S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.

BACKGROUND: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. RESULTS: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. CONCLUSIONS: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

Evaluation of muscle tissue and liver glycogen of cattle submitted to transport over long distances and subjected to emergency slaughter / Avaliação do tecido muscular e glicogênio hepático de bovinos transportados por longas distâncias e submetidos ao abate de emergência

The study evaluated the effect of transportation over long distances on cattle muscle tissue of submitted to emergency slaughter in slaughterhouses in northern Tocantins, Brazil. The evaluations consisted in pH, muscle and liver glycogen, muscle histopathology and creatine kinase (CK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Animals were placed into two groups: Experimental Group (EG), consisting of 19 bovines intended for immediate emergency slaughter, and Control Group (CG), composed of 24 bovines slaughtered in accordance with the normal flow. CK and ALT levels were high in EG. AST did not differ between groups. EG showed higher muscle pH and mean of degenerate fibers, mainly on the intercostal. However, muscle and liver glycogen did not differ between groups. In conclusion, cattle transported over long distances and subjected to immediate emergency slaughter showed markedly stress condition, with changes in biochemical parameters in the muscle tissue, determined by cellular degeneration.(AU)

O presente trabalho objetivou avaliar o efeito do transporte em longas distâncias sobre o tecido muscular de bovinos encaminhados ao abate de emergência. Foram avaliados pH, glicogênio muscular e hepático, análise histopatológica muscular, creatina quinase (CK), alanina aminotransferase (ALT) e aspartato aminotransferase (AST). Os animais foram alocados em dois grupos: grupo experimental (GE), constituído por 19 bovinos destinados ao abate de emergência, e grupo controle (GC), composto por 24 bovinos abatidos de acordo com o fluxo normal do frigorífico. A CK e a ALT estavam aumentadas no GE. O AST não diferiu entre os grupos. O GE apresentou maior percentual de fibras degeneradas, e o músculo intercostal teve maior quantidade de degenerações. O pH muscular foi superior no GE. O glicogênio muscular e o hepático não diferiram entre os grupos. Concluiu-se que bovinos encaminhados ao abate de emergência sofrem estresse severo pelo transporte por longas distâncias, com alterações bioquímicas no tecido muscular determinada pela degeneração celular.(AU)

The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients.

We examined the effect of alemtuzumab and basiliximab induction therapy on patient survival and freedom from bronchiolitis obliterans syndrome (BOS) in double lung transplantation. The United Network for Organ Sharing database was reviewed for adult double lung transplant recipients from 2006 to 2013. The primary outcome was risk-adjusted all-cause mortality. Secondary outcomes included time to BOS. There were 6117 patients were identified, of whom 738 received alemtuzumab, 2804 received basiliximab, and 2575 received no induction. Alemtuzumab recipients had higher lung allocation scores compared with basiliximab and no-induction recipients (41.4 versus 37.9 versus 40.7, p < 0.001) and were more likely to require mechanical ventilation before to transplantation (21.7% versus 6.5% versus 6.2%, p < 0.001). Median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 versus 2352 versus 1967 days, p = 0.001). Alemtuzumab (hazard ratio 0.80, 95% confidence interval 0.67-0.95, p = 0.009) and basiliximab induction (0.88, 0.80-0.98, p = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% versus 55.4 versus 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS.

Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.

BACKGROUND: SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. PATIENTS AND METHODS: SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. RESULTS: Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. CONCLUSION: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Alteraciones en la dispensación de medicamentos en las boticas del distrito de Chiclayo / Alterations in drug dispensation by private sector pharmacies in the district of Chiclayo

Objetivos: Determinar las alteraciones más frecuentes en la dispensación de medicamentos en las cadenas de boticas del distrito de Chiclayo: El estudio La población accesible fueron 30 boticas, de las cuales sólo 28 boticas se encontraron y evaluaron. Se visitó cada una de las boticas y mediante una receta médica, una lista de medicamentos y una relación de síntomas que respondan, respectivamente, al análisis de nuestros objetivos secundarios. Hallazgos: Se encontró que en el 21% de las boticas visitadas se cambió la prescripción médica por personal laboral, en el 100% de las boticas visitadas se vendió medicamentos sin receta médica y en 100% de aquellas se indicó una medicación sin haberla ésta prescrito por ningún médico. Conclusiones: En el 21% de las cadenas de boticas del distrito de Chiclayo, la prescripción médica puede ser cambiada; en el 100% de las cadenas de boticas de este distrito los medicamentos pueden ser fácilmente adquiridos sin la necesidad de presentar una receta; y en el 100% de las cadenas de boticas de dicho distrito podría indicarse medicación por el personal laboral.(AU)

