bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation
Authors: Min Dullei , Taylor Patricia A. , Panoskaltsis-Mortari Angela , Chung Brile , Danilenko Dimitry M. , Farrell Catherine , Lacey David L. , Blazar Bruce R. , Weinberg Kenneth I.
Published: October 2002

Decreased thymopoietic capacity contributes to the severe and clinically significant immune deficiency seen after bone marrow transplantation (BMT). One mechanism for thymopoietic failure is damage to the interleukin 7 (IL-7)–producing thymic epithelial cells (TECs) by irradiation and chemotherapy, which can be partially treated by IL-7 administration. Pretreatment of BMT recipients with keratinocyte growth factor (KGF, or Fgf7), an epithelial cell–specific growth factor, protects mucosal, cutaneous, and pulmonary epithelial cells from cytotoxic therapy-induced damage in experimental murine models. Like other epithelial cells, TECs specifically express KGF receptors. Because KGF specifically protects KGF receptor–bearing epithelial cells and post-BMT immune deficiency is caused by loss of TECs, we hypothesized that KGF pretreatment would improve post-BMT thymic function. To test the hypothesis, BMT recipient mice were given KGF or placebo prior to congenic or allogeneic BMT. Administration of KGF before murine BMT significantly increased the capacity of the thymus to generate donor-derived thymocytes. KGF pretreatment also normalized the proportion of thymic subpopulations, increased the number of naive T cells in the periphery, and improved the response to neoantigen immunization. KGF treatment caused increased production of intrathymic IL-7, and the thymopoietic effects of KGF required an intact IL-7 signaling pathway. These results demonstrate that KGF may have immunomodulatory effects by a unique mechanism of protection of TECs. Furthermore, thymic injury and prolonged posttransplantation immune deficiency in BMT recipients can be prevented by KGF administration.
Breaking the rules? X-ray examination of hematopoietic stem cell grafts at international airports
Authors: Petzer Andreas L. , Speth Hans-Georg , Hoflehner Elisabeth , Clausen Johannes , Nachbaur David , Gastl Günther , Gunsilius Eberhard
Published: October 2002

Hematopoietic stem cell grafts from unrelated donors are commonly transported by aircraft. They must not be subjected to x-rays during security checks, which may cause inconvenient discussions between the courier and the airport security staff. We exposed hematopoietic stem cells from mobilized peripheral blood to a widely used x-ray hand-luggage control system. Cell viability as well as growth in vitro of mature progenitor cells (colony-forming cells), primitive progenitor cells (long-term culture-initiating cells), and lymphocytes were not altered even after 10 passages through the hand-luggage control system. Thus, repeated exposure to the low radiation dose of hand-luggage control systems (1.5 ± 0.6 μSv per exposure) seems to be harmless for hematopoietic stem cells, which should simplify the international transport of stem cell grafts.
Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study
Authors: Junghanss Christian , Boeckh Michael , Carter Rachel A. , Sandmaier Brenda M. , Maris Michael B. , Maloney David G. , Chauncey Thomas , McSweeney Peter A. , Little Marie-Térèse , Corey Lawrence , Storb Rainer
Published: October 2002

Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly being explored as therapy in patients who are not eligible for conventional myeloablative HSCT. Whether these transplants are associated with reduced risk of transplantation-related infections is unknown. We analyzed the incidence of posttransplantation cytomegalovirus (CMV) infections in 56 consecutive mycophenolate mofetil (MMF) patients with hematologic malignancies who underwent nonmyeloablative HSCT (TBI, 2Gy, day 0; MMF/cyclosporine after transplantation). In addition, 18 of 56 patients received 30 mg/m2/d fludarabine on days −4 to −2. Most donors were HLA matched and related (93%). Each case patient was matched to 2 controls who were treated by conventional HSCT during the same time period (January 1997 through April 2000). Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P = .11), viremia (P = .16), and disease (P = .08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P = .01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P = .02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and pre-emptive ganciclovir treatment similar to that of myeloablative HSCT patients.
Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression
Authors: Baron Frédéric , Turhan Ali G. , Giron-Michel Julien , Azzarone Bruno , Bentires-Alj Mohamed , Bours Vincent , Bourhis Jean Henri , Chouaib Salem , Caignard Anne
Published: October 2002

