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)

Adsorption mechanisms of hexavalent chromium from aqueous solutions on modified activated carbons.

Functional groups of the activated carbon play the major role in metals removal from aqueous solutions and, for this reason, different treatments can be used to modify the adsorbent surface improving the adsorption capacity for a particular pollutant. In this research, oxidation with nitric acid, heating under an inert atmosphere, and ammonia treatment were applied to modify the activated carbon surface. The modified adsorbents were used for the removal of hexavalent chromium (Cr(VI)) from aqueous solutions at different concentrations (10-500 mg L-1), pH 6, and 25 °C. Adsorption mechanisms of Cr(VI) on the activated carbon were proposed based on the surface chemistry, adsorption/reduction, and desorption experiments. Findings demonstrate that acid functional groups of the activated carbon had an important effect on the hexavalent chromium removal. For instance, a high reduction of Cr(VI) to Cr(III) (50%) was obtained by the oxidized adsorbents, whereas the heat treated adsorbents achieved a low reduction (35%), but the ammonia-treated activated carbon achieved the lowest reduction (20%). The heat-treated adsorbent showed the best Cr(VI) adsorption capacity (48 mg g-1), especially at equilibrium Cr(VI) concentration lower than 200 mg L-1, and the fastest adsorption kinetics among the studied adsorbents. Furthermore, the highest Cr(VI) desorption (90%) was achieved with 0.1 N NaOH-NaCl solutions. In summary, an anionic/reduction coupled adsorption mechanism of Cr(VI) seems to be feasible, and the heat-treated activated carbon is an interesting option for sequestering Cr(VI) species from aqueous effluents.

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.

Determining optimal conditions to produce activated carbon from barley husks using single or dual optimization.

When producing activated carbons from agricultural by-products, certain properties, such as yield and specific surface area, are very important for obtaining an economical and promising adsorbent material. Nevertheless, many researchers have not simultaneously optimized these properties and have obtained different optimal conditions for the production of activated carbon that either increases specific surface area but decreases yield or vice versa. In this research, the production of activated carbon from barley husks (BH) by chemical activation with zinc chloride was optimized by using a 2(3) factorial design with replicates at the central point, followed by a central composite design with two responses (the yield and iodine number) and three factors (the activation temperature, activation time, and impregnation ratio). Both responses were simultaneously optimized by using the desirability functions approach to determine the optimal conditions of this process. The findings reveal that after the simultaneous dual optimization, the maximal response values were obtained at an activation temperature of 436 °C, an activation time of 20 min, and an impregnation ratio of 1.1 g ZnCl2/g BH, although the results after the single optimization of each response were quite different. At these conditions, the predicted values for the iodine number and yield were 829.58 ± 78.30 mg/g and 46.82 ± 2.64%, respectively, whereas experimental tests produced values of 901.86 mg/g and 48.48%, respectively. Moreover, activated carbons from BH obtained at the optimal conditions primarily developed a porous structure (mesopores > 71% and micropores > 28%), achieving a high surface area (811.44 m(2)/g) that is similar to commercial activated carbons and lignocellulosic-based activated carbons. These results imply that the pore width and surface area are large enough to allow the diffusion and adsorption of pollutants inside the adsorbent particles. In summary, two responses were optimized to determine the optimal conditions for the production of activated carbons because it is possible to increase both the specific surface area and yield.

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice.

L-DOPA alleviates the motor symptoms of Parkinson's disease, but its long-term use is associated with undesirable dyskinesia. We now tested whether exercise can attenuate this L-DOPA-induced dyskinesia (LID). We tested the effects of exercise on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. Animals were treated with L-DOPA/benserazide (25/12.5 mg/kg, i.p.) without and with possibility to exercise (running wheel) during 2 weeks. Exercise drastically prevented the development of LID, and its associated aberrant striatal signaling, namely the hyperphosphorylation of dopamine and cAMP-regulated phosphoprotein 32 kDa protein and c-Fos expression. Our results indicate that exercise can partially prevent the development of LID through the normalization of striatopallidal dopaminergic signaling.

Low CD4/CD8 Ratio in Bronchus-Associated Lymphoid Tissue Is Associated with Lung Allograft Rejection.

Background. Bronchus-associated lymphoid tissue (BALT) has been associated with lung allograft rejection in rat transplant models. In human transplant recipients, BALT has not been linked to clinically significant rejection. We hypothesize that the immunohistochemical composition of BALT varies with the presence of acute lung allograft rejection. Methods. We retrospectively examined 40 human lung allograft recipients transplanted from 3/1/1999 to 6/1/2008. Patients were grouped by frequency and severity of acute rejection based on International Society of Heart Lung Transplant (ISHLT) criteria. Transbronchial biopsies were reviewed for BALT by a blinded pathologist. BALT if present was immunohistochemically stained to determine T-and B-cell subpopulations. Results. BALT presence was associated with an increased frequency of acute rejection episodes in the first year after transplantation. Patients with a lower CD4/CD8 ratio had an increased rejection rate; however, BALT size or densities of T-cell and B-cell subpopulations did not correlate with rejection rate. Conclusion. The presence of BALT is associated with an increased frequency of rejection one year after transplant. The lower the CD4/CD8 ratio, the more acute rejection episodes occur in the first year after transplantation. The immunohistochemical composition of BALT may predict patients prone to frequent episodes of acute cellular rejection.

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)

Experimental design for the optimization of copper biosorption from aqueous solution by Aspergillus terreus.