bjective: To determine the most frequent alterations in the drug dispensation in pharmacy chains in the Chiclayo District. The study: Accessible population was 30 pharmacies, of which only 28 pharmacies were found and evaluated. He visited each of the pharmacies and used a prescription drug list and a list of symptoms that correspond respectively to the analysis of our secondary objectives. Findings: We found that in 21% of the pharmacies visited the prescription was changed by working staff, 100% visited sold drugs as if they were over the counter medications and 100% of those indicated a drug without having a doctor prescribed it. Conclusions: in 21% of the pharmacy chains in the district of Chiclayo, the prescription can be changed, in 100% of the pharmacy chains in this district drugs can be easily purchased without a prescription file, and also can drugs be sold indicated by working staff and not a doctor.(AU)

High-intensity physical exercise disrupts implicit memory in mice: involvement of the striatal glutathione antioxidant system and intracellular signaling.

Physical exercise is a widely accepted behavioral strategy to enhance overall health, including mental function. However, there is controversial evidence showing brain mitochondrial dysfunction, oxidative damage and decreased neurotrophin levels after high-intensity exercise, which presumably worsens cognitive performance. Here we investigated learning and memory performance dependent on different brain regions, glutathione antioxidant system, and extracellular signal-regulated protein kinase 1/2 (ERK1/2), serine/threonine protein kinase (AKT), cAMP response element binding (CREB) and dopamine- and cyclic AMP-regulated phosphoprotein (DARPP)-32 signaling in adult Swiss mice submitted to 9 weeks of high-intensity exercise. The exercise did not alter the animals' performance in the reference and working memory versions of the water maze task. On the other hand, we observed a significant impairment in the procedural memory (an implicit memory that depends on basal ganglia) accompanied by a reduced antioxidant capacity and ERK1/2 and CREB signaling in this region. In addition, we found increased striatal DARPP-32-Thr-75 phosphorylation in trained mice. These findings indicate an increased vulnerability of the striatum to high-intensity exercise associated with the disruption of implicit memory in mice and accompanied by alteration of signaling proteins involved in the plasticity of this brain structure.

Schwannoma benigno del nervio infraorbitario: reporte de un caso y revisión de la literatura / Infraorbital nerve benign Schwannoma: a case report and review of the literature

Los schwannomas son tumores de naturaleza benigna o maligna, originados a partir de las células de Schwann de la vaina de mielina de nervios periféricos, autónomos y pares craneanos. Dentro de estos últimos, el nervio trigémino es el segundo en frecuencia en ser afectado. Se presenta el caso de una paciente de 33 años portadora de una neuralgia trigeminal izquierda típica de 4 meses de evolución, con un estudio imagenológico que muestra un tumor originado del nervio infraorbitario izquierdo. Se practica exéresis de la lesión, cuyo estudio histológico revela un schwannoma benigno del nervio infraorbitario. No existen casos con afectación de este nervio publicados a la fecha en la literatura internacional que se ha revisado.

Schwannomas are benign or malignant tumors that arise from Schwann cells in the myelin sheath of peripheral, autonomic or cranial nerves. Among the latter, involvement of the trigeminal nerve is usually the second in frequency. We report the case of a 33 year old patient presenting with a left trigeminal neuralgia of 4 month of evolution. The imaging study showed a tumor of the left infraorbital nerve. The lesion was excised, and the histological study revealed a benign Schwannoma of the infraorbital nerve. To our knowledge, this is the first report of this nerve being affected.

Surgery for chronic obstructive pulmonary disease: the place for lung volume reduction and transplantation.

Lung volume reduction surgery and lung transplantation have been shown to improve lung function, exercise capacity, and quality of life in patients with advanced emphysema. Because the indications for both surgical procedures overlap, lung volume reduction surgery may be used as an alternative treatment or as a "bridge" to lung transplantation. In this article, we discuss patient selection, clinical outcome parameters, and the morbidity and mortality associated with each surgical procedure. We focus on the different preoperative predictors of good and poor outcomes after lung volume reduction surgery, the role of pulmonary rehabilitation, and the preferred surgical techniques for lung volume reduction surgery. An overview of the postoperative care of emphysema patients who undergo single-lung transplantation is also discussed.