Chronic myeloid leukemia is a clonal myeloproliferative expansion of transformed primitive hematopoietic progenitor cells characterized by high-level expression of BCR-ABL chimeric gene, which induces growth factor independence. However, the influence of BCR-ABL expression on cell-mediated cytotoxicity is poorly understood. In the present study, we asked whether BCR-ABL expression interferes with leukemic target sensitivity to natural killer (NK) cell cytolysis. Our approach was based on the use of 2 BCR-ABL transfectants of the pluripotent hematopoietic cell line UT-7 expressing low (UT-7/E8, UT-7/G6) and high (UT-7/9) levels of BCR-ABL. As effector cells, we used CD56bright, CD16−, CD2− NK cells differentiated in vitro from CD34 cord blood progenitors. We demonstrated that BCR-ABL transfectants UT-7/9 were lysed by NK cells with a higher efficiency than parental and low UT-7/E8.1 and UT-7/G6 transfectants. This enhanced susceptibility to lysis correlated with an increase in expression of intercellular adhesion molecule 1 (ICAM-1) by target cells. Treatment of UT-7/9 cells by STI571 (a specific inhibitor of the abl kinase) resulted in a decrease in NK susceptibility to lysis and ICAM-1 down-regulation in target cells. Furthermore, the constitutive activation of nuclear factor-κB (NF-κB) detected in BCR-ABL transfectant UT-7/9, was significantly attenuated when cells were treated by STI571. Interestingly, inhibition of NF-κB activation by BAY11-67082 (a specific NF-κB inhibitor) resulted in down-regulation of ICAM-1 expression and a subsequent decrease in NK-induced killing of UT-7/9 transfectants. Our results show that oncogenic transformation by BCR-ABL may increase susceptibility of leukemic progenitors to NK cell cytotoxicity by a mechanism involving overexpression of ICAM-1 as a consequence of NF-κB activation.
A novel costimulatory signaling in human T lymphocytes by a splice variant of CD28
Authors: Hanawa Haruo , Ma Yong , Mikolajczak Sebastian A. , Charles Matthew L. , Yoshida Tetsuya , Yoshida Ryoko , Strathdee Craig A. , Litchfield David W. , Ochi Atsuo
Published: October 2002

We have characterized a splice variant (isoform) of the human CD28 T cell costimulatory receptor. The nucleotide sequence of this CD28 isoform was identical to that of CD28 in the signal peptide, the transmembrane domain, and the cytoplasmic tail, but it was missing a large segment of the extracellular ligand-binding domain, which is encoded by the second exon. This isoform (CD28i), whose message level exceeded 25% of CD28, was a transmembrane homodimer. CD28i was found noncovalently associated with CD28 and was tyrosine-phosphorylated/PI3-kinase–complexed following the crosslinking of CD28, and the CD28 costimulatory signal was enhanced in T cells expressing CD28i. These data demonstrate that CD28i, via noncovalent association with CD28, plays a role as a costimulatory signal amplifier in human T cells.
Intracellular regulation of tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis in human multiple myeloma cells
Authors: Mitsiades Nicholas , Mitsiades Constantine S. , Poulaki Vassiliki , Anderson Kenneth C. , Treon Steven P.
Published: October 2002

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL, Apo2 ligand) effectively kills multiple myeloma (MM) cells in vitro irrespective of refractoriness to dexamethasone and chemotherapy. Because clinical trials with this anticancer agent are expected shortly, we investigated the signaling pathway of TRAIL-induced apoptosis in MM. We detected rapid cleavage of caspases-8, -9, -3, and -6, as well as the caspase substrates poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor-45 (DFF45), but not caspase-10, upon TRAIL treatment in sensitive MM cells, pointing to caspase-8 as the apical caspase of TRAIL signaling in MM cells. These phenomena were not observed or were significantly delayed in TRAIL-resistant MM cells, suggesting that resistance may arise from inhibition at the level of caspase-8 activation. Higher levels of expression for various apoptosis inhibitors, including FLICE-inhibitory protein (FLIP), and lower procaspase-8 levels were present in TRAIL-resistant cells and sensitivity was restored by the protein synthesis inhibitor cycloheximide (CHX) and the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), which both lowered FLIP and cellular inhibitor of apoptosis protein-2 (cIAP-2) protein levels. Forced expression of procaspase-8 or FLIP antisense oligonucleotides also sensitized TRAIL-resistant cells to TRAIL. Moreover, the cell permeable nuclear factor (NF)–κB inhibitor SN50, which sensitizes TRAIL-resistant cells to TRAIL, also inhibited cIAP2 protein expression. Finally, CHX, BIM, and SN50 facilitated the cleavage and activation of procaspase-8 in TRAIL-resistant cells, confirming that inhibition of TRAIL-induced apoptosis occurs at this level and that these agents sensitize MM cells by relieving this block. Our data set a framework for the clinical use of approaches that sensitize MM cells to TRAIL by agents that inhibit FLIP and cIAP-2 expression or augment caspase-8 activity.
Mechanical properties of rat bone marrow and circulating neutrophils and their responses to inflammatory mediators
Authors: Saito Hajime , Lai Jean , Rogers Rick , Doerschuk Claire M.
Published: October 2002

