In diabetic patients, ␣-lipoic acid (LA) improves skeletal muscle glucose transport, resulting in increased glucose disposal; however, the molecular mechanism of action of LA is presently unknown. We studied the effects of LA on basal and insulin-stimulated glucose transport in cultured rat L6 muscle cells that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in these cells, they were more sensitive and responsive to insulin than wild-type L6 cells. LA, at concentrations ≤1 mmol/l, had only small effects on glucose transport in cells not exposed to oxidative stress. When cells were exposed to glucose oxidase and glucose to generate H 2 O 2 and cause oxidative stress, there was a marked decrease in insulinstimulated glucose transport. Pretreatment with LA over the concentration range of 10-1,000 µmol/l protected the insulin effect from inhibition by H 2 O 2 . Both the R and S isomers of LA were equally effective. In addition, oxidative stress caused a significant decrease (~50%) in reduced glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated protein kinase. Pretreatment with LA prevented both of these events, coincident with protecting insulin action. These studies indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance. Diabetes 50: [404][405][406][407][408][409][410] 2001

Paroxetine is a novel antidepressant drug with selective serotonin (5-HT) reuptake inhibitory properties. In a double-blind placebo-controlled crossover sleep laboratory study the single-dose effects on objective and subjective sleep and awakening qualities were investigated after paroxetine 20, 30 and 40 mg morning doses (PX 20, 30, 40), paroxetine 30 mg evening dose, fluoxetine 40 mg morning dose (FX 40) and placebo in 18 healthy young volunteers. The drugs were orally administered in 2-wk intervals. In addition to each drug night, the adaptation night and washout night were recorded. Polysomnographic investigations (10:30 p.m. to 6:00 a.m.) showed a delayed sleep onset only after the morning intake of paroxetine, PX 40 being statistically different from placebo. Total sleep time and sleep efficiency deteriorated under morning PX 30, PX 40 and evening PX 30 as compared to placebo. The nocturnal wake time and sleep stage 1 increased under the paroxetine. Rapid eye movement (REM) reduction (min and %) occurred dose dependently after all paroxetine doses, but the REM latency was lengthened only after the morning intake. The suppressant effect on REM sleep is characteristic for antidepressants and was still significant in the washout nights following PX 40 and evening PX 30. The only statistically relevant finding under 40 mg fluoxetine referred to the increase of REM latency in both drug and washout nights. In contrast to objective results, subjective sleep quality remained generally unchanged. Attention, concentration and reaction performance improved under paroxetine as compared to baseline. The deterioration of well-being under PX 40 might be related to the appearance of drowsiness and nausea. Blood pressure and pulse rate were unaffected.

Objective: Two main functional imaging approaches have been used to measure regional lung perfusion using Electrical Impedance Tomography (EIT): venous injection of a hypertonic saline contrast agent and imaging of its passage through the heart and lungs, and digital filtering of heart-frequency impedance changes over sequences of EIT images. This paper systematically compares filtering-based perfusion estimates and bolus injection methods to determine to which degree they are related. Approach: EIT data was recorded on 7 mechanically ventilated newborn lambs in which ventilation distribution was varied through changes in posture between prone, supine, left-and right-lateral positions. Perfusion images were calculated using frequency filtering and ensemble averaging during both ventilation and apnoea time segments for each posture to compare against contrast agent-based methods using Jaccard distance score. Main Results: Using bolus-based EIT measures of lung perfusion as the reference frequency filtering techniques performed better than ensemble averaging and both techniques performed equally well across apnoea and ventilation data segments. Significance: Our results indicate the potential for use of filtering-based EIT measures of heart-frequency activity as a non-invasive proxy for contrast agent injection-based measures of lung perfusion.

Animal experiments suggest that total liquid ventilation (TLV) induces less ventilatorinduced lung injury (VILI) than conventional mechanical gas ventilation. However, TLV parameters that optimally minimize VILI in newborns remain unknown. Our objective was to compare lung inflammation between low (L-V T) and high (H-V T) liquid tidal volume and evaluate impacts on the weaning process. Sixteen anesthetized and paralyzed newborn lambs were randomized in an L-V T group (initial tidal volume of 10 mL/kg at 10/min) and an H-V T group (initial tidal volume of 20 mL/kg at 5/min). Five unventilated newborn lambs served as controls. After 4 h of TLV in the supine position, the lambs were weaned in the prone position for another 4 h. The levels of respiratory support needed during the 4 h post-TLV were compared. The anterior and posterior lung regions were assessed by a histological score and real-time quantitative PCR for IL1B, IL6, and TNF plus 12 other exploratory VILI-associated genes. All but one lamb were successfully extubated within 2 h post-TLV (72 ± 26 min vs. 63 ± 25 min, p = 0.5) with similar FiO 2 at 4 h post-TLV (27 ± 6% vs. 33 ± 7%, p = 0.3) between the L-V T and H-V T lambs. No significant differences were measured in histological inflammation scores between L-V T and H-V T lambs, although lambs in both groups exhibited slightly higher scores than the control lambs. The L-V T group displayed higher IL1B mRNA expression than the H-V T group in both anterior (2.8 ± 1.5-fold increase vs. 1.3 ± 0.4-fold increase, p = 0.02) and posterior lung regions (3.0 ± 1.0-fold change increase vs. 1.1 ± 0.3-fold increase, p = 0.002), respectively. No significant differences were found in IL6 and TNF expression levels. Gene expression changes overall indicated that L-V T was associated with a qualitatively distinct inflammatory gene expression profiles compared to H-V T , which may indicate different clinical effects. In light of these findings, further mechanistic studies are warranted. In conclusion, we found no advantage of lower tidal volume use, which was in fact associated with a slightly unfavorable pattern of inflammatory gene expression.

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