Context Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. Objective To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. Design, Setting, and Patients Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. Intervention Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. Main Outcome Measures Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. Results Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, PՅ.01 for both groups; QOL, PϽ.001 for both groups), with a larger decrease in pain for the NCPB group (P = .005). From repeated measures analysis, pain was also lower for NCPB over time (P = .01). However, opioid consumption (P = .93), frequency of opioid adverse effects (all PϾ.10), and QOL (P=.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of Ն5/10) vs opioid-only patients (14% vs 40%, P=.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P=.26, proportional hazards regression). Conclusion Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.

We hypothesized that considerable force reserve exists for the diaphragm muscle (DIAm) to generate transdiaphragmatic pressures (Pdi) necessary to sustain ventilation. In rats, we measured Pdi and DIAm EMG activity during different ventilatory (eupnea and hypoxia (10% O2) – hypercapnia (5% CO2)) and non-ventilatory (airway occlusion and sneezing induced by intranasal capsaicin) behaviors. Compared to maximum Pdi (Pdimax - generated by bilateral phrenic nerve stimulation), the Pdi generated during eupnea (21±2%) and hypoxia-hypercapnia (28±4%) were significantly less (P<0.0001) than that generated during airway occlusion (63±4%) and sneezing (94±5%). The Pdi generated during spontaneous sighs was 62±5% of Pdimax. Relative DIAm EMG activity (root mean square [RMS] amplitude) paralleled the changes in Pdi during different ventilatory and non-ventilatory behaviors (r2=0.78; p<0.0001). These results support our hypothesis of a considerable force reserve for the DIAm to accomplish ventilatory behaviors. A model for DIAm motor unit recruitment predicted that ventilatory behaviors would require activation of only fatigue resistant units.

Sarcopenia, defined as muscle weakness and fiber atrophy, of respiratory muscles such as the diaphragm (DIAm) has not been well characterized. The DIAm is the main inspiratory muscle and knowledge of DIAm sarcopenia is important for establishing the effects of aging on respiratory function. We hypothesized that aging is associated with a loss of DIAm force and reduced fiber cross-sectional area (CSA), and that these changes vary across fiber types. DIAm sarcopenia was assessed in young (5 month; n=11) and old (23 month; n=12) wild-type mice reflecting ~100 and 75% survival, respectively. In addition, DIAm sarcopenia was evaluated in BubR1H/H mice (n=4) that display accelerated aging (~60% survival at 5 months) as a result of expression of a hypomorphic allele (H) of the mitotic checkpoint protein BubR1. Maximum specific force (normalized for CSA) of the DIAm was 34% less in old mice and 57% lower in BubR1H/H mice compared to young mice. Mean CSA of type IIx and/or IIb DIAm fibers was 27% smaller in old wild-type mice and 47% smaller in BubR1H/H mice compared to young mice. Mean CSA of type I or IIa fibers was not different between groups. Collectively these results demonstrate sarcopenia of the DIAm in aging wild-type mice and in BubR1H/H mice displaying accelerated aging. Sarcopenia may limit the ability of the DIAm to accomplish expulsive, non-ventilatory behaviors essential for airway clearance. As a result, these changes in the DIAm may contribute to respiratory complications with aging.

Abstract-Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis.Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10 Ϫ9 to 10 Ϫ5 mol/L) and Ca 2ϩ ionophore (10 Ϫ9 to 10 Ϫ6 mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10 Ϫ10 to 10 Ϫ5 mol/L) compared with aortic rings from C57BL/6J mice (PϽ0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O 2 Ϫ ) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10 Ϫ5 mol/L), reduced O 2 Ϫ production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (PϽ0.05). [ 14 C]L-Citrulline assay showed a decrease of Ca 2ϩ -dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (PϽ0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (PϽ0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O 2 Ϫ and reduced endothelial NO synthase enzyme activity. Key Words: endothelium Ⅲ nitric oxide Ⅲ superoxide anion Ⅲ apolipoprotein E Ⅲ atherosclerosis A therosclerosis is a chronic process, which can be triggered by cardiovascular risk factors such as hypercholesterolemia, aging, hypertension, and diabetes mellitus. 1 Endothelium-derived vasoactive factors play an important regulatory role in vascular homeostasis and pathogenesis of atherosclerosis because of the strategic position of the endothelium between the vascular smooth muscle cells (VSMCs) and the circulating blood. 2,3 NO is a potent vasodilator that is formed in endothelial cells from L-arginine by endothelial NO synthase (eNOS), which is constitutively expressed. 4 -6 NO production is activated by the stimulation of cell surface receptors or by mechanical forces such as shear stress. 7,8 Accumulating evidence suggests that alterations in the NO pathway play a central role in endothelial dysfunction induced by hypercholesterolemia. This may be of major importance inasmuch as NO can substantially inhibit several components of the atherogenic process, such as VSMC contraction and proliferation, platelet aggregation, and monocyte adhesion. 9,10 Previous studies identified 3 mechanisms responsible for reduced bioavailability of NO in arteries exposed to hypercholester...