Correlation of changes in quality of life after lung volume reduction surgery with changes in lung function, exercise, and gas exchange.

STUDY OBJECTIVES: To evaluate correlations between improvement in quality of life (QOL) in patients with severe COPD before and after they undergo lung volume reduction surgery (LVRS) with changes in pulmonary function tests, gas exchange, exercise performance, and alterations in medical management. DESIGN: Case-series analysis. SETTING: University hospital. PATIENTS: Forty-two patients (mean [+/- SD] age, 56+/-8 years; 53% women) with severe airflow obstruction (FEV(1), 0.62+/-0.2 L), and moderate to severe hyperinflation (total lung capacity [TLC], 6.9+/-1.7 L). INTERVENTION AND MEASUREMENTS: All patients underwent bilateral LVRS via median sternotomy. Measurements of lung function, symptom-limited cardiopulmonary exercise testing, the total distance the patient was able to walk in 6 min in a corridor, and sickness impact profile (SIP) scores were made before and 3 months after LVRS. SIP scores are inversely proportional to the level of function and QOL. RESULTS: Compared to baseline, FEV(1) increased (0.87+/-0.3 vs. 0.62+/-0.2 L, respectively; p<0.01) while residual volume significantly decreased (3.2+/-1.8 vs. 6.3+/-1.2 L, respectively; p<0.004) at 3 months post-LVRS. On cardiopulmonary exercise testing, values increased from baseline to post-LVRS for total exercise time (9.0+/-2.2 vs. 6.0+/-1.5 min, respectively; p = 0.045), maximum oxygen uptake (VO(2)) (16+/-3 vs. 11+/-2 mL/kg/min, respectively; p = 0.01), and maximum minute ventilation (VE) (33+/-9 vs. 28+/-5 L/min, respectively; p = 0.03). The percentage change in the oxygen cost of breathing (VO2/VE ratio) from low to high workloads during exercise was significantly lower after LVRS (p = 0.002). There was no significant change in oxygenation after LVRS (PaO(2)/fraction of inspired oxygen, 331+/-27 vs. 337+/-39, respectively; p = 0.76), but PaCO(2) tended to be lower (41+/-9 vs. 48+/-6 mm Hg, respectively; p = 0.07). Overall SIP scores were significantly lower after LVRS than before (8+/-4 vs. 15+/-2, respectively; p = 0.002). Changes in SIP scores correlated with the change in VO2/VE ratio from low to high workloads, with patients having the smallest changes in VO2/VE ratio having the smallest changes in SIP scores after LVRS (r = 0.6; p = 0.01). Improved or lower SIP scores also tended to correlate with a reduction in residual volume/TLC ratio (r = 0.45; p = 0.09), and there was a linear correlation with a statistically significant Pearson r value with decreased steroid requirements (r = 0.7; p = 0.001). Moreover, changes in psychological SIP subscore tended to correlate with diminished oxygen requirements post-LVRS (r = 0.45; p = 0.09). However, there was no significant correlation between changes in SIP scores and routine measurements of lung function, exercise performance, or gas exchange. CONCLUSION: There is an association between an improvement in QOL and reduced hyperinflation after LVRS. Reduced hyperinflation may lead to more efficient work of breathing during exercise and, therefore, to an increased ability to perform daily activities. Changes in QOL scores correlate best with behaviorally based variables that directly affect the patient's well-being, such as systemic steroid administration.

Prospective randomized trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease.