Neutrophils are continuously released from the bone marrow (BM), and this release is accelerated during inflammation. This study compared the mechanical properties of mature neutrophils within the BM and the circulating blood, as well as the role of microtubule rearrangement in the release of neutrophils from the BM in rats. Neutrophils isolated from the BM were stiffer than neutrophils in the circulating blood, using magnetic twisting cytometry. BM neutrophils also contained more F-actin within the submembrane region than circulating neutrophils when examined using confocal microscopy, suggesting that mature quiescent neutrophils within the BM are stiffer than circulating neutrophils because of increased formation of F-actin beneath the plasma membrane. Complement protein 5 fragments or formylmethionyl-leucylphenylalanine (fMLP) induced a stiffening response within 2 minutes that was greater in circulating than in BM neutrophils. This stiffening required F-actin formation within the submembrane region but not microtubule rearrangement in both circulating and BM neutrophils. fMLP-induced shape changes were more pronounced in circulating than in BM neutrophils, which showed fewer and smaller pseudopods and fewer membrane irregularities. In vivo, fMLP induced neutropenia, sequestration of neutrophils within the pulmonary capillaries, and release of neutrophils from the BM. Studies using colchicine demonstrated that rearrangement of microtubules was not required for any of these processes but was required for normal trafficking of neutrophils through the pulmonary capillaries.
Differential effect of CD28 versus B7 blockade on direct pathway of allorecognition and self-restricted responses
Authors: Haspot Fabienne , Villemain Florence , Laflamme Geneviève , Coulon Flora , Olive Daniel , Tiollier Jérôme , Soulillou Jean-Paul , Vanhove Bernard
Published: October 2002

Immunosuppression with B7 antagonists might have 2 opposite effects: reducing T-cell costimulation through CD28 but also preventing CTLA-4 from transmitting its negative regulatory signal. We therefore hypothesized that a selective blockade of CD28 might be qualitatively different from blocking B7. It was previously reported that CD28 modulation prolongs allograft survival in the rat and reverses induction of experimental autoimmune encephalomyelitis in mice. However, whether CD28 or B7 blockade results in similar immunosuppression on alloimmune and self-restricted responses to soluble antigens has not yet been investigated. Here, we addressed this issue in vitro with antagonist anti-CD28 Fab fragments and in vivo using the modulating anti-rat JJ319 monoclonal antibody. As in the inhibition of B7 with CTLA4 immunoglobulin, anti-CD28 Fab fragments inhibited allogenic T-cell proliferation in mixed cultures. In vivo modulation of CD28 blocked the expansion of alloreactive T cells and promoted their apoptosis. In contrast, selective blockade of CD28 did not modify T-cell proliferative responses and antibody production to soluble antigens, whereas blocking B7 with CTLA4 immunoglobulin did. Our data show that blocking CD28, while leaving CTLA4-B7 interactions undisturbed, inhibits alloreactive CD4+ T-cell expansion but does not modify the response to nominal antigens presented in the context of a self-major histocompatibility complex. That B7 engagement is needed for self-restricted responses whereas engagement of CD28 is not essential adds to the suggestion that another unidentified ligand of B7 might deliver a costimulatory signal in the absence of CD28.
Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell–depleted bone marrow transplantation
Authors: Chen Benny J. , Cui Xiuyu , Chao Nelson J.
Published: October 2002