In the adult rat, there is a general correspondence between the sizes of motoneurons, motor units, and muscle fibers that has particular functional importance in motor control. During early postnatal development, after the establishment of singular innervation, there is rapid growth of diaphragm muscle (Dia(m)) fibers. In the present study, the association between Dia(m) fiber growth and changes in phrenic motoneuron size (both somal and dendritic) was evaluated from postnatal day 21 (D21) to adulthood. Phrenic motoneurons were retrogradely labeled with fluorescent tetramethylrhodamine dextran (3,000 MW), and motoneuron somal volumes and surface areas were measured using three-dimensional confocal microscopy. In separate animals, phrenic motoneurons retrogradely labeled with choleratoxin B-fragment were visualized using immunocytochemistry, and dendritic arborization was analyzed by camera lucida. Between D21 and adulthood, Dia(m) fiber cross-sectional area increased by approximately 164% overall, with the growth of type II fibers being disproportionate to that of type I fibers. There was also substantial growth of phrenic motoneurons ( approximately 360% increase in total surface area), during this same period, that was primarily attributable to an expansion of dendritic surface area. Comparison of the distribution of phrenic motoneuron surface areas between D21 and adults suggests the establishment of a bimodal distribution that may have functional significance for motor unit recruitment in the adult rat.

Studies of motoneuron plasticity during development or in response to injury or disease rely on the ability to correctly identify motoneurons innervating specific muscle groups. Commonly, injections of retrograde tracer molecules into a target muscle or into a transected nerve are used to label specific motoneuron pools. However, intramuscular injection does not consistently label all motoneurons in the target pool; and either injection site may involve additional surgical procedures and muscle or nerve perturbations. For instance, retrograde labeling of phrenic motoneurons by injection into the diaphragm muscle is commonly employed in studies of plasticity in respiratory motor control. Diaphragm intramuscular injection involves a laparotomy, and this additional surgery may limit the ability to conduct labeling studies particularly in small animals. In the present study, we provide validation of a novel method for phrenic motoneuron labeling using intrapleural injection of Alexa 488-conjugated cholera toxin subunit B. Only phrenic motoneurons were labeled in the cervical spinal cord as verified by co-staining with rhodamine-conjugated dextran injected into the diaphragm muscle or applied via phrenic nerve dip. Thoracic intercostal motoneurons and some dorsal root ganglia neurons were also labeled by intrapleural injection, but there was no evidence of transsynaptic labeling. Phrenic motoneuron labeling was not present if the phrenic nerve was transected prior to intrapleural injection. This novel method is ideally suited for morphological studies and analyses of mRNA expression in isolated phrenic motoneurons using techniques such as laser capture microdissection.

In patients undergoing primary elective lower extremity arthroplasty, obesity, poor American Society of Anesthesiologists physical status classification, and lack of thromboprophylaxis are independent risk factors for clinically relevant thromboembolic events.

A C 2 cervical spinal cord hemisection (SH) interrupts descending inspiratory-related drive to phrenic motoneurons located between C 3 and C 5 in rats, paralyzing the ipsilateral hemidiaphragm muscle. There is gradual recovery of rhythmic diaphragm muscle activity ipsilateral to cervical spinal cord injury over time, consistent with neuroplasticity and strengthening of spared, contralateral descending premotor input to phrenic motoneurons. Brainderived neurotrophic factor (BDNF) signaling through the tropomyosin related kinase receptor subtype B (TrkB) plays an important role in neuroplasticity following spinal cord injury. We hypothesized that 1) increasing BDNF/TrkB signaling at the level of the phrenic motoneuron pool by intrathecal BDNF delivery enhances functional recovery of rhythmic diaphragm activity after SH, and 2) inhibiting BDNF/ TrkB signaling by quenching endogenous neurotrophins with the soluble fusion protein TrkB-Fc or by knocking down TrkB receptor expression in phrenic motoneurons using intrapleurallydelivered siRNA impair functional recovery after SH. Diaphragm EMG electrodes were implanted bilaterally to verify complete hemisection at the time of SH and 3 days post-SH. After SH surgery in adult rats, an intrathecal catheter was placed at C 4 to chronically infuse BDNF or TrkB-Fc using an implanted mini-osmotic pump. At 14 days post-SH, all intrathecal BDNF treated rats (n=9) displayed recovery of ipsilateral hemidiaphragm EMG activity, compared to 3 out of 8 untreated SH rats (p < 0.01). During eupnea, BDNF treated rats exhibited 76 ± 17% of pre-SH root mean squared EMG vs. only 5 ± 3% in untreated SH rats (p < 0.01). In contrast, quenching endogenous BDNF with intrathecal TrkB-Fc treatment completely prevented functional recovery up to 14 days post-SH (n=7). Immunoreactivity of the transcription factor cAMP response element-binding protein (CREB), a downstream effector of TrkB signaling, increased in phrenic motoneurons following BDNF treatment (n=6) compared to artificial cerebrospinal fluid treatment (n=6; p < 0.001). Intrapleural injections of non-sense or TrkB siRNA were administered after SH to specifically target phrenic motoneurons. At 14 days post-SH, none out of 9 TrkB siRNA treated rats displayed functional recovery compared to 5 out of 9 non-sense siRNA treated rats. These results indicate that BDNF/TrkB signaling in phrenic motoneuron pool plays a critical role in functional recovery after cervical spinal cord injury.