Effects of all-trans-retinoic acid on superoxide generation in intact neutrophils and a cell-free system

To determine the pathophysiology of the retinoic acid syndrome which occurs during all- trans -retinoic acid (ATRA) treatment of acute promyelocytic leukaemia patients, we investigated the direct effects of ATRA on the function of human neutrophils. We found that ATRA (10–200 μ M ) dose-dependently stimulated superoxide (O⁻₂) generation in intact neutrophils. The maximal activity of ATRA-stimulated O⁻₂ generation was 3.0 nmol/min/10⁶ cells. Adding EGTA to the assay mixture did not affect the activity nor was the intracellular free calcium concentration changed upon stimulation. The treatment of neutrophils with 0.1 μ M staurosporine, an antagonist of protein kinase C, for 10 min, enhanced the activity of ATRA-stimulated O⁻₂ generation up to 186% of that for control samples. Wortmannin (1 μ M ), an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), reduced this stimulatory activity by 67%. These results suggest that ATRA activates the signalling pathway related to PI 3-kinase rather than that utilizing calcium and protein kinase C. ATRA enhanced the O⁻₂ generated in a sodium-dodecyl-sulphate (SDS) cell-free system, resulting in rates up to 288% higher than that seen with SDS alone. This enhancement was not affected by pretreatment with staurosporine or wortmannin. ATRA may thus directly activate and/or enhance the function of neutrophils.     

Pulmonary gas exchange in the morbidly obese

The literature on pulmonary gas exchange at rest, during exercise, and with weight loss in the morbidly obese (body mass index or BMI ≥ 40 kg m⁻²) is reviewed. Forty-one studies were found (768 subjects weighted mean = 40 years old, BMI = 48 kg m⁻²). The alveolar-to-arterial oxygen partial pressure difference (AaDO₂) was large at rest in upright subjects at sea level (23, range 5–38 mmHg) while the arterial pressure of oxygen (PaO₂) was low (81, range 50–95 mmHg). Arterial pressure of carbon dioxide (PaCO₂) was normal. At peak exercise (162 W), gas exchange improves. Weight loss of 45 kg (BMI = −13 kg m⁻²) over 18 months is associated with an improvement in PaO₂ (by 10 mmHg, range 1–23 mmHg), a reduction in AaDO₂ (by 8 mmHg, range −3 to −16 mmHg), and PaCO₂ (by −3 mmHg, range 3 to −14 mmHg) at rest. Every 5–6 kg reduction in weight increases PaO₂ by 1 and reduces AaDO₂ by 1 mmHg, respectively. Morbidly obese women have better gas exchange at rest compared with morbidly obese men which is likely due to lower waist-to-hip ratios in women than from differences in weight or BMI.     

Human Neutrophil Functions Are Inhibited In Vitro by Clinically Relevant Ethanol Concentrations

Neutrophils [polymorphonuclear neutrophils (PMNs)] play a pivotal role in host defense in man. These defenses may be compromised, however, in alcohol users and abusers. We therefore evaluated the effect of ethanol levels (12.5 to 500 mg/dl), on key functions of human PMNs—chemotaxis and production of reactive oxygen species—and on changes in cytosolic-free calcium ([Ca²⁺]_i), a pivotal intracellular mechanism of PMN activation. Ethanol significantly inhibited chemotaxis as evaluated by formyl-methionyl-leucyl-phenylalanine (fMLP)-induced upregulation of surface adhesion molecules (CD11b), fMLP-induced PMN elongation was only inhibited by a very high ethanol concentration of 500 mg/dl. Production of reactive oxygen species by normal PMNs was assessed by either chemiluminescence (CL) for hypochlorous acid or ferricytochrome c reduction (FCR) for superoxide anions. For PMN stimulated by fMLP, ethanol inhibited CL but not FCR. For PMNs activated by phorbol myristate acetate, ethanol inhibited both CL and FCR. Ethanol did not alter baseline [Ca²⁺]_i, as assessed by videomicroscopy using the Ca²⁺-sensing fluorescent dye Fura-2-AM, but did significantly potentiate the increase in peak [Ca²⁺]_i, levels that occurs in response to stimulation by fMLP. Calcium channel blockers attenuated ethanol's inhibition of CL. Thus, acute in vitro ethanol, at clinically relevant concentrations, can inhibit several critical aspects of PMN functions. But, in PMNs, unlike neural cells, these inhibitory effects do not seem to be mediated by decreases in Ca²⁺ influx or in [Ca²⁺]_i.     

