Inhaled nitric oxide therapy via nasopharyngeal tube in an infant with end-stage pulmonary hypertension

Abstract The delivery of nitric oxide (NO) via a nasopharyngeal tube is an alternative to endotracheal intubation. A male infant with end-stage pulmonary hypertension (PH) due to a severe hypoplastic lung developed a PH crisis on day 145 and received NO inhalation via a nasopharyngeal tube. Clinical improvement was maintained for 7 days with18–22ppm NO inhalation. The patient remained in close physical contact with his parents without the use of sedation. Blood methemoglobin levels remained below 1%. The environmental NO levels were less than 0.06 ppm and NO₂ less than 0.3 ppm throughout the treatment, well within the safety margin. On day 152, the patient succumbed to hypoxemia and heart failure. The use of a nasopharyngeal NO delivery system without sedation, as an alternative to endotracheal intubation with sedation, was a practical method in treating a patient with PH while maintaining a certain quality of life for the patient and the family.     

Bone Evaluation by Microdensitometry in Patients with Juvenile Reumatoid Arthritis

To evaluate the hand bones of patients with juvenile rheumatoid arthritis (JRA) objectively, 30 patients with JRA were examined by microdensitometric analysis (MD). The results were as follows: 1) Among the nine indices of MD, %σGS/D, reflecting the bone mineral content, correlated well with the stage of JRA determined by roentgenological findings of the hand bones. 2) %σGS/D showed remarkable improvement after the remission of JRA. 3) Rheumatoid factor (RF) positive JRA showed statistically low %σGS/D compared with RF negative JRA, and kept a low %σGS/D for a long period from the onset in contrast to RF negative JRA. 4) %σGS/D in the patients with JRA treated with steroid decreased more rapidly according to the dosage of steroid than in the patients with SLE. Based on these results it is suggested that MD seems to be useful in evaluating the bone objectively, and not only steroid but also RF seems to be a factor leading to bone destruction in patients with JRA.     

Non-protein-bound transition metals and hydroxyl radical generation in cerebrospinal fluid of newborn infants with hypoxic ischemic encephalopathy

Among various hypothetical mechanisms for the in vivo production of reactive oxygen species, transition metal-catalyzed reactions in cooperation with a biologic reducing agent like ascorbic acid or superoxide may be some of the most important. In the present study, we retrospectively examined the existence of non-protein-bound metal ions, an essentially hazardous pro-oxidant form of various transition metals, and the occurrence of metal-catalyzed reactive oxygen species production in cerebrospinal fluid (CSF) of 10 infants with hypoxic ischemic encephalopathy (HIE) subsequent to perinatal asphyxia and 12 control infants within 72 h of birth. Non-protein-bound iron was detected in eight out of 10 CSF samples from the HIE infants and its level was significantly correlated with Sarnat's clinical stage, whereas none of the control infants had detectable non-protein-bound iron levels. Non-protein-bound copper was below the detection limit in all CSF samples from both groups. Ascorbic acid was significantly increased in the CSF of HIE infants when compared with that of controls (means, 664.9 versus 449.4 microM, p = 0.008). ortho-Tyrosine and meta-tyrosine, which are highly specific and sensitive markers of protein oxidation induced by hydroxyl radicals, were significantly higher in HIE infants than in controls when evaluated by the ratio relative to their source amino acid, phenylalanine [means, 110.5 versus 75.4, p = 0.018 for ortho-tyrosine/phenylalanine; 104.6 versus 67.7 (nM/microM x 10(2)), p = 0.048 for meta-tyrosine/phenylalanine]. Both ratios were significantly correlated with non-protein-bound iron, but not with ascorbic acid. Our preliminary observations provide direct evidence that hydroxyl radicals are generated in the CNS during asphyxiation. Iron chelation therapy could be worth developing as a neuroprotective strategy for perinatal asphyxia.     