Significant delays in engraftment and lymphoid recovery are the 2 major challenges in cord blood transplantation. The cause for this delay is presumed to be the low numbers of hematopoietic precursors found in one unit of cord blood. One approach to increase the stem cell doses could be to combine cord blood units from different donors differing at the major histocompatibility complex (MHC). As a first step toward this goal, the kinetics of hematologic engraftment and immune reconstitution were compared between 1 unit (2.5 × 106 cells) of T-cell–depleted bone marrow cells from a single donor (C57BL/6 [H2b] or SJL/J [H2s]) and 2 units from different donors (C57BL/6 + SJL/J) after transplantation into lethally irradiated (8.5 Gy) BALB/c recipients (H2d). Addition of T-cell–depleted bone marrow from an MHC-mismatched allogeneic donor doubled the white blood counts compared with recipients of one single unit on days +10 and +14. Similar effects were also observed on platelets. The beneficial effect of additional cells on peripheral T-cell counts were first observed on day +14. Cells both from donors (C57BL/6 and/or SJL/J) and recipients (BALB/c) contributed to myeloid and lymphoid reconstitution. The chimeras containing cells from 3 strains of mice were able to mount a recall immune response. Our data suggest that combining stem cells from MHC-mismatched allogeneic donors is feasible, that it has beneficial effects on myeloid engraftment and T-cell phenotypic recovery, and that the long-term stable mixed chimeras are immunologically normal following T-cell–depleted bone marrow transplantation.
Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site
Authors: Tentori Lucio , Leonetti Carlo , Scarsella Marco , d'Amati Giulia , Portarena Ilaria , Zupi Gabriella , Bonmassar Enzo , Graziani Grazia
Published: October 2002

Temozolomide (TZM) is a DNA-methylating agent that has recently been introduced into various clinical trials for treatment of solid or hematologic neoplasias, including brain lymphomas. In the current study, we have investigated whether the antitumor activity of TZM could be selectively enhanced at the central nervous system (CNS) site by intracerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. Mice were injected intracranially with lymphoma cells. The PARP inhibitor NU1025 (1 mg/animal) was delivered intracerebrally, whereas TZM was given as a single or a fractionated dose of 200 mg/kg by intraperitoneal administration. Results indicated that this drug combination significantly enhanced the survival of tumor-bearing mice and that this fractionated modality of treatment was the most effective schedule. Increased survival time was related to a marked reduction of tumor growth, as evidenced by histologic studies. Treatment with TZM alone was ineffective. This is the first report exploring in vivo the combination of TZM with PARP inhibitor for intracerebral neoplasias.
Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells
Authors: Kitazono Masaki , Rao Vemulkonda Koneti , Robey Rob , Aikou Takashi , Bates Susan , Fojo Tito , Goldsmith Merrill E.
Published: October 2002

Adenovirus infection of hematopoietic cells frequently requires high virus concentrations and long incubation times to obtain moderate infection levels because these cells have low levels of Coxsackie and adenovirus receptor (CAR) and αv integrin. The effect of treatment with FR901228 (depsipeptide), a histone deacetylase inhibitor in phase 2 clinical trials, was studied in K562 cells, granulocyte–colony-stimulating factor–mobilized peripheral blood mononuclear cells (PBMCs), and CD34+ peripheral blood stem cells (PBSCs). FR901228 increased CAR and αvintegrin RNA levels and histone H3 acetylation. FR901228 treatment before adenovirus infection was associated with at least a 10-fold increase in transgene expression from a β-galactosidase–expressing adenoviral vector. More than 80% of the PBMCs or CD34+ PBSCs from 7 different donors were β-galactosidase–positive after adenovirus infection with a multiplicity of infection of 10 for 60 minutes. Increased CAR, αv integrin, and acetylated histone H3 levels were observed in PBMCs from a patient treated with FR901228. These studies suggest that FR901228 can increase the efficiency of adenoviral infection in hematopoietic cells.
Prognostic significance of cellular vascular endothelial growth factor expression in chronic phase chronic myeloid leukemia
Authors: Verstovsek Srdan , Kantarjian Hagop , Manshouri Taghi , Cortes Jorge , Giles Francis J. , Rogers Anna , Albitar Maher
Published: October 2002

The impact of elevated vascular endothelial growth factor (VEGF) expression on the course of chronic myeloid leukemia (CML) is unknown. By radioimmunoassay, we measured pretreatment cellular VEGF protein in bone marrow samples from 184 (148 chronic and 36 accelerated/blastic phases) CML patients and found the levels to be 1.6-fold higher than in 31 normal control bone marrow samples (P = .000 01). No significant differences were found in VEGF levels by different phases of CML (P = .1). VEGF levels correlated with older age (P = .01) and higher platelet count (P = .0003), but also with smaller spleen size (P = .004), lower white blood cell count (P = .0006), and lower percentage of peripheral blasts (P = .04). With the use of Cox proportional hazard model and VEGF levels as a continuous variable, high VEGF levels correlated with shorter survival of patients in chronic CML (P = .008). Multivariate analysis showed that VEGF was not independent of the synthesis stage (P = .09). These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.
Low- and high-dose fluticasone propionate in asthma; effects during and after treatment
Authors: Gershman NH , Wong HH , Liu JT , Fahy JV
Published: October 2002