Impaired neutrophil chemotaxis in patients with thalassaemia major

Summary. Random and directed migration, O-₂ production. degradation and adhesion were studied in neutrophils obtained from patients with homozygous β-thalassaemia and iron overload, in the presence or absence of thalassaemic serum. The only significant defect found was an impairment in directed chemotaxis, further depressed after addition of thalassaemic serum. The chemotactic defect was encountered in all the patients that have suffered from pyogenic infections except one, and was not correlated with the severity of the iron overload. It is suggested that the described neutrophil migration impairment may contribute to the tendency towards infection in certain patients with homozygous β-thalassaemia.     

Expression of adhesion molecules and functional stimulation in human neutrophils: modulation by GM-CSF and role of the Bcr gene

Although devoid of proliferative capacity, polymorphonuclear neutrophils (PMN) express receptors for haemopoietic growth factors and need growth factors for survival and functional stimulation. This study showed that in vitro treatment of human PMN with GM-CSF for up to 48 h increases cell surface expression of the β2-integrin molecules CD11b/CD18 and CD11c/CD18 and of the receptor for the chemotactic peptide fMLP. Such modifications are usually expression of PMN activation. PMN treated with GM-CSF also displayed increased phagocytosis of latex particles and enhanced oxidative burst and superoxide anion release. Since integrins mediate PMN adhesion to endothelium, homotypic adhesion, chemotaxis/phagocytosis and the triggering of respiratory burst, our results suggested that functional stimulation of PMN persisted following prolonged exposure of PMN to growth factors and that it was not a temporary phenomenon which lasted only for the first 12–24 h of treatment. We also used oligonucleotides antisense to the Bcr gene mRNA to inhibit expression of the gene and evaluate its function in PMN, following the recent observation that PMN from Bcr-null mutant mice produced increased amounts of reactive oxygen metabolites upon activation. The antisense oligonucleotides had no effect on the parameters investigated. This may indicate that increased production of O⁻₂ by neutrophils in which the Bcr gene is not expressed requires either that gene expression is absent in the earlier stages of myeloid differentiation/maturation, so that when inhibition occurs in the terminally differentiated neutrophils their functional status is no longer influenced, or that the residual low-level expression of the gene which may be present in the antisense-treated cells is sufficient to provide a normal response to stimulation.     

Mobilization and transplantation of Philadelphia chromosome-negative peripheral blood progenitor cells in patients with CML

Mobilization and transplantation of peripheral blood progenitor cells (PBPCs) was investigated in patients with stage IA or stage IIA chronic myelogenous leukaemia (CML) using combination chemotherapy with idarubicin, cytosine arabinoside and etoposide (ICE) followed by simultaneous administration of rhG-CSF and rhIL-2 or rhG-CSF alone. 17 patients (stage IA: 12; stage IIA: five) were mobilized. Chemotherapy, cytokine priming and collection of PBPCs were well tolerated. Using large-volume aphereses, a median number of 10.6 × 10⁷/kg b.w. of MNC were harvested, which yielded between 0.15 and 21.0 × 10⁶ CD34⁺ cells/kg b.w. High numbers of CD34⁺ HLA-DR⁻ cells could be obtained. Autologous transplantation of mostly Ph⁻ apheresis products was performed in 16/17 patients after high-dose chemotherapy. 10 patients achieved a complete or major cytogenetic remission (stage IA: seven; stage IIA: three), but six patients did not respond cytogenetically. Median follow-up after transplantation was 18+ months. Our data show that this very efficient treatment modality for PBPC mobilization in CML was safe and able to induce major and sustained cytogenetic responses in the majority of patients.     

VO2 Max and Anaerobic Threshold in Hypertension: A Tissue Doppler Study

Background: Hypertension can impair left ventricular (LV) relaxation causing shortness of breath and reduced exercise capacity, which may affect the clinical evaluation of the symptomatic hypertensive patient. In this study we used tissue Doppler imaging (TDI) to identify correlates of anaerobic threshold (AT) and maximum oxygen uptake (VO₂ Max). Our goal was to assess the feasibility of TDI as a surrogate of functional capacity in hypertensive individuals. Methods: We studied subjects without metabolic syndrome and with normal LV function (ejection fraction (EF) >50%) . Traditional echocardiographic variables were obtained before and after a cardiopulmonary exercise test. Systolic (S) and diastolic (E ' and A ' ) myocardial velocities were measured at the basal septal (bs) and posterior (bp) walls. Results: After multivariate analysis, resting E ' bp ( r = 0.56, P < 0.002) and isovolumic relaxation time (IVRT) ( r =− 0.49, I < 0.03) correlated with VO₂ Max, while A Valsalva correlated with AT ( r =− 0.46, P < 0.03) . Peak stress E '/ A ' bp correlated with age and gender corrected METs ( r =− 0.63, P < 0.0004) and VO₂ Max ( r =− 0.39, P< 0.04). Conclusions: Resting E ' bp and peak stress E '/ A ' bp correlate with VO₂ Max in hypertensive patients. TDI may be an important tool when assessing symptoms in this population.     