Selective effect of cinnarizine on the vestibular nucleus neurons

Summary Effects of cinnarizine were studied on the lateral vestibular nucleus (LVN) and spinal trigeminal nucleus (STN) of cats anesthetized with -chloralose. Cinnarizine did not produce any obvious alterations of the field potential and spike generation of type B interneurons in STN elicited by trigeminal nerve stimulation as well as the field potential in LVN by vestibular nerve stimulation. Spike generation of monosynaptic LVN neurons elicited by the suprathreshold stimulus to the vestibular nerve was unaffected by cinnarizine up to 4 mg/kg. When the subthreshold stimulus was applied to the vestibular nerve, however, the spike number of LVN monosynaptic neurons was significantly increased after cinnarizine treatment. The enhancement of spike firing by cinnarizine upon both supra- and subthreshold stimuli to the vestibular nerve was found to be more pronounced in LVN polysynaptic neurons than monosynaptic ones. Since the effect of cinnarizine on LVN neurons was not dose-dependent, it is suggested that the enhanced responsiveness of the neurons by the drug might be due to an increase of blood flow, but not to a direct excitation of the neurons themselves.     

Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement

OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) beta1, beta2, and IL-18Ralpha in LPLs was analyzed by flow cytometry. The functional activity of IL- 12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-gamma production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rbeta2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-gamma production and IL-2Ralpha expression when exposed to both IL- 12 and IL- 18, but neither IL- 12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Ralpha monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Ralpha expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.     

Pivotal role of Notch signaling in regulation of erythroid maturation and proliferation

Notch signaling plays an important role in cell fate decisions in developmental systems. To clarify its role in committed hematopoietic progenitor cells, we investigated the effects of Notch signaling in erythroid colony forming cells (ECFCs) generated from peripheral blood. ECFCs express Notch receptors, Notch1 and Notch2, and Notch ligands Delta1, Delta4, and Jagged1. When we assayed the effects of Notch ligands on erythroid maturation by flow cytometry, we found that immobilized Delta1 and immobilized Delta4 in particular inhibited maturation, whereas Jagged1 had no effect. In addition, Delta4 inhibited proliferation without reducing cell viability. Increases in expression levels of the Notch target gene hairy enhancer of split (HES) -1 were evident by real-time PCR after stimulation with immobilized Delta4. The effect of soluble Delta4 on expression of HES-1 was less pronounced than that seen with the immobilized form, indicating that all surface-bound ligands are important for effective signal transduction. When ECFCs were cultured in the presence of soluble Delta4 at a low cell concentration, erythroid maturation was slightly inhibited, but at a high concentration, maturation was promoted via competition of soluble Delta4 with endogenous ligands. These results indicate a pivotal role of Notch signaling in regulating erythroid maturation and proliferation, and further suggest that cell-cell interactions modulate growth of erythroid progenitor cells via Notch system.     

Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction

Menthol, known as a cold receptor agonist, has widely been used in the relief of respiratory symptoms such as coughing and chest congestion. Previous studies have demonstrated that menthol reduces bronchoconstriction and airway hyperresponsiveness. The aim of this study was to examine the effects of menthol and icilin, another cold receptor agonist, on airway smooth muscle contraction. Isometric force was monitored using epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. Intracellular Ca(2+) concentrations were assessed by fura-2 fluorescence. (-)Menthol (0.01-1mM) inhibited contraction induced by methacholine (MCh, 0.01-10muM) and high extracellular K(+) concentrations (20-60mM) in a concentration-dependent manner. Moreover, the increases of intracellular Ca(2+) concentrations induced by MCh or high K(+) were significantly reduced by (-)menthol. Icilin (100muM) also significantly attenuated contraction induced by MCh or high K(+). The inhibitory effect of 1mM (-)menthol on MCh-induced contraction was significantly higher at cool temperature (24-26 degrees C) than at 37 degrees C. The present results demonstrate that inhibition of Ca(2+) influx plays an important role in the menthol-mediated inhibition of contraction in airway smooth muscle. Furthermore, our findings indicate that stimulation of unknown cold receptors may be involved in these mechanisms. These findings suggest that the use of menthol is beneficial for reducing respiratory symptoms because of its inhibitory effects on airway smooth muscle contraction.     

