Ventilatory interaction between oxygen and carbon dioxide in the preterm primate

The steady state ventilatory response to inhaled CO2 was measured in eleven unanesthetized premature Macaca nemestrina during the first 3 wk of life in different steady state background O2 mixtures hypoxia (FIO2 = 0.08 or 0.12), normoxia (FIO2 = 0.21) and hyperoxia (FIO2 = 0.96). Hyperoxic delta VI/delta PACO2 and delta P0.2/ delta PACO2 were significantly greater than hypoxic delta VI/ delta PACO2 and delta P0.2/delta PACO2, respectively, at both 2 and 21 days postnatal age by the Mann Whitney test of nonparametric ranking (2 days: 89.. and 80.2 degrees versus 88.7 and 56.4 degrees, respectively; 21 days: 89.3 and 76.6 degrees versus 50.2 and 57.1 degrees, respectively; p less than 0.05). Hypoxic delta VI/delta PACO2 was significantly depressed compared to normoxic delta VI/ delta PACO2 only at 21 days of age (50.2 versus 89.4 degrees, respectively; p less than 0.05); hyperoxic CO2 sensitivity and normoxic CO2 sensitivity did not differ at either age. The ventilatory interaction between O2-CO2 in the neonatal primate appears to be the inverse of the typical adult ventilatory interaction. It is hypothesized that differential changes in brain stem blood flow between neonates and adults might explain this difference in O2-CO2 ventilatory interaction.     

Diaphragmatic pressures in piglets: Transvenous versus direct phrenic nerve stimulation

We examined transdiaphragmatic pressure (Pdi) generation during both direct (DPNS) and transvenous (TVPNS) modes of phrenic nerve stimulation in anesthetized piglets of varying postnatal age. Pdi measurements during TVPNS were not statistically different from those obtained during DPNS (p > 0.10). Furthermore, a good correlation (r = 0.98, p < 0.001) was obtained when the mean Pdi measurements obtained by both methods were compared. We conclude that TVPNS can be used in lieu of DPNS to generate Pdi. Furthermore, our data suggest that this technique can be used to study the effects of various experimental manipulations on diaphragmatic force output within a developmental context.     

Effect of pentoxifylline on cytokine- and eicosanoid-induced acute pulmonary hypertension in piglets.

The methylxanthine derivative pentoxifylline (PTF) demonstrates vasodilatory properties in vivo. We tested the hypothesis that PTF infusion would blunt or inhibit tumor necrosis factor-alpha (TNF alpha)-induced and U46,619-induced increases in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) in the neonatal piglet and would do so by altering production of eicosanoid vasoactive mediators. Anesthetized, paralyzed piglets (age 10-29 d) were randomized and treated with a 30-min infusion of TNF alpha alone (n = 13 animals), with a combination of TNF alpha plus pretreatment and continuous infusion with PTF (n = 6), or with a combination of U46,619 for 30 min plus pretreatment and continuous infusion of PTF (n = 5). There was no difference in pulmonary or systemic hemodynamic indices between the three groups at baseline. PVR was significantly elevated at 15 min and at 2 h in the TNF alpha-only group. The TNF alpha-induced rise in mean pulmonary artery pressure and PVR was inhibited by the PTF until 2 h, by which time PVR was elevated above baseline and was comparable to the value found in animals treated with only TNF alpha. PTF produced no inhibition in the U46,619-induced elevation of PVR during the 30-min simultaneous treatment. In the PTF + TNF alpha group, mean systemic blood pressure declined to 50% of baseline value (p less than 0.02) by 2 h of age. No significant decline was noted in mean systemic arterial pressure of the TNF alpha-only or the U46,619-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

RO 31-8220 activates c-Jun N-terminal kinase and glycogen synthase in rat adipocytes and L6 myotubes. Comparison to actions of insulin

The activation of c-Jun N-terminal kinase (JNK) by insulin and anisomycin has been reported to result in increases in glycogen synthase (GS) activity in rat skeletal muscle (Moxham et al., J Biol Chem, 1996, 271:30765-30773). In addition, the protein kinase C (PKC) inhibitor, RO 31-8220, has been reported to activate JNK in rat-1 fibroblasts (Beltman et al., J Biol Chem, 1996, 271:27018-27024). Presently, we found that the RO 31-8220, as well as insulin, activated JNK and GS and stimulated glucose incorporation into glycogen in rat adipocytes and L6 myotubes. In contrast to activation of JNK, RO 31-8220 inhibited extracellular response kinases 1 and 2 (ERK1/2) and had no significant effects on protein kinase B (PKB). Stimulatory effects of RO 31-8220 on JNK and glycogen metabolism were not explained by PKC inhibition, as other PKC inhibitors were without effect on glucose incorporation into glycogen and have no effect on JNK (Beltman et al., J Biol Chem, 1996, 271:27018). Insulin, on the other hand, activated JNK, as well as PKB and ERK1/2. However, stimulatory effects of insulin on GS and glucose incorporation into glycogen appeared to be fully intact and additive to those of RO 31-8220, despite the fact that insulin did not provoke additive increases in JNK activity above those observed with RO 31-8220 alone. Our findings suggest that JNK serves to activate GS during the action of RO 31-8220 in rat adipocytes and L6 myotubes; insulin, on the other hand, appears to activate GS largely independently of JNK.     

Phorbol ester inhibition of insulin-stimulated deoxyribonucleic acid synthesis in BC3H-1 myocytes

Insulin and 12-O-tetradecanoyl phorbol 13-acetate (TPA) each acutely stimulates hexose transport, amino acid uptake, and pyruvate dehydrogenase activity in the BC3H-1 myocyte in a nonadditive fashion, suggesting that the acute effects of insulin and TPA are mediated through a common mechanism of action. Here we have demonstrated that while chronic incubation with insulin stimulated DNA synthesis by 3- to 6-fold, TPA, in contrast, did not stimulate DNA synthesis and, indeed, caused a 70% inhibition of insulin-stimulated DNA synthesis in a dose-dependent fashion. In differentiated myocytes, insulin maximally stimulated hydroxyurea-sensitive [3H]thymidine incorporation into DNA at 200-400 nM with an ED50 of 5-8 nM, suggesting that insulin stimulates DNA synthesis via the insulin receptor rather than through growth factor receptors. Phorbol ester inhibition of insulin-stimulated DNA synthesis was specific for the active tumor-promoting phorbols and the synthetic diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol. Maximal TPA inhibition of insulin-stimulated DNA synthesis was observed at 100 nM with an ID50 of 30 nM TPA, values analogous to those required for TPA stimulation of hexose transport in the myocyte. Chronic incubation with TPA did not inhibit insulin-stimulated protein synthesis, acute K+ flux, K+ accumulation, cytosolic thymidine levels, or insulin binding, indicating that TPA inhibits a specific intracellular event mediating DNA synthesis and suggesting that the acute and chronic effects of insulin in BC3H-1 myocytes are regulated by distinct pathways.     

Levodopa‐carbidopa intestinal gel in advanced Parkinson's disease: Final 12‐month,open‐label results

Motor complications in Parkinson's disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l ‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐ dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l‐ dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.