Assay of α-N-Acetylgalactosaminyltransferases in Human Sera: Further Evidence for Several Types of Am Individuals

Abstract. The study of the α - N -acetylgalactosaminyltransferase in the sera of 19 individuals belonging to the rare A_m blood group makes it possible to confirm the heterogeneity of this phenotype established on genetical and immunological criteria. Two groups of subjects, Am and A_y, can be distinguished.
For the individuals of the first group, named A_m, 15 samples (7 families) have been studied, the phenotype is inherited as an allele at the ABO locus. 14 of these subjects, have an α - N -acetylgalactosaminyltransferase whose kinetic properties were similar to those of A₁ subjects. In one family, however, the A transferase detected is of the A₂ type. On a quantitative level, the enzyme activities of these sera only reached 30–50% of the average value observed for A₁ or A₂ subjects, respectively.
These facts suggest the existence of a genetic inhibitor, possibly linked to the ABO locus, preventing either an A₁ or A₂ gene from acting at the level of some cellular lines and leading therefore to the recognition of phenotypes named A^A₁^m and A^A₂^m
On the contrary, under the experimental conditions used, no α - N -acetylgalactosaminyltransferase activity was detected among the four individuals of the second group, named A_y by W einer et al. [37], and whose appeareance in siblings results from the action of a recessive modifying y^A gene.     

Effect of Ethanol on Prostacyclin, Thromboxane, and Prostaglandin E Production in Human Umbilical Veins

The purpose of this study was to determine the effects of ethanol on prostacyclin (PGE, prostaglandin E (PGE), and thromboxane (TXA₂ production in perfused human umbilical veins.
PGI₂, PGE, and TXA₂ levels were measured from human umbilical veins perfused with either 25, 50, or 100 mM ethanol by radioimmunoassay of their stable metabolites. Alcohol content was measured by an enzymatic spectrophotometric assay. Data were analyzed by ANOVA and Fisher's Protected Least Significant Difference Test.
Ethanol decreased PGI₂ production in a concentration-dependent manner ( p < 0.05). In a concentration of 25 mM, ethanol did not affect PGI₂ production, whereas 50 mM decreased levels after 60 min of perfusion ( p < 0.01). With 100 mM ethanol, PGI₂ production was decreased after 15, 30, and 60 min of perfusion ( p s < 0.05), and the TXA²/PGI₂ ratio was significantly elevated at all time points (p < 0.01). Ethanol (100 mM) did not affect TXA₂ or PGE production.
Reduction of PGl₂ levels and the increase in the TXA₂/PGI₂ ratio seen after ethanol perfusion in umbilical veins may cause vascular disruption in the umbilical-placental circulation. This may, in part, be a contributing mechanism to the teratogenic effects of ethanol.     

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy

Summary.  During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Δ0–48), the slope (λ₁) and the efficiency factor (ε) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Δ0–48 and steeper λ₁ (−1.77log₁₀ IU/mL ± 0.66 and −2.04/day ± 0.76) compared to nine non-RVR patients (−0.66log₁₀ IU/mL ± 0.39; P  = 0.019 and −0.76/day ± 0.41; P  = 0.019). When divided by SVR, a greater Δ0–48 and steeper λ₁ were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.     