Several uncontrolled studies report improvement in lung function, gas exchange, and exercise capacity after bilateral lung volume reduction surgery (LVRS). We recruited 200 patients with severe chronic obstructive pulmonary disease (COPD) for a prospective randomized trial of pulmonary rehabilitation versus bilateral LVRS with stapling resection of 20 to 40% of each lung. Pulmonary function tests, gas exchange, 6-min walk distance, and symptom-limited maximal exercise testing were done in all patients at baseline and after 8 wk of rehabilitation. Patients were then randomized to either 3 additional months of rehabilitation or LVRS. Thirty-seven patients met study criteria and were enrolled into the trial. Eighteen patients were in the medical arm; 15 of 18 patients completed 3 mo of additional pulmonary rehabilitation. Thirty-two patients underwent LVRS (19 in the surgical arm, 13 crossover from the medical arm). After 8 wk of pulmonary rehabilitation, pulmonary function tests remained unchanged compared with baseline data. However, there was a trend toward a higher 6-min walk distance (285 +/- 96 versus 269 +/- 91 m, p = 0.14) and total exercise time on maximal exercise test was significantly longer compared with baseline values (7.4 +/- 2.1 versus 5.8 +/- 1.7 min, p < 0.001). In 15 patients who completed 3 mo of additional rehabilitation, there was a trend to a higher maximal oxygen consumption (V O(2)max) (13.3 +/- 3.0 versus 12.6 +/- 3.3, p < 0.08). In contrast, at 3 mo post-LVRS, FVC (2.79 +/- 0.59 versus 2.36 +/- 0.55 L, p < 0.001) and FEV(1) (0.85 +/- 0.3 versus 0.65 +/- 0.16 L, p < 0.005) increased whereas TLC (6.53 +/- 1.3 versus 7.65 +/- 2.1 L, p < 0.001) and residual volume (RV) (3.7 +/- 1.2 versus 4.9 +/- 1.1 L, p < 0.001) decreased when compared with 8 wk postrehabilitation data. In addition, Pa(CO(2)) decreased significantly 3 mo post-LVRS compared with 8 wk postrehabilitation. Six-minute walk distance (6MWD), total exercise time, and V O(2)max were higher after LVRS but did not reach statistical significance. However, when 13 patients who crossed over from the medical to the surgical arm were included in the analysis, the increases in 6MWD (337 +/- 99 versus 282 +/- 100 m, p < 0.001) and V O(2)max (13.8 +/- 4 versus 12.0 +/- 3 ml/kg/min, p < 0.01) 3 mo post-LVRS were highly significant when compared with postrehabilitation data. The Sickness Impact Profile (SIP), a generalized measure of quality of life (QOL), was significantly improved after 8 wk of rehabilitation and was maintained after 3 mo of additional rehabilitation. A further improvement in QOL was observed 3 mo after LVRS compared with the initial improvement gained after 8 wk of rehabilitation. There were 3 (9.4%) postoperative deaths, and one patient died before surgery (2.7%). We conclude that bilateral LVRS, in addition to pulmonary rehabilitation, improves static lung function, gas exchange, and QOL compared with pulmonary rehabilitation alone. Further studies need to evaluate the risks, benefits, and durability of LVRS over time.

Relationship between resting hypercapnia and physiologic parameters before and after lung volume reduction surgery in severe chronic obstructive pulmonary disease.

Patients with severe chronic obstructive pulmonary disease (COPD) have varying degrees of hypercapnia. Recent studies have demonstrated inconsistent effects of lung volume reduction surgery (LVRS) on PaCO2; however, most series have excluded patients with moderate to severe hypercapnia. In addition, no study has examined the mechanisms responsible for the reduction in PaCO2 post-LVRS. We obtained spirometry, body plethysmography, diffusion capacity, respiratory muscle strength, 6-min walk test, and incremental symptom-limited maximal exercise data in 33 consecutive patients pre- and 3 to 6 mo post-LVRS, and explored the relationship between changes in PaCO2 and changes in the measured physiologic variables. All patients underwent bilateral LVRS via median sternotomy and stapling resection by the same cardiothoracic surgeon. Patients were 57 +/- 8 yr of age with severe COPD, hyperinflation, and air trapping (FEV1, 0.73 +/- 0.2 L; TLC, 7.3 +/- 1.6 L; residual volume [RV], 4.8 +/- 1.4 L), and moderate resting hypercapnia (PaCO2, 44 +/- 7 mm Hg; range, 32 to 56 mm Hg). Post-LVRS, PaCO2 decreased by 4% (PaCO2 pre 44 +/- 7 mm Hg, PaCO2 post 42 +/- 5 mm Hg; p = 0.003). Patients with higher baseline values of PaCO2 had the greatest reduction in PaCO2 post-LVRS (r = -0.61, p < 0.001). Significant correlations existed between reduction in PaCO2 and changes in FEV1 (r = -0.56; p = 0.0007), maximal inspiratory pressure (PImax) (r = -0.46; p = 0.009), diffusing capacity of the lungs for carbon monoxide (DLCO) (r = -0.47; p = 0.008), and RV/TLC (r = 0.41; p = 0. 02). Correlation existed also between reduction in PaCO2 and breathing pattern at maximal exercise: maximal minute ventilation (V Emax) (r = -0.47; p = 0.009), and tidal volume (VT) (r = -0.40; p = 0.02). The changes in PaCO2 post-LVRS showed marked intersubject variability. We conclude that LVRS, by reducing hyperinflation, air trapping, and improving respiratory muscle function, enables the lung and chest wall to act more effectively as a pump, thereby increasing alveolar ventilation and reducing baseline resting PaCO2. In addition, patients with higher baseline levels of PaCO2 demonstrate the greatest reduction in PaCO2 post-LVRS, and should not be excluded from receiving LVRS.