An experimental design methodology was applied to study the effects of temperature, pH, biomass dose, and stirring speed on copper removal from aqueous solutions by Aspergillus terreus in a biosorption batch system. To identify the effects of the main factors and their interactions on copper removal efficiency and to optimize the process, a full 2(4) factorial design with central points was performed. Four factors were studied at two levels, including stirring speed (50-150 min(-1)), temperature (30-50°C), pH (4-6) and biosorbent dose (0.01-0.175 g). The main factors observed were pH and biomass dose, along with the interactions between pH and biomass, and stirring speed. The optimal operational conditions were obtained using a response surface methodology. The adequacy of the proposed model at 99% confidence level was confirmed by its high adjusted linear coefficient of determination (R(Adj)(2)=0.9452). The best conditions for copper biosorption in the present study were: pH 6, biosorbent dose of 0.175 g, stirring speed of 50 min(-1) and temperature of 50°C. Under these conditions, the maximum predicted copper removal efficiency was 68.52% (adsorption capacity of 15.24 mg/g). The difference between the experimental and predicted copper removal efficiency at the optimal conditions was 4.8%, which implies that the model represented very well the experimental data.

Artificial Neural Network for predicting biosorption of methylene blue by Spirulina sp.

An artificial neural network (ANN) was used to predict the biosorption of methylene blue on Spirulina sp. biomass. Genetic and anneal algorithms were tested with different quantity of neurons at the hidden layers to determine the optimal neurons in the ANN architecture. In addition, sensitivity analyses were conducted with the optimised ANN architecture for establishing which input variables (temperature, pH, and biomass dose) significantly affect the predicted data (removal efficiency or biosorption capacity). A number of isotherm models were also compared with the optimised ANN architecture. The removal efficiency or the biosorption capacity of MB on Spirulina sp. biomass was adequately predicted with the optimised ANN architecture by using the genetic algorithm with three input neurons, and 20 neurons in each one of the two hidden layers. Sensitivity analyses demonstrated that initial pH and biomass dose show a strong influence on the predicted removal efficiency or biosorption capacity, respectively. When supplying two variables to the genetic algorithm, initial pH and biomass dose improved the prediction of the output neuron (biosorption capacity or removal efficiency). The optimised ANN architecture predicted the equilibrium data 5,000 times better than the best isotherm model. These results demonstrate that ANN can be an effective way of predicting the experimental biosorption data of MB on Spirulina sp. biomass.

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.

Congruence of quality of life among infertile men and women: findings from a couple-based study.

BACKGROUND: It has been consistently demonstrated that infertility is associated with quality of life (QOL) impairments. Research to date has mostly focused on individual's reactions to infertility (mainly women), without an examination of how the partner is reacting to the same condition. The few studies that assessed QOL among couples did not use couple-based analyses, consequently not considering the intra-couple effects. The objectives of this study were to explore the congruence of QOL perception within infertile couples and to estimate the effect of depression levels on the congruence. METHODS: In total, 162 couples were interviewed in an assisted reproduction clinic cross-sectionally. Subjects completed a socio-demographic form, World Health Organization Quality of Life-BREF and the Beck Depression Inventory independently. The statistical strategy was guided to ensure that subjects would be explored within pairs at all times and not as independent groups. Paired t-tests were run, and Cohen's effect was estimated. Depression levels were controlled by linear multiple regressions and repeated-measures ANCOVAs. RESULTS: Out of the five QOL domain scores, only two showed a significant discrepancy between partners (psychological and social relationship domains). Male depression was a significant predictor for all five QOL difference scores, whereas female depression was associated with three (overall, psychological and physical). Moreover, it was demonstrated that, except for the psychological domain and for the female depression on the physical domain, the load of depression as a predictor of the QOL difference scores was markedly low, accounting for not more than 7.5% of the variance of congruence between men's and women's QOL. CONCLUSION: Our findings suggest that QOL scores do not differ markedly between spouses. Since QOL seemed similarly affected in both men and women, consideration might be given to offering interventions to them as a dyad. These results are not in line with the previous non-paired studies, and further investigations are required to address this dissimilarity.

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.

Discrepancy between severity of lung impairment and seniority on the lung transplantation list.

BACKGROUND: Organ allocation for lung transplantation, based mainly on accrued time on a waiting list, may not be an equitable system of organ allocation. To provide an objective view of the current practice concerning lung allocation, and timing for transplantation, we examined illness severity and list seniority in patients on a lung transplantation waiting list. METHODS: Adult patients awaiting lung transplantation underwent testing for mean pulmonary artery pressure (mPpa), maximum oxygen consumption (VO2 max), 6-minute walk distance (6MWD), forced expiratory volume in 1 second, mean partial pressure of carbon dioxide, partial pressure of oxygen/fractional concentration of inspired oxygen, and diffusing capacity of the lung for carbon monoxide. Relationships between physiological variables and waiting list rankings were then determined. RESULTS: Thirty-four patients were tested and there was no correlation between time spent waiting on the list and mPpa (r=0.01; P=.94), VO2 max percentage predicted (r=0.07; P=.71), or 6MWD (r=0.15; P=.42). Many patients with functional impairments as indicated by low maximum VO2 or by short 6MWD are scheduled to receive their transplant after patients with levels that indicate a lower degree of risk. When compared with a hypothetical reranking based on mean Ppa, 24 of the 34 patients (71%) on our current waiting list were found to be 5 positions higher or lower than this new risk-based ranking. Sixteen patients (47%) were 10 or more positions away from their hypothetical severity-based ranking, and 9 (26%) were at least 15 positions out of place. Sixteen of the 34 patients were ranked lower than they would be based on a severity of illness using the pulmonary artery pressure alone, 17 were ranked higher than "should be" based on pulmonary artery mean, and only 1 patient (ranked in position 15) was appropriately positioned based on seniority and severity of disease based on PA mean. CONCLUSION: Rank order for lung transplantation has no relationship with illness severity, and the discrepancy between disease severity and seniority on the lung waiting list may compromise overall outcomes in the lung transplantation population.

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.