A fat-derived metabolite regulates a peptidergic feeding circuit in Drosophila.

Here, we show that the enzymatic cofactor tetrahydrobiopterin (BH4) inhibits feeding in Drosophila. BH4 biosynthesis requires the sequential action of the conserved enzymes Punch, Purple, and Sepiapterin Reductase (Sptr). Although we observe increased feeding upon loss of Punch and Purple in the adult fat body, loss of Sptr must occur in the brain. We found Sptr expression is required in four adult neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (NPY). As expected, feeding flies BH4 rescues the loss of Punch and Purple in the fat body and the loss of Sptr in NPF neurons. Mechanistically, we found BH4 deficiency reduces NPF staining, likely by promoting its release, while excess BH4 increases NPF accumulation without altering its expression. We thus show that, because of its physically distributed biosynthesis, BH4 acts as a fat-derived signal that induces satiety by inhibiting the activity of the NPF neurons.

Functional class and targeted therapy are related to the survival in patients with pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) is an orphan disease showing poor prognosis. The purpose of study was to evaluate clinical factors influencing outcomes in PAH. MATERIALS AND METHODS: Patients who were diagnosed with PAH at a single center were reviewed retrospectively. Forty patients (34.9±14.5 years, 80% of female) were enrolled. RESULTS: Causes were congenital heart disease in 24 (60%), connective tissue disease in 8 (20%) and idiopathic PAH in 6 (15%). Sixteen patients (40%) were WHO functional class III or IV at the time of diagnosis. Twenty seven patients (67.5%) received molecular targeted therapy. During follow-up (53.6±45.5 months), 10 patients (25%) died and 1-, 2-, and 8 year survival rates were 91.3%, 78.7%, and 66.8%, respectively. As expected, median survival of patients with functional class I or II were significantly longer than patients with III or IV (p=0.041). Interestingly, patients with molecular targeted therapy showed longer survival than conventional therapy (p=0.021). CONCLUSION: WHO functional class at the time of diagnosis was the strong predictor of survival, and molecular targeted therapy could significantly improve the survival. Therefore, early screening and intensive management would be crucial to improve the prognosis in the patient with PAH.

Efficacy of inhaled iloprost in cor pulmonale and severe pulmonary hypertension associated with tuberculous destroyed lung.

Chronic obstructive pulmonary disease (COPD) is one of the causes of cor pulmonale. Cor pulmonale patients with pulmonary hypertension have a significant lower survival rate than patients without. However, there is no conclusive treatment options in cor pulmonale and pulmonary hypertension associated with COPD until now. We report a patient with cor pulmonale and pulmonary hypertension associated with severe form of COPD and tuberculous destroyed lung who achieved marked clinical, functional and echocardiographic hemodynamic improvements with inhaled iloprost for six months.

Identification of a novel insect neuropeptide, CNMa and its receptor.

To identify ligands for orphan GPCRs, we searched novel neuropeptide genes in the Drosophila melanogaster genome. Here, we describe CNMa, a novel cyclic neuropeptide that is a highly potent and selective agonist for the orphan GPCR, CG33696 (CNMaR). Phylogenetic analysis revealed that arthropod species have two paralogous CNMaRs, but many taxa retain only one. Drosophila CNMa potently activates CNMaR-2 from Apis mellifera, suggesting both receptors are functional. Although CNMa is conserved in most arthropods, Lepidoptera lack the CNMa gene. However, they retain the CNMaR gene. Bombyx CNMaR showed low sensitivity to Drosophila CNMa, hinting toward the existence of additional CNMaR ligand(s).

Natalisin, a tachykinin-like signaling system, regulates sexual activity and fecundity in insects.

An arthropod-specific peptidergic system, the neuropeptide designated here as natalisin and its receptor, was identified and investigated in three holometabolous insect species: Drosophila melanogaster, Tribolium castaneum, and Bombyx mori. In all three species, natalisin expression was observed in 3-4 pairs of the brain neurons: the anterior dorso-lateral interneurons, inferior contralateral interneurons, and small pars intercerebralis neurons. In B. mori, natalisin also was expressed in two additional pairs of contralateral interneurons in the subesophageal ganglion. Natalisin-RNAi and the activation or silencing of the neural activities in the natalisin-specific cells in D. melanogaster induced significant defects in the mating behaviors of both males and females. Knockdown of natalisin expression in T. castaneum resulted in significant reduction in the fecundity. The similarity of the natalisin C-terminal motifs to those of vertebrate tachykinins and of tachykinin-related peptides in arthropods led us to identify the natalisin receptor. A G protein-coupled receptor, previously known as tachykinin receptor 86C (also known as the neurokinin K receptor of D. melanogaster), now has been recognized as a bona fide natalisin receptor. Taken together, the taxonomic distribution pattern of the natalisin gene and the phylogeny of the receptor suggest that natalisin is an ancestral sibling of tachykinin that evolved only in the arthropod lineage.

A gene-networked gel matrix-supported lipid bilayer as a synthetic nucleus system.