Improvements in lung function, exercise, and quality of life in hypercapnic COPD patients after lung volume reduction surgery.

STUDY OBJECTIVE: To determine the impact of preoperative resting hypercapnia on patient outcome after bilateral lung volume reduction surgery (LVRS). METHODS: We prospectively examined morbidity, mortality, quality of life (QOL), and physiologic outcome, including spirometry, gas exchange, and exercise performance in 15 patients with severe emphysema and a resting PaCO2 of > 45 mm Hg (group 1), and compared the results with those from 31 patients with a PaCO2 of < 45 mm Hg (group 2). RESULTS: All preoperative physiologic and QOL indices were more impaired in the hypercapnic patients than in the eucapnic patients. The hypercapnic patients exhibited a lower preoperative FEV1, a lower diffusing capacity of the lung for carbon monoxide, a lower ratio of PaO2 to the fraction of inspired oxygen, a lower 6-min walk distance, and higher oxygen requirements. However, after surgery both groups exhibited improvements in FVC (group 1, p < 0.01; group 2, p < 0.001), FEV1 (group 1, p=0.04; group 2, p < 0.001), total lung capacity (TLC; group 1, p=0.02; group 2, p < 0.001), residual volume (RV; group 1, p=0.002; group 2, p < 0.001), RV/TLC ratio (group 1, p=0.03; group 2, p < 0.001), PaCO2 (group 1, p=0.002; group 2, p=0.02), 6-min walk distance (group 1, p=0.005; group 2, p < 0.001), oxygen consumption at peak exercise (group 1, p=0.02; group 2, p=0.02), total exercise time (group 1, p=0.02; group 2, p=0.02), and the perceived overall QOL scores (group 1, p=0.001; group 2, p < 0.001). However, because the magnitude of improvement was similar in both groups, and the hypercapnic group was more impaired, the spirometry, lung volumes, and 6-min walk distance remained significantly lower post-LVRS in the hypercapnic patients. There was no difference in mortality between the groups (p=0.9). CONCLUSIONS: Patients with moderate to severe resting hypercapnia exhibit significant improvements in spirometry, gas exchange, perceived QOL, and exercise performance after bilateral LVRS. The maximal achievable improvements in postoperative lung function are related to preoperative level of function; however, the magnitude of improvement can be expected to be similar to patients with lower resting PaCO2 levels. Patients should not be excluded from LVRS based solely on the presence of resting hypercapnia. The long-term benefit of LVRS in hypercapnic patient remains to be determined.

Effect of lung volume reduction surgery on diaphragm strength.