Improved formulations of antisense oligodeoxynucleotides using wrapped liposomes.

Previously, we demonstrated that wrapping dextran fluorescein anionic/cationic lipid complexes with neutral lipids produced a stable formulation that markedly increased the duration of the compound in plasma after intravenous administration to rats. The improved drug-delivery properties of the wrapped liposomes (WL) relative to other formulations suggested that this technology could offer important advantages for the administration of other polyanionic drugs, including antisense oligodeoxynucleotides (ODN). In the present study, we investigated the value of WL for formulating fluorescence-labeled phosphorothioated ODN (F-ODN). WL encapsulating F-ODN/cationic lipid complexes were prepared efficiently using similar methodology to that used in our earlier study. Studies confirmed that these WL were stable in vitro. Following intravenous administration to mice, free F-ODN and naked F-ODN/cationic lipid complexes were rapidly eliminated whereas administration of the WL resulted in high blood concentrations of drug that were maintained for several hours. Additional studies were conducted in mice that were inoculated with tumor cells (Caki-1 xenograft model, human kidney); in these experiments, intravenous administration of WL delivered 13 times more F-ODN to the tumor site than achieved after injection of free F-ODN.     

Prospective multicenter study of the causative organisms of community-acquired pneumonia in adults in Japan

Although a wide variety of recognized pathogens causes community-acquired pneumonia, the precise etiology in Japan remains unknown. We prospectively investigated the etiology in 232 patients with community-acquired pneumonia who visited 20 community-general hospitals. New diagnostic methods, using polymerase chain reaction (PCR) assays and urinary antigen tests were employed, in addition to conventional methods. The frequency of identification of causative pathogens was high (73.3%), and the leading organism was Streptococcus pneumoniae (24.6%), followed by Haemophilus influenzae (18.5%), viruses (16.4%), Chlamydia pneumoniae (6.5%), Mycoplasma pneumoniae (5.2%), and Legionella spp. (3.9%). S. pneumoniae and M. pneumoniae were the most prevalent pathogens in younger patients, and S. pneumoniae and H. influenzae were the most prevalent in elderly patients. Multiple or mixed infections were found in 25.9% of all patients and in 35.3% with a causal diagnosis. The results have important practical implications for the initial treatment of adult patients with community-acquired pneumonia. See Appendix     

Imaging of pulmonary emphysema: A pictorial review

The term ‘emphysema’ is generally used in a morphological sense, and therefore imaging modalities have an important role in diagnosing this disease. In particular, high resolution computed tomography (HRCT) is a reliable tool for demonstrating the pathology of emphysema, even in subtle changes within secondary pulmonary lobules. Generally, pulmonary emphysema is classified into three types related to the lobular anatomy: centrilobular emphysema, panlobular emphysema, and paraseptal emphysema. In this pictorial review, we discuss the radiological – pathological correlation in each type of pulmonary emphysema. HRCT of early centrilobular emphysema shows an evenly distributed centrilobular tiny areas of low attenuation with ill-defined borders. With enlargement of the dilated airspace, the surrounding lung parenchyma is compressed, which enables observation of a clear border between the emphysematous area and the normal lung. Because the disease progresses from the centrilobular portion, normal lung parenchyma in the perilobular portion tends to be preserved, even in a case of far-advanced pulmonary emphysema. In panlobular emphysema, HRCT shows either panlobular low attenuation or ill-defined diffuse low attenuation of the lung. Paraseptal emphysema is characterized by subpleural well-defined cystic spaces. Recent topics related to imaging of pulmonary emphysema will also be discussed, including morphometry of the airway in cases of chronic obstructive pulmonary disease, combined pulmonary fibrosis and pulmonary emphysema, and bronchogenic carcinoma associated with bullous lung disease.