Comparative study of peripheral blood progenitor cell collection in patients with multiple myeloma after single-dose cyclophosphamide combined with rhGM-CSF or rhG-CSF

Summary. Patients suffering from high-risk multiple myeloma (MM) were randomized to receive single high-dose cyclophosphamide followed by either rhGM-CSF or rhG-CSF in order to harvest circulating peripheral blood progenitor cells. The safety of the procedure, the mobilization kinetics, the relative efficacy of rhGM-CSF and rhG-CSF to mobilize progenitor cells and their relative toxicity were studied. Special attention was paid to the antigenic profile of CD34⁺ progenitor cells.
Group I patients (n=ll) were treated with cyclophosphamide 4 g/m² i.v. followed by rhGM-CSF at 10 /ig/kg/d by subcutaneous administration. Group II (n=ll) patients received rhG-CSF s.c. at 10/zg/kg/d after the same dose cyclophosphamide. Both mobilization regimens appeared to be equally effective. No significant differences in absolute numbers of circulating progenitors, determined by CD34 expression or in yields of MNC, CFU-GM, BFU-E and CD34 subsets were observed. rhGM-CSF administration resulted however in delayed haemopoietic recovery and an increased complication rate.
We conclude that rhG-CSF may be preferred because of its markedly lower toxicity and lower in-hospital costs.     

Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation

Factors affecting mobilization and engraftment were analysed in 54 patients undergoing transplant using autologous PBSCs mobilized with high-dose recombinant granulocyte stimulating factor (rhG-CSF). Patients received 5-7 d of rhG-CSF. 16 μg/kg/d, administered subcutaneously. PBSCs were harvested by leukapheresis using automated continuous-flow blood cell separators beginning on day 4 of rhG-CSF, processing 10 litres of whole blood, for 2-6 consecutive days. Transplants were performed for the following diseases: breast cancer (n = 22), non-Hodgkin's lymphoma (n = 18), multiple myeloma (n = 7) and other (n = 7). Engraftment was rapid with patients reaching a neutrophil count of 1 × 10⁹/1a median of 12 d (range 9-22) after transplant. Platelets > 20 × 10⁹/1 independent of transfusion support were achieved a median of day 10 (range 7-60) after infusion. Multiple factors potentially influencing engraftment were examined using a Cox regression model. The number of CD34⁺ cells per kg was highly correlated with the time to achievement of granulocyte and platelet recovery (P < 0.012, 0.0001). The use of a post-infusion growth factor and a radiation preparative regimen was important for neutrophil recovery, and a diagnosis of breast cancer was important for platelet recovery. In an analysis by linear regression of the logarithm of CD34⁺ cells collected, lower age, marrow without disease, no prior radiation, and lower number of prior chemotherapy regimens, were important factors influencing larger numbers of CD34⁺ cells in collections.     

Effect of ammonium ion on the hydrophobic and barrier properties of the gastric mucus gel layer: Implications on the role of ammonium in H. pylori-induced gastritis

Abstract Infection with the bacterium Helicobacter pylori is associated with both the development of gastritis and an attenuation in the hydrophobic properties of the stomach. In order to better understand the effect of ammonium, one of the major products of H. pylori urease on these properties, a series of in vivo and in vitro experiments was performed. In the in vivo studies rats were intragastrically administered NH⁴Cl alone and in combination with the mucolytic agent, Muco-Mist, in various dosing strategies and concentrations. It was determined that the intragastric administration of four consecutive doses of a NH₄Cl/Muco-Mist mixture (20 mmol/L/5%) was capable of converting the stomach from a hydrophobic to hydrophilic state as determined by contact angle analysis. Further, the treated rats became more susceptible to the injurious effect of luminal acid as determined by measuring the haemoglobin concentration of a collected gastric perfusate. In the in vitro studies it was determined that exposure of the hydrophobic surface of a synthetic mucus gel layer to increasing concentrations of NH₄Cl (0–20 mmol/L) resulted in a rapid transition to a hydrophilic state and an associated increase in the flux of H⁺ across its surface.
Helicobacter pylori may induce an attenuation in both mucosal hydrophobicity and barrier properties by producing high concentrations of NH⁺₄ in the mucus gel layer. The molecular mechanism of this action may be related to the chemical similarities of NH⁺₄ and choline-based phospholipids which contribute to the stomach's hydophobic surface.     

Changes in neutrophil counts and functions after the administration of recombinant human granulocyte colony-stimulating factor in a patient with chronic idiopathic neutropenia]

The cause of chronic idiopathic neutropenia (CIN) is unknown. Recently recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been purified. Many studies of effects of rhG-CSF on the patients with neutropenia have been undertaken. We examined changes in neutrophil counts and functions after the administration of rhG-CSF in a patient with CIN. Six hours after the intravenous administration of 40 micrograms of rhG-CSF, neutrophil counts were raised from 90 to 1570/microliters, and the increased neutrophils functioned normally; chemotaxis, phagocytosis and O2(-) generation. It is suggested that rhG-CSF is beneficial for the treatment of infection in patients with CIN.     

