the normal control subjects (240+/-47x10(9)/L). The concentrations of cytokines in the bone marrow correlated well with those in the peripheral blood. The endogenous levels of TPO, IL-6, and sIL-6 receptor were significantly higher in both CT and patients with RT than those in normal control subjects. The median level of IL-6 was significantly higher in patients with RT than in patients with CT (40 pg/mL vs. 5 pg/mL; P<.001); however, there was no detectable difference in TPO and sIL-6 receptor levels between the two groups. Significantly higher levels of SCF and IL-8 were also found in patients with CT as compared with those found in normal control subjects (median 2460 pg/mL vs 1995 pg/mL, P<.05; 20 ng/mL vs. 5 ng/mL, P = .001; respectively). Finally, IL-11 and IL-3 levels were undetectable in most patients with thrombocytosis. Our results reveal that the endogenous levels of TPO, IL-6, sIL-6 receptor, IL-8, and SCF are elevated in patients with CT or RT. These cytokines appear to be active mediators involved in the regulation of thrombopoiesis during clonal and reactive thrombocytosis.

In vitro effect of granulocyte-colony stimulating factor and all-trans retinoic acid on the expression of inflammatory cytokines and adhesion molecules in acute promyelocytic leukemic cells.

Differentiation therapy with all-trans retinoic acid (ATRA) represents a landmark approach in the treatment of acute promyelocytic leukemia (APL). However, a potentially fatal complication of retinoic acid (RA) syndrome occurs in about a quarter of patients and its pathophysiology is still unclear. In order to investigate whether or not the treatment with ATRA leads to increased elaboration of inflammatory cytokines and adhesion molecules by the APL cells, the expression of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-8, L-selectin and intercellular adhesion molecule-1 (ICAM-1) was examined in the APL cells after induction of differentiation with ATRA in the presence or absence of granulocyte-colony stimulating factor (G-CSF) or IL-3 in the present study. Cytokine elaboration by the treated cells was detected using both Northern blotting and enzyme-linked immunosorbent assay. Our results have shown that ATRA induces an increased expression of IL-8, IL-1beta, TNF-alpha and ICAM-1 in APL cells, which can be amplified by the addition of G-CSF. These data imply that the induction of inflammatory cytokines in APL cells may play an important role in the pathogenesis of RA syndrome. Furthermore, G-CSF, through its potent differentiating activity, may increase the risk of such complications during ATRA treatment.

A comparison of apnea-hypopnea indices derived from different definitions of hypopnea.

We examined the effects of arousal- and desaturation-based scoring criteria on the apnea-hypopnea index (AHI) and on the measured prevalence of obstructive sleep apnea (OSA). Ninety-four randomly selected patients underwent overnight polysomnography. Studies were scored according to three different criteria for hypopnea, as defined by a >= 10 s discernible reduction in thoracoabdominal movement associated with: (1) >= 4% decrease in oxygen saturation (SaO2) (Type A); (2) either a >= 4% decrease in SaO2 or an arousal (Type B); or (3) electroencephalographically based arousal alone (Type C). Excellent correlation existed between AHI-A, AHI-B, and the oxygen desaturation index (ODI) (r > 0.98). AHI-A and AHI-B differed by only 2.04 +/- 1.72/h (2 SD). AHI-A and AHI-B differed from the ODI by 1.04 +/- 4.07/h and 3.07 +/- 4.30/h, respectively. Despite these small differences, use of the Type B rather than Type A definition resulted in an extra case of OSA being diagnosed for every 14 to 31 patients tested, depending on the definition of OSA (AHI: >= 5, 10, 15, or 20/h). The addition of arousal-based scoring criteria for hypopnea causes only small changes in the AHI, but if OSA is defined solely by an AHI value, the measured prevalence of OSA will increase.

Obstacle avoidance for autonomous land vehicle navigation in indoor environments by quadratic classifier.

A vision-based approach to obstacle avoidance for autonomous land vehicle (ALV) navigation in indoor environments is proposed. The approach is based on the use of a pattern recognition scheme, the quadratic classifier, to find collision-free paths in unknown indoor corridor environments. Obstacles treated in this study include the walls of the corridor and the objects that appear in the way of ALV navigation in the corridor. Detected obstacles as well as the two sides of the ALV body are considered as patterns. A systematic method for separating these patterns into two classes is proposed. The two pattern classes are used as the input data to design a quadratic classifier. Finally, the two-dimensional decision boundary of the classifier, which goes through the middle point between the two front vehicle wheels, is taken as a local collision-free path. This approach is implemented on a real ALV and successful navigations confirm the feasibility of the approach.

Identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a repressor of C/EBPbeta-mediated gene activation.

Transcription factor C/EBPbeta has been known to regulate a wide array of genes including those involved in the acute-phase response. One of the molecular mechanisms underlying transcription activation by C/EBPbeta is through protein-protein interaction with other transcription factors. Here we report the identification and characterization of physical and functional interactions between C/EBPbeta and heterogeneous nuclear ribonucleoprotein (hnRNP) K. This interaction results in the repression of C/EBPbeta-dependent trans-activation of the agp gene. Footprinting assays indicate that hnRNP K cannot bind to the promoter region of agp gene or interfere with the binding of C/EBPbeta to its cognate DNA site. Furthermore, agp gene activation by the synergistic interaction of Nopp140 and C/EBPbeta is abolished by hnRNP K. The kinetics of appearance of C/EBPbeta-hnRNP K complex in the nuclear extract after initiation of acute-phase reaction indicates that hnRNP K functions as a negative regulator of C/EBPbeta-mediated activation of agp gene.