Since lung volume reduction surgery (LVRS) reduces end-expiratory lung volume, we hypothesized that it may improve diaphragm strength. We evaluated 37 patients for pulmonary rehabilitation and LVRS. Before and 8 wk after pulmonary rehabilitation, 24 patients had spirometry, lung volumes, diffusion capacity, incremental symptom limited maximum exercise test, 6-min walk test, maximal static inspiratory and expiratory mouth pressures, and transdiaphragmatic pressures during maximum static inspiratory efforts and bilateral supramaximal electrophrenic twitch stimulation measured. Twenty patients (including 7 patients who crossed over after completing pulmonary rehabilitation) had baseline measurements postrehabilitation, and 3 mo post-LVRS. Patients were 58 +/- 8 yr of age, with severe COPD and hyperinflation (FEV1, 0.69 +/- 0.21 L; RV, 4.7 +/- 1.4 L). Nineteen patients had bilateral LVRS performed via median sternotomy and stapling, and 1 patient had unilateral LVRS via thorascopy with stapling. After rehabilitation, spirometry and DL(CO)/VA were not different, and lung volumes showed a slight worsening in hyperinflation. Gas exchange, 6-min walk distance, maximum oxygen uptake (VO2max), and breathing pattern during maximum exercise did not change after rehabilitation, but total exercise time was significantly longer. Inspiratory muscle strength (PImax, Pdi(max combined), Pdi(max sniff), Pdi(max), Pdi(twitch)), was unchanged after rehabilitation. In contrast, after LVRS, FVC increased 21%, FEV1 increased 34%, TLC decreased 13%, FRC decreased 23%, and FRC(trapped gas) and RV decreased by 57 and 28%, respectively. PCO2 was lower (44 +/- 6 versus 48 +/- 6 mm Hg, p < 0.003) and 6-min walk distance increased (343 +/- 79 versus 250 +/- 89 m, p < 0.001), as did total exercise time during maximum exercise (9.2 +/- 1.9 versus 6.9 +/- 2.7 min, p < 0.01). Minute ventilation (29 +/- 8 versus 21 +/- 6 L/min, p < 0.001) and tidal volume (1.0 +/- 0.33 versus 0.84 +/- 0.25 L, p < 0.001) during maximum exercise increased whereas respiratory rate was lower (28 +/- 6 versus 32 +/- 7 breaths/min, p < 0.02). Measurements of respiratory muscle strength (PImax, 74 +/- 28 versus 50 +/- 18 cm H2O, p < 0.002; Pdi(max combined), 80 +/- 25 versus 56 +/- 29 cm H2O, p < 0.01; Pdi(max sniff), 71 +/- 7 versus 46 +/- 27 cm H2O, p < 0.01; Pdi(twitch), 15 +/- 5 versus 7 +/- 5 cm H2O, p < 0.01) were all greater post-LVRS. Inspiratory muscle workload as measured by Pdi TTI was lower following LVRS (0.07 +/- 0.02 versus 0.09 +/- 0.03, p < 0.03). On multiple regression analysis, increases in PImax correlated significantly with decreases in RV and FRC(trapped gas) after LVRS (r = 0.67, p < 0.03). We conclude that LVRS significantly improves diaphragm strength that is associated with a reduction in lung volumes and an improvement in exercise performance. Future studies are needed to determine the relationship and stability of these changes over time.

Effect of N-acetylcysteine on human diaphragm strength and fatigability.

Free radical injury is believed to be important in diaphragm dysfunction. N-Acetylcysteine (NAC) is a potent free radical scavenger shown in animal models to attenuate diaphragm fatigue; however, its effects on human diaphragm function are unknown. We assessed diaphragm function by electrophrenic twitch stimulation (PdiT) and twitch occlusion (to yield Pdimax) in four healthy subjects 35 +/- 3 yr of age (mean +/- SD). We intravenously administered NAC (150 mg/kg in 250 ml D5W) or placebo (CON) (250 ml D5W) in a randomized manner after subjects were premedicated with antihistamines. There were no significant side effects with the infusion. After infusion, we measured baseline Pdimax and PdiT at FRC. Diaphragm fatigue was then induced by subjects breathing through an inspiratory resistive load. Pdimax and PdiT were then measured at 15 to 30 min and 1, 2, 3, 4, and 20-25 h after fatigue. Times to fatigue were 13 +/- 4 min (CON) and 21 +/- 6 min (NAC) (p = 0.04). At 15 min after fatigue, PdiT was reduced to 40% (CON) compared with 30% (NAC) initial PdiT value (p = 0.05). Other twitch characteristics (maximal rate of relaxation and maximal contraction rate) were reduced to a greater degree after placebo compared with NAC. There were no significant differences in the rate of recovery between CON and NAC. Pdimax at 30 min after fatigue was significantly greater with NAC; however, at 1 h after fatigue, Pdimax for CON and NAC were not different, suggesting similar rates of recovery in high-frequency fatigue. These data suggest that NAC may attenuate low-frequency human diaphragm fatigue.

Stability of improvements in exercise performance and quality of life following bilateral lung volume reduction surgery in severe COPD.

STUDY OBJECTIVE: To evaluate the long-term stability of improvements in exercise capacity and quality of life (QOL) after lung volume reduction surgery (LVRS). DESIGN: Case-series analysis. SETTING: University hospital. PATIENTS: Twenty-six patients with severe airflow obstruction (mean FEV1 of 0.67+/-0.18 L) and moderate to severe hyperinflation (mean total lung capacity of 7.30+/-1.90 L). INTERVENTION AND MEASUREMENTS: All patients underwent bilateral LVRS via median sternotomy. Serial measurement of lung function, symptom-limited cardiopulmonary exercise tests, 6-min walk distances (6MWD), and sickness impact profile (SIP) scores were done before, and at 3, 6, 12, and 18 months after surgery. RESULTS: FEV1 (0.93+/-0.29 vs 0.68+/-0.19 L, p<0.001) increased while residual volume (3.47+/-1.2 vs 4.77+/-1.5 L, p<0.001) decreased significantly at 3 months post-LVRS compared to baseline, and these changes were maintained at 12 to 18 months follow-up. Similarly, the increase in 6MWD at 3 months post-LVRS (340+/-84 vs 251+/-114 m, p<0.001) was sustained at all follow-up times. On cardiopulmonary exercise testing, total exercise time (9.0+/-1.8 vs 6.1+/-1.9 min, p<0.001), oxygen uptake at peak exercise (VO2 peak) (14.9+/-4 vs 11.9+/-3 mL/kg/min, p<0.001), maximum oxygen pulse (7.43+/-2.37 vs 5.85+/-1.96 mL/beat, p<0.005), and maximum minute ventilation (VEmax) (30.3+/-10 vs 23.5+/-7.1 L/min, p<0.001) increased significantly at 3 months post-LVRS. On serial study following LVRS, total exercise time remained significantly greater at 6 (8.5+/-1.38 min) and 12 months (8.71+/-2.0 min) post-LVRS compared to baseline (5.81+/-1.9 min, p<0.05). VO2 peak tended to be higher at all follow-up periods (3 months, 16.1+/-4.3; 6 months, 14.5+/-2.6; 12 months, 14.1+/-3.5 mL/kg) compared to baseline (12.6+/-3.9 mL/kg, p=0.08). Similarly, maximum O2 pulse tended to be higher in all follow-up studies (3 months, 8.45+/-2.7; 6 months, 7.6+/-1.7; 12 months, 7.42+/-2.1 mL/beat) compared to baseline (6.39+/-2.5 mL/beat, p=0.06). Higher VEmax continued to be observed at 6 (30+/-10 L/min) and 12 months (28+/-10 L/min) post-LVRS, compared to baseline (23+/-7 L/min, p=0.02). VEmax post-LVRS was significantly higher at 3 and 6 months compared to baseline on post-hoc analysis (p<0.05). Overall SIP scores were lower at 3 months (7 vs 18, p<0.0002) post-LVRS and were sustained in long-term follow-up. CONCLUSION: We conclude that bilateral LVRS via median sternotomy in selected patients with severe, diffuse emphysema improves exercise performance and QOL at 3 months following LVRS and these improvements are maintained for at least 12 to 18 months in follow-up.

Management of advanced chronic obstructive pulmonary disease.

Successful Management of patients with advanced COPD includes not only a comprehensive therapeutic strategy tailored to the individual patient but also active patient participation. Figures 1 and 2 outline the medical and surgical treatment options for patients with advanced COPD. Patients who are actively smoking should be strongly advised to quit smoking. Bronchodilators and corticosteroids can improve symptoms and may prevent a further decline in lung function in selected COPD patients. The judicious use of antibiotics during an acute exacerbation may be required. O2 therapy improves survival and neuropsychiatric function in COPD patients with hypoxemia. Maintenance of proper nutrition is of utmost importance. A structured outpatient pulmonary rehabilitation is helpful in improving functional capacity and sense of breathlessness. In COPD patients who fail medical therapy, noninvasive positive pressure ventilation and surgical therapy may be considered.

Lung volume reduction surgery in ventilator-dependent COPD patients.