β+ Thalassaemia—Portuguese type: clinical, haematological and molecular studies of a newly defined form of β thalassaemia

S ummary . Nitrous oxide inactivates vitamin Bi₂ and in man can produce a megaloblastic anaemia. Haematological and biochemical changes were studied in nine surgical patients ventilated with 70% N₂0 for up to 24 h and in three control patients. There was a rise in the numbers of hypersegmented neutrophils in peripheral blood following N2O. Serial bone marrow aspirates showed gross megaloblastic change after 24 h of N₂0 which had reverted to normoblastic but dyserythropoietic haemopoiesis by 1 week. Giant forms of early myeloid precursors were also seen after 24 h ventilation with N₂0 but by 1 week abnormalities were evident in more mature cells, metamyelocytes and segmented neutrophils. Megalo-blastosis was associated with abnormal dU suppression which showed a correction pattern similar to that seen in vitamin Bi₂ deficiency. Administration of N₂0 was also associated with a progressive rise in serum folate and fall in serum methionine levels. No similar patterns were seen in the three control patients.     

Five haplotypes in Black β-thalassaemia heterozygotes: three are associated with high and two with low Gγ values in fetal haemoglobin

Genotypes at seven different polymorphic restriction sites (5'to the ° gene, at the ^G γ, at the ^A γ, at the Ψβ , 3'to the Ψβ , at the β , and 3'to the β genes) were analysed by restriction endonuclease mapping of the DNA from 66 Black β -thalassaemia heterozygotes from Georgia and several of their normal relatives. Five different haplotypes were observed. Three of these were associated with high ^G γ values in the small amount of Hb F (0.8-8.3%) present in the blood of these patients and two with low ^G γ values. One haplotype [- + - ++++] that occurred on two of every three β thalassaemia chromosomes was associated with high ^G γ levels, and is the same as that found in some Black SS patients also having high ^G γ values (Gilman & Huisman, 1984). Two others [- ++ - + - +] and [−+−−+++] were also associated with high ^G γ, while two [−−−−+++] and [+−−−−++] were associated with low ^G γ. Variation in haematological data, mainly MCV and MCH values, was found to be caused in part by the type of β -thalassaemia (defined by its haplotype) and by the presence of an additional α-thalassaemia-2 heterozygosity or homozygosity.     

Effects of rhG-CSF, 5-fluorouracil and extramedullary irradiation on murine megakaryocytopoiesis in vivo

Summary The aim of this study was to systematically characterize possible rhG-CSF effects on the murine megakaryocyte-platelet system (untreated and recovering from chemotherapy or extramedullary irradiation). In untreated, splenectomized male B₆D₂F₁ mice rhG-CSF treatment (50μg/kg/d for up to 8d) markedly decreased femoral megakaryocytopoiesis. CFU-Meg, small acetylcholinesterase-positive (SAChE) cells, and megakaryocytes were significantly reduced to 35–70%: platelets, however, were not affected. Peripheral CFU-Meg and CFU-GM increased up to 200-fold. Following a single injection of 5-FU (150mg/kg) on day O, rhG-CSF (50 μg/kg/d) on days 1–8 suppressed the megakaryocytopietic recovery as indicated by significantly lower platelet numbers on day 9. Granulopoietic recovery was accelerated by rhG-CSF. When rhG-CSF treatment was started on day 5, no beneficial effect on granulopoietic recovery was observed, but again platelet levels were significantly lower on day 9, indicating that within the first 4 d of rhG-CSF application, recruitment or lineage competition was not a critical event. To test for the effects of extramedullary irradiation on circulating progenitors, mice pretreated with 50 μg/kg/d of rhG-CSF for 8 d received irradiation to the chest with 500 cGy resulting in a substantial kill of circulating CFU-Meg and CFU-GM of up to 99%. However, this striking decrease of blood progenitors did not significantly affect their total body contents. This sutdy indicates that rhG-CSF treatment can impair bone marrow megakaryocytopoiesis, which might be an important consideration for those clinical situations that carry a high potential for treatment-induced thrombocytopenia.     