A spheroidal transgene-networked gel matrix was designed as a synthetic nucleus system. It was spheroidically manufactured using both advanced lithography and DNA nanotechnology. Stable Aqueorea coerulescens green fluorescent protein (AcGFP)-encoding gene cross-networks have been optimized in various parameters: the number of gene-networked gel (G-net-gel) spheroids, the concentration of a AcGFP plasmid in the scaffold, and the molar ratio between the X-DNA building blocks and the gene. It was then assessed that 800 units of the gene networked gel matrix at a 4000:1 molar ratio of X-DNA blocks and AcGFP gene components accomplished 20-fold enhanced in vitro protein expression efficiency for 36 h. Furthermore, once with lipid capping, it reproduced the natural nucleus system, demonstrating the 2-fold increased levels of messenger RNAs (mRNAs) relative to solution phase vectors.

An alternative approach to needle placement in cervicothoracic epidural injections.

The use of fluoroscopy guidance together with the loss of resistance technique during epidural injections has been advocated lately; moreover, epidural injections in the absence of fluoroscopic guidance have a high rate of inaccurate needle-tip placement during the injections. However, the approach to the lower cervical and upper thoracic epidural space may be challenging due to its obscure lateral fluoroscopic views from overlying normal tissue structures. In this case, we report an alternative oblique C-arm fluoroscopy guided view approach to supplement the standard anterior-posterior and lateral fluoroscopic views to facilitate successful needle placement and precise anatomical localization of the epidural space.

Effects of inhaled iloprost on congenital heart disease with Eisenmenger syndrome.

Identification of the pathophysiology associated with Eisenmenger syndrome has led to the evaluation of targeted therapies. Iloprost is one such targeted therapy used for patients with Eisenmenger syndrome. This study aimed to assess the efficacy and safety of iloprost used for patients with Eisenmenger syndrome. In this study, 12 patients with Eisenmenger syndrome (mean age, 33.2 ± 12.1 years; 75% female) started receiving iloprost 10 µg/dose administered six times a day. Of the 12 patients, 9 were classified as New York Heart Association (NYHA) functional class 3, and three were categorized as functional class 4. Changes in 6-min walk distance, NYHA functional class, oxygen saturation at resting, and results after the 6-min walk test were checked, as well as changes in right ventricle diameter and pulmonary arterial pressure shown by echocardiography. The distance during a 6-min walk increased from 255.8 ± 120.4 to 349.4 ± 134.7 m (p = 0.013), and 10 patients improved their NYHA functional class by one grade (p = 0.007). The mean resting oxygen saturation (SpO(2)) increased from 80.6 ± 14.2 to 84.9 ± 13.0% (p = 0.040), and after the 6-min walk test, it increased from 63.8 ± 22.9 to 68.8 ± 21.5% (p = 0.007). The mean right ventricle diameter during the diastolic phase changed from 53.7 ± 4.8 to 51.4 ± 3.9 mm (p = 0.068), and the mean pulmonary arterial pressure changed from 62.8 ± 13.7 to 58.9 ± 11.7 mmHg (p = 0.059). Neither death nor critical adverse effects occurred for any patients. Mild headache and dyspnea were common reports during the iloprost treatments. No patients stopped the therapy due to these adverse effects. Iloprost is well tolerated and appears to be beneficial in the management of patients with Eisenmenger syndrome.

Vasorelaxant mechanisms of ketamine in rabbit renal artery.

BACKGROUND: Ketamine is a non-barbiturate anesthetic agent which has various effects on the cardiovascular system. Among them, ketamine is known for its hypotensive properties. The hypotension is thought to be mediated by a direct effect on vascular smooth muscles. This study is designed to examine the effects of ketamine on KCl- and histamine-induced contraction in isolated rabbit renal arteries. METHODS: Endothelium-intact or -denuded smooth muscle rings were prepared and mounted in myographs for isometric tension measurements. The inhibitory effect of ketamine were investigated in smooth muscle rings precontracted with either 50 mM KCl- or 10 µM histamine. RESULTS: Ketamine (0.1-100 µg/ml) produced similar concentration-dependent inhibition of contractile responses induced by either 50 mM KCl or 10 µM histamine. The respective IC(50) values measured for ketamine following precontractions by 50 mM KCl and 10 µM histamine were 28.9 µg/ml (105.5 µM) and 26.7 µg/ml (97.5 µM). The inhibitory effect of 30 µg/ml ketamine were similarly observed after removal of endothelium or pretreatment with N(G)-Nitroarginine Methyl Ester (0.1 mM). The inhibitory effect of 30 µg/ml ketamine on histamine-evoked contraction was reduced by either tetraethylammonium (10 mM) or iberiotoxin, a large conductance Ca(2+)-activated K(+) channel blocker. However, depletion of intracellular Ca(2+) stores by ryanodine (10 µM) or thapsigargin (10 µM) showed no significant effect on 30 µg/ml ketamine-induced relaxation. Pre-incubation with 30 µg/ml ketamine significantly inhibited CaCl(2)-induced contraction at almost all ranges of concentration. CONCLUSIONS: Ketamine-induced relaxation of rabbit renal arteries is mediated by both the activation of large conductance Ca(2+)-activated K(+) channel and the inhibition of Ca(2+) influx.