BACKGROUND: Lung volume reduction surgery has been advocated recently as adjunctive surgical therapy to improve lung and chest wall mechanics in selected patients with diffuse emphysema. Although clear-cut guidelines to select candidates have not been fully established, patients decompensated with significant pulmonary artery hypertension and hypercapnic respiratory failure are currently not considered suitable subjects. Accordingly, ventilator-dependent COPD patients are not considered candidates for this procedure. However, because ventilator-dependent COPD patients have an exceptionally poor prognosis, we elected to offer them this promising, but unproved surgical intervention. Herein, we describe the outcome of these three patients. PATIENTS: The 3 patients had recurrent exacerbations of COPD precipitating respiratory failure, and following aggressive medical therapy remained mechanically ventilated for 11 to 16 weeks (1 patient had a brief period of successful weaning before returning to mechanical ventilation). Prior to surgery, the patients had severe hypercapnia and cor pulmonale. Compared with preoperative values, surgery resulted in improvements in PaO2/FIO2, 304 +/- 80 (SD) vs 229 +/- 48 mm Hg, reductions in PaCO2, 44 +/- 3 vs 60 +/- 9 mm Hg, increases in FVC, 1.63 + 0.52 vs 1.09 +/- 0.05 L, and maximum inspiratory pressure, 57 +/- 22 vs 29 +/- 12 cm H2O. Postoperative complications included persistent air leaks and one tension pneumothorax. Patients weaned from mechanical ventilation after 10 to 21 days all were discharged home and they continue to demonstrate improved gas exchange and functional status. CONCLUSIONS: Lung volume reduction surgery in select, ventilator-dependent COPD patients can result in improved gas exchange and respiratory mechanics that enable successful weaning and overall improved functional status.

Treatment of left pneumonectomy syndrome with an expandable endobronchial prosthesis.

Postneumonectomy syndrome has only been described after a right pneumonectomy except in cases of congenital mediastinal anomalies or right-sided aortic arch. Placement of Silastic prostheses into the empty hemithorax is the preferred surgical treatment; however, other nonsurgical options exist. Herein, we report a case of left postpneumonectomy syndrome in an adult who was successfully treated with the placement of an endobronchial stent.

Transposición de Omentum majus en lesiones traumáticas de la médula espinal / Omentum majus transposition in traumatic lesions of the spinal cord

El presente trabajo resume la experiencia del Centro Iberolatinoamericano de Trasplante y Regeneración del Sistema Nervioso de Cuba en el tratamiento de lesiones traumáticas de la médula espinal, aplicando la técnica de transposición de Omentum Majus reportada inicialmente por el Dr. Harry Goldsmith. Estudiamos 40 pacientes con lesiones traumáticas de la médula espinal, de predominio dorso-lumbar, en fase aguda, subaguda y crónica, en un período evolutivo posquirúrgico no menor de 3 meses. Los enfermos que habían recibido tratamiento fisiátrico previo sin mejorías ulteriores, fueron evaluados por las escalas internacionales de Frankel, Karnovsky y el Index de Bartell, 1, 3, 6 y 12 meses después de la operación. En todos los pacientes fue definida la intensidad de la lesión mediante estudios clínicos, imagenólogicos y electrofisiológicos. Comprobamos mejoría evolutiva de diferentes grados en los casos estudiados, con mayor recuperación de los pacientes intervenidos en estadíos tempranos postlesionales. Concluimos que esta técnica constituye una opción terapéutica para algunos pacientes con lesiones traumáticas de la médula espinal

Transposición de omentum majus y transplante de tejido nervioso embrionario en pacientes con lesiones traumáticas crønicas de la m dula espinal / Omentum majus transposition in transplant of embryonic nervous tissue in patients with traumatic chronic lesions of the spinal cord

Presentamos el análisis de un estudio de 6 pacientes con secuelas crónicas de traumatismos raquimedulares a los cuales se les realizó trasplante de corteza cerebelosa embrionaria y transposición de Omentum Majus en los segmentos medulares afectados. En todos los casos la intervención se efectuó como mínimo, dos años después de la injuria traumática, previamente se intentó reabilitación por un período no menor de 3 meses, demostrándose que no existía recuperación neurológica con anterioridad a la aplicación de la técnica. Los enfermos fueron evaluados clínica y electrofisiológicamente 1, 3, 6 y 12 meses después del acto operativo, según escalas internacionalmente reconocidas (Karnovski, Frankel, Bartell y CNT), evidenciándose recuperación parcial sensitivo-motora y de funciones vegetativas. Se concluye que la aplicación de este método terapéutico puede beneficiar a pacientes con mielopatía post-traumática de largo tiempo de evolución