Insulin glulisine, insulin lispro and regular human insulin show comparable end-organ metabolic effects: an exploratory study

Aims:  To compare the end-organ metabolic effects of insulin glulisine (glulisine), insulin lispro (lispro) and regular human insulin (RHI) in patients with type 1 diabetes mellitus.
Methods:  Eighteen patients with type 1 diabetes mellitus (mean age 36.9 ± 8.6 years, BMI 23.6 ± 2.8 kg/m², haemoglobin A_1c 7.4 ± 0.9%) were randomized in this single-centre, double-blind, three-period cross-over, standard Latin-square, euglycaemic glucose clamp trial. Patients received sequential, primed stepwise intravenous infusions of glulisine, lispro or RHI (infusion rates were increased in a stepwise manner from an initial rate of 0.33 [180 min] to 0.66 [180 min] and 1.00 [180 min] mU/kg/min). The primary variables were the suppression of endogenous glucose production ( S _EGP) and glucose uptake (GU).
Results:  Mean basal endogenous glucose production (EGP) was 1.88, 2.12 and 2.12 mg/kg/min for glulisine, lispro and RHI respectively. Mean (±s.e.) maximum absolute S _EGP (adjusted for basal EGP) was −1.64 ± 0.06, −1.72 ± 0.05 and −1.56 ± 0.05 mg/kg/min respectively. Mean (±s.e.) maximum absolute increase in GU (adjusted for basal GU) was 6.46 ± 0.26, 6.23 ± 0.24 and 6.72 ± 0.24 mg/kg/min respectively. There were no clinically relevant differences between the three insulin treatments with respect to serum insulin, free fatty acid (FFA), glycerol or lactate levels. No serious adverse events and no episodes of severe hypoglycaemia were reported.
Conclusions:  This study shows that glulisine, lispro and RHI have similar effects on S _EGP, GU, FFA, glycerol and lactate levels, providing evidence for similar end-organ metabolic effects.     

Preoperative use of inhaled tiotropium in lung cancer patients with untreated COPD

Background and objective:   Lung cancer patients with COPD are at high risk during surgery. Tiotropium, a long-acting bronchodilator, is a preferred maintenance therapy for COPD, but its efficacy in the perioperative period has not been clarified.
Methods:   A retrospective review was performed of the medical records of 102 patients with primary lung cancer and COPD, who underwent scheduled surgery. Twenty-one lung cancer patients with untreated mild-to-severe COPD received tiotropium preoperatively. Spirometry was performed prior to and after 2 weeks of treatment with tiotropium, and at 3 months after surgery.
Results:   Two-week preoperative treatment with tiotropium significantly improved respiratory symptoms and pulmonary function as reflected by FVC (median 3.43 L pretreatment vs 3.52 L post-treatment), FEV₁ (median 2.06 L vs 2.32 L) and FEV₁% (73.2% vs 81.0%) (all P  < 0.001). Postoperative FEV₁% was significantly increased from a median of 56.0% (interquartile range 51.6–60.3) to 63.4% (60.8–66.0) ( P  < 0.001). The increase in FEV₁ was inversely associated with severity of COPD ( r  = −0.59, P  < 0.005). Lung resections were successfully accomplished without complications. The postoperative FEV₁ predicted prior to tiotropium treatment was underestimated (median predicted postoperative FEV₁ 1.65 L vs median measured postoperative FEV₁ 1.96 L, P  < 0.001).
Conclusions:   Preoperative treatment with tiotropium may facilitate surgical treatment for lung cancer patients with COPD. This is encouraging for COPD patients who may require curative lung resections.     

Cough-reflex sensitivity to inhaled capsaicin in COPD associated with increased exacerbation frequency

Background and objective:   The causes of exacerbations in COPD patients are poorly understood. This study examined the association between cough-reflex sensitivity in patients with stable COPD and the frequency of subsequent exacerbations.
Methods:   The sampling frame for cases and controls for this study was patients attending a hospital outpatient clinic. cough-reflex sensitivity was evaluated using the log concentration of capsaicin causing five or more coughs (log C₅). Subsequent COPD exacerbations were identified prospectively via symptom-based diaries over a 12-month period.
Results:   The study group comprised 45 COPD subjects and 10 controls. Mean log C₅ was lower in the COPD group than in the control group (0.97 (95% confidence interval (CI): 0.76–1.18) versus 1.26 (95% CI: 0.81–1.71), P  = 0.095). In the COPD group, log C₅ was negatively correlated with serum CRP level ( r  = −0.36, P  = 0.02) and significantly associated with the exacerbation frequency ( r  = −0.38, P  = 0.01). Stepwise multiple regression analysis showed that cough-reflex sensitivity was significantly associated with exacerbation frequency ( r ² = 0.15, P  = 0.01).
Conclusions:   Hypersensitivity of the cough reflex to inhaled capsaicin might reflect airway inflammation in stable COPD patients, which predisposes to frequent exacerbations.