An incremental-learning-by-navigation approach to vision-based autonomous land vehicle guidance in indoor environments using vertical line information and multiweighted generalized Hough transform technique.

An incremental learning by navigation approach to vision based autonomous land vehicle (ALV) guidance in indoor environments is proposed. The approach consists of three stages: initial learning, navigation, and model updating. In the initial learning stage, the ALV is driven manually, and environment images and other status data are recorded automatically. Then, an offline procedure is performed to build an initial environment model. In the navigation stage, the ALV moves along the learned environment automatically, locates itself by model matching, and records necessary information for model updating. In the model updating stage, an offline procedure is performed to refine the learned model. A more precise model is obtained after each navigation-and-update iteration. Used environment features are vertical straight lines in camera views. A multiweighted generalized Hough transform is proposed for model matching. A real ALV was used as the testbed, and successful navigation experiments show the feasibility of the proposed approach.

Transcriptional induction of the agp/ebp (c/ebp beta) gene by hepatocyte growth factor.

Hepatocyte growth factor (HGF) is a pleiotropic factor with mitogenic, morphogenic, motogenic, cytotoxic, or growth inhibitory activity. Although the signaling of HGF is mediated through the cell membrane receptor c-Met, the molecular mechanism of downstream signal transduction remains obscure. In this report, we present evidence that shows HGF can stimulate the expression of AGP/EBP (C/EBP beta) and NF-kappaB, which are both key transcription factors responsible for the regulation of many genes under stress conditions or during the acute-phase response. Biochemical and functional analysis indicates that the HGF-responsive element is located in the region -376 to -352 (URE1) of the 5'-upstream regulatory sequence of agp/ebp. Activation of NF-kappaB by HGF was observed to precede the induction of agp/ebp. Further studies indicate that NF-kappaB can cooperate with AGP/EBP or other members of the C/EBP family to activate the agp/ebp gene in both URE1 and URE2-dependent manner. These results suggest that the induction of the agp/ebp gene by HGF is mediated at least in part by its activation of NF-kappaB. The activated NF-kappaB then interacts with AGP/EBP, resulting in the induction of agp/ebp.

Primary transplantation of allogeneic peripheral blood stem cell for severe aplastic anemia.

Primary allogeneic peripheral blood stem cell transplantation (allo-PBSCT) has not been previously described in the treatment of severe aplastic anemia (SAA). We report a patient with SAA who underwent primary allo-PBSCT with cells from her HLA-identical sibling and achieved rapid bone marrow reconstitution. The patient has been in complete remission with normal blood counts for 9 months following allo-PBSCT. This suggests that primary allo-PBSCT is a safe and effective alternative in the treatment of SAA.

Identification and characterization of a nucleolar phosphoprotein, Nopp140, as a transcription factor.

Expression of the alpha-1 acid glycoprotein (AGP) gene (agp) is activated by a key transcription factor, AGP/enhancer-binding protein (AGP/EBP, commonly called C/EBP beta), in the liver during the acute-phase response. In addition to this positive regulation, agp is negatively regulated by nucleolin (T. H. Yang et al., Mol. Cell. Biol. 14:6068-6074, 1994). Other factors involve in positive regulation of the agp gene are poorly characterized. In a systematic search for factors that may interact with AGP/EBP, we have identified Nopp 140, a phosphoprotein of 140 kDa, by immunoaffinity chromatography. Nopp 140 not only functions as a transcriptional activator per se but also interacts with AGP/EBP to synergistically activate the agp gene in an AGP/EBP-binding motif-dependent manner. In addition to interacting with AGP/EBP, Nopp140 interacts specifically with TFIIB. Distinct regions of Nopp140 that interact with AGP/EBP and TFIIB have been characterized. The sequence of Nopp140 contains several stretches of serine- and acidic amino acid-rich sequences which are also found in ICP4 of herpes simplex virus type 1, a known transcription factor that interacts with TFIIB. The physical interaction between TFIIB and wild-type Nopp140 or several deletion mutants of Nopp140 correlates with the ability of Nopp140 to activate the agp gene synergistically with AGP/EBP. Thus, the molecular mechanism for agp gene activation may involve the interaction of AGP/EBP and TFIIB mediated by coactivator Nopp140.

Identification of a novel variant hepatocyte growth factor secreted by spleen-derived stromal cells.

Stromal cells can interact with parenchymal cells by secreting various cytokines to affect the growth, differentiation or movement of the latter. Here we report the identification and characterization of a novel variant hepatocyte growth factor (HGF) from the conditioned medium of stromal cells derived from mouse spleen. Compared to human HGF, it has much lower heparin-binding activity and lacks the beta-chain. Its molecular weight, 70 kDa, is very close to that of the alpha-chain of HGF. Human HGF homologue was not found in the conditioned medium. The conditioned medium of stromal cells, like recombinant HGF, could inhibit the growth of rat hepatoma cells. The inhibitory activity was presumably attributed to this novel HGF because the inhibitory activity, as the existence of this novel HGF, was confined to the identical fractions after heparin-column chromatography. Furthermore, this activity could be specifically abrogated by neutralizing anti-HGF antibodies.