Irinotecan plus carboplatin in patients with extensive-disease small-cell lung cancer.

This study was designed to evaluate the efficacy and safety of irinotecan in combination with carboplatin in previously untreated, extensive-disease small-cell lung cancer (ED-SCLC). Patients with histologically or cytologically confirmed ED-SCLC received irinotecan (60 mg/m(2) on days 1, 8, and 15) plus carboplatin (AUC 5 on day 1) every 4 weeks. Treatment was repeated until disease progression, unacceptable toxicity, or up to 6 cycles. Forty-four patients were enrolled. In an intent-to-treat analysis, the overall response rate (RR) was 75% (8 complete responses and 25 partial responses). The median progression-free (PFS) and overall survival (OS) were 5.6 and 8.7 months, respectively. The principle toxicities were neutropenia and diarrhea. Grade 3-4 neutropenia occurred in 30% of the patients and 7% of patients presented with febrile neutropenia. Grade 3-4 diarrhea occurred in 21% of the patients. A subgroup consisting of patients ≥ 65 years of age had outcomes similar to the younger group <65 years of age. The objective RR was 72% in the patients <65 years of age and 77% in the patients ≥ 65 years of age (P = .738). The median PFS and OS (<65 years vs. ≥ 65 years) were 5.3 vs. 5.6 months (P = .835) and 9.0 vs. 8.7 months (P = .648), respectively. The combination of irinotecan and carboplatin is active and tolerable in patients with ED-SCLC. This regimen could be considered as a treatment option for patients of advanced age.

The effect of pneumoperitoneum and Trendelenburg position on respiratory mechanics during pelviscopic surgery.

BACKGROUND: Conventional pelviscopic surgery requires pneumoperitoneum with CO(2) gas insufflation and lithotomy-Trendelenburg position. Pneumoperitoneum and Trendelenburg position may influence intraoperative respiratory mechanics in anesthetic management. This study was conducted to investigate the influence of pneumoperitoneum and Trendelenburg position on respiratory compliance and ventilation pressure. METHODS: Twenty-five patients scheduled for elective gynecologic laparoscopy were evaluated. The patients had no preexisting lung or heart disease or pathologic lung function. Conventional general anesthesia with thiopental sodium, lidocaine, rocuronium, and sevoflurane was administered. The peak inspiratory pressure, plateau pressure, and end-tidal CO(2) were measured before and after creation of pneumoperitoneum with an intraabdominal pressure of 12 mmHg, then after 10 minutes and 30 minutes in the 20° Trendelenburg position, and after deflation of pneumoperitoneum. The dynamic lung compliance was then calculated. RESULTS: Following creation of pneumoperitoneum, there was a significant increase in peak inspiratory pressure (6 cmH(2)O), plateau pressure (7 cmH(2)O), and end-tidal CO(2) (5 mmHg), while dynamic lung compliance decreased by 12 ml/cmH(2)O. Overall, the Trendelenburg position induced no significant hemodynamic or pulmonary changes. CONCLUSIONS: The effects of pneumoperitoneum significantly reduced dynamic lung compliance and increased peak inspiratory and plateau pressures. The Tredelenburg position did not change these parameters.

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer.

BACKGROUND/AIMS: The efficacy and safety of pemetrexed, gefitinib, and erlotinib administration in previously treated patients with non-small cell lung cancer (NSCLC) were compared. METHODS: THE STUDY PATIENTS MET THE FOLLOWING CRITERIA: histologically confirmed, previously treated advanced (stage IIIB or IV) or recurrent NSCLC; a measurable lesion; ≥ 18 years of age; Eastern Cooperative Oncology Group Performance status 0 to 2; and no prior exposure to the three study drugs. Patients received 500 mg/m(2) of pemetrexed intravenously every 3 weeks with vitamin supplementation, gefitinib (250 mg/day per os), or erlotinib (150 mg/day per os). RESULTS: Of 57 patients (pemetrexed, 20; gefitinib, 20; and erlotinib, 17), 55 were evaluated for a response. The numbers of males, smokers, and squamous histology were increased in the pemetrexed group compared to the other groups. The objective response rates were 5.3%, 25.0%, and 12.5% (p = 0.22), and the disease control rates (DCR) were 5.3%, 40.0%, and 50.0%, respectively (p < 0.01). The median progression-free survival (PFS) was 1.7, 3.5, and 4.4 months (p < 0.01) and the median overall survival (OS) was 5.6, 21.8, and 21.5 months (p = 0.04), respectively. In subgroup analyses, patients with non-squamous histology, males, and a smoking history had a higher DCR and longer PFS with gefitinib and erlotinib than with pemetrexed. All three chemotherapeutic agents had manageable toxicities. CONCLUSIONS: Both oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) had comparable efficacy and safety. The superior PFS and OS of EGFR TKIs with more favorable baseline clinical characteristics than those of pemetrexed suggest the impact of baseline clinicopathological factors.