The dose dependency of the effects of inhaled corticosteroids on markers of asthmatic airway inflammation have not been well studied. There is a need to study the dose/response effects on this inflammation. In order to determine the dose/response effects of fluticasone propionate (FP), 24 asthmatic subjects were randomized to low- (100 microg x day(-1)) or high-dose (1,000 microg x day(-1)) FP for six weeks followed by placebo for 3 weeks. During treatment, the median increase in forced expiratory volume in one second (FEV1)was 12% in the high-dose group (p<0.05) and 10% in the low-dose group (p<0.05) (p>0.05 between groups); the median decrease in the percentage of sputum eosinophils was 93% in the high-dose group (p<0.05) and 46% in the low-dose group (p<0.05) (p>0.05 between groups). Symptoms, salbutamol use, morning peak flow, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), sputum eosinophil cationic protein concentration and tryptase activity improved significantly in both groups (p<0.05), but only the improvement in salbutamol use was greater in the high-dose group (p<0.05). During the run-out, the improvements in FEV1 and PC20 were rapidly reversed in both groups, but the improvements in peak flow and tryptase activity persisted; the improvement in sputum eosinophil concentration persisted only in the high-dose group (p<0.05). It was concluded that dose/response effects for FP are not easily demonstrable because low-dose FP is quite effective. For most outcomes, the effects of high- and low-dose FP are relatively short-lived after treatment is stopped. This finding raises questions about the extent to which inhaled corticosteroids are disease-modifying in asthma.
Development of severe hypoxaemia in chronic obstructive pulmonary disease patients at 2,438 m (8,000 ft) altitude
Authors: Christensen CC , Ryg M , Refvem OK , Skjonsberg OH
Published: October 2002

The arterial oxygen tensions (Pa,02) in chronic obstructive pulmonary disease (COPD) patients travelling by air, should, according to two different guidelines, not be lower than 7.3 kPa (55 mmHg) and 6.7 kPa (50 mmHg), respectively, at a cabin pressure altitude of 2,438 m (8,000 ft). These minimum in-flight Pa,O2 values are claimed to correspond to a minimum Pa,O2 of 9.3 kPa (70 mmHg) at sea-level. The authors have tested whether this limit is a safe criterion for predicting severe in-flight hypoxaemia. The authors measured arterial blood gases at sea-level, at 2,438 m and at 3,048 m (10,000 ft) in an altitude chamber at rest and during light exercise in 15 COPD patients with forced expiratory volume in one second (FEV1) <50% of predicted, and with sea-level Pa,O2 >9.3 kPa. Resting Pa,O2 decreased below 7.3 kPa and 6.7 kPa in 53% and 33% of the patients, respectively, at 2,438 m, and in 86% and 66% of the patients at 3,048 m. During light exercise, Pa,O2 dropped below 6.7 kPa in 86% of the patients at 2,438 m, and in 100% of the patients at 3,048 m. There was no correlation between Pa,O2 at 2,438 m and pre-flight values of Pa,O2, FEV1 or transfer factor of the lung for carbon monoxide. In contrast to current medical guidelines, it has been found that resting arterial oxygen tension >9.3 kPa at sea-level does not exclude development of severe hypoxaemia in chronic obstructive pulmonary disease patients travelling by air. Light exercise, equivalent to slow walking along the aisle, may provoke a pronounced aggravation of the hypoxaemia.
Relationship of carbon dioxide tension in arterial blood to pulmonary wedge pressure in heart failure
Authors: Lorenzi-Filho G. , Azevedo E.R. , Parker J.D. , Bradley T.D.
Published: October 2002

Hypocapnia contributes to the genesis of Cheyne-Stokes respiration and central sleep apnoea in patients with congestive heart failure (CHF) and is associated with increased mortality. However, the cause of hypocapnia in patients with chronic stable CHF is unknown. Since pulmonary congestion can induce hyperventilationviastimulation of pulmonary vagal afferents, the present study tested the hypothesis that in patients with CHF (carbon dioxide tension in arterial blood (Pa,CO2)) is inversely related to pulmonary capillary wedge pressure (PCWP), and that alterations in PCWP would cause inverse changes inPa,CO2.

In 11 CHF patients undergoing diagnostic cardiac catheterization, haemodynamic variables and arterial blood gas tensions were measured simultaneously at baseline. In three patients, these measurements were repeated after coronary angiographic dye infusion and nitroglycerine infusion.

At baseline,Pa,CO2correlated inversely with PCWP (r=−0.80, p=0.003). In the three patients in whom multiple measurements were made, acute alterations in PCWP caused inversely proportional changes inPa,CO2.

The present study concludes that in patients with congestive heart failure, pulmonary capillary wedge pressure is an important determinant of carbon dioxide tension in arterial blood. These findings imply that hypocapnia in patients with chronic stable congestive heart failure is a respiratory manifestation of elevated left ventricular filling pressures.
BAX and p16INK4Aare independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer
Authors: Gessner C. , Liebers U. , Kuhn H. , Stiehl P. , Witt C. , Schauer J. , Wolff G.
Published: October 2002

Clinical studies suggest prognostic relevance of p16INK4Ain nonsmall cell lung cancer (NSCLC) while conflicting results for p53 have been published. However, the importance of the apoptosis regulating gene BAX, a downstream regulator of p53, on the prognosis of NSCLC is unknown. The present study investigated the prognostic relevance of BAX with respect to the status of p53 and p16INK4Ain 61 patients with advanced NSCLC.

Protein expression of BAX, p53 and p16INK4Awas investigated retrospectively by immunohistochemistry. Tumour deoxyribonucleic acid (DNA) was screened for p53 mutations by single strand-conformation polymorphism polymerase chain reaction (PCR) and BAX frameshift mutations by fragment length analysis.

Patients with positive BAX protein expression had a significantly longer median survival (14 months) than those patients without BAX expression (6 months, p=0.0004). In contrast, p53 status did not influence prognosis. Patients with p16INK4Anegative tumours had a significantly shorter survival (4 months) than those with p16INK4Aprotein expression (15 months, p=0.0001). Furthermore, the loss of p16INK4Aprotein expression correlated strongly with the pressure of distant and advanced lymph-node metastases. The best survival was seen in a subgroup of 20 patients with positive p16INK4Aexpression and intact BAX (p=0.0002).

The results of the present study suggest that the loss of BAX and p16INK4Aexpression are independent markers for poor prognosis in nonsmall cell lung cancer. The study suggests that multimarker analysis of genes involved in apoptosis may be useful for determining individual therapy and for identifying targets for gene-replacement therapy. This should be assessed in a prospective study with a larger cohort of patients.
High postoperative risk after pneumonectomy in elderly patients with right-sided lung cancer
Authors: van Meerbeeck J.P. , Damhuis R.A.M. , Vos de Wael M.L.
Published: October 2002

The present study investigated postoperative mortality (POM), its predictors and relationship with long-term survival in patients who underwent surgery for lung cancer.

The 30-day mortality after thoracotomy in 1,830 patients from the Flemish multicentre hospital-based lung cancer registry was analysed according to patient, tumour, treatment and hospital characteristics and compared with 5-yr survival figures for the same patients.

Overall POM was 4.4%. In univariate analysis age, extent of surgery and low hospital volume were associated with a higher POM. In multiple regression analysis age, extent of surgery and side of the pneumonectomy proved to be independent predictors of POM. In patients aged >70 yrs who underwent right-sided pneumonectomy POM was 17.8%.

Overall, mortality was comparable to published series from referral centres. Age and extent of resection are the main predictors of postoperative mortality in lung-cancer patients. In the operable elderly patient, age alone does not justify denying the survival benefit experienced by resection of lung cancer. The high mortality after right-sided pneumonectomy in elderly patients warrants caution, as the treatment benefit may become marginal.
The SleepStripTM: an apnoea screener for the early detection of sleep apnoea syndrome
Authors: Shochat T. , Hadas N. , Kerkhofs M. , Herchuelz A. , Penzel T. , Peter J.H. , Lavie P.
Published: October 2002

Sleep apnoea syndrome (SAS) is a largely undiagnosed and prevalent disorder. It is associated with cardiovascular morbidity as well as excessive daytime sleepiness and poor quality of life. In the present study the SleepStripTM, a novel screening device is introduced, which is low cost and easy to use and is aimed for widespread use.

The results of three independent validation studies, which compared the SleepStripTMscore (Sscore) against “gold standard” polysomnographically-determined apnoea/hypopnoea index (AHI), are reported both separately and combined. Four hundred and two patients suspected of SAS underwent full polysomnography recordings concomitantly with the use of the SleepStripTM.

For all samples combined, the correlation between AHI and Sscore was r=0.73, sensitivity and specificity values ranged from 80–86% and 57–86% respectively, and the area under the curve derived from receiver-operating characteristic curves ranged from 0.81–0.92 at varying AHI thresholds.

Though not intended as a substitute for polysomnography, the SleepStripTMmay provide initial screening information, which may be useful in both clinical and experimental settings.
Costs of asthma are correlated with severity: a 1-yr prospective study
Authors: Godard P. , Chanez P. , Siraudin L. , Nicoloyannis N. , Duru G.
Published: October 2002

Asthma prevalence is increasing and asthma-related costs are likely to increase, but few studies have analysed the relationship of asthma costs and severity. The impact of severity on costs was quantified in a cohort of 318 asthmatic patients followed up prospectively for 1 yr.

Patients presenting with a broad range of severity of the disease (intermittent, mild persistent, moderate persistent, severe persistent) were recruited by chest physicians throughout France and treated for 1 yr according to customary clinical practice and following international guidelines. Severity, direct and indirect costs, and quality of life (QoL) were assessed. A multivariate analysis was conducted to relate factors contributing to the costs measured.

Mean direct costs for goods and services excluding hospitalization, numbers of consultations, supplementary examinations, and the use and cost of bronchodilators and corticosteroids, indirect costs of days lost from work, and adverse QoL parameters all increased significantly with increasing severity. This also applied to mean age, body weight, asthma duration, depression of forced expiratory volume in one second, and inhaled corticosteroid posology in the 234 patients completing the study. There was a significant relationship (r=0.614, p<0.001) between direct costs (hospitalization and cures were excluded) and three domains of the QoL questionnaire (mobility, pain and energy).

Overall costs of asthma (including individual direct costs, indirect costs, and intangible quality of life costs) are clearly related to severity. This is the first study in asthma to combine rigorous independent classification of grades of severity in statistically valid numbers of patients of grades receiving “real-world” treatment and followed-up prospectively for 1 yr. It allowed severity to be accurately related to direct, indirect and intangible costs of asthma. Quality of life explained a significant part of these costs.
Adjustment to chronic obstructive pulmonary disease: the importance of psychological factors
Authors: McCathie H.C.F. , Spence S.H. , Tate R.L.
Published: October 2002

Research has indicated a weak relationship between the degree of physical problems and quality of life in patients with chronic obstructive pulmonary disease (COPD). The importance of adaptive psychological functioning to maintain optimum quality of life has long been recognized, but there is a lack of empirical evidence concerning the nature of psychological factors involved in adjustment to COPD.

Ninety-two males completed questionnaires to determine their coping strategies, levels of self-efficacy of symptom management and social support. Adjustment was measured in terms of depression, anxiety and quality of life. Symptom severity, socioeconomic status, duration of disease and age, which have been demonstrated to be of consequence in COPD, were used as control variables in hierarchical multiple regression analyses.

Higher levels of catastrophic withdrawal coping strategies and lower levels of self-efficacy of symptom management were associated with higher levels of depression, anxiety and a reduced quality of life. Higher levels of positive social support were linked to lower levels of depression and anxiety, while higher levels of negative social support were linked to higher levels of depression and anxiety.

To maximize quality of life in patients with chronic obstructive pulmonary disease, psychological factors need to be carefully assessed and addressed.
Exhaled carbon monoxide is not elevated in patients with asthma or cystic fibrosis
Authors: Zetterquist W. , Marteus H. , Johannesson M. , Nordvall S.L. , Ihre E. , Lundberg J.O.N. , Alving K.
Published: October 2002

Increased levels of exhaled carbon monoxide (fractional concentration of CO in expired gas (FE,CO)), measured with an electrochemical sensor, have been reported in patients with inflammatory airway disorders, such as asthma, rhinitis and cystic fibrosis. This study aimed to evaluate these findings by using a fast-response nondisperse infrared (NDIR) analyser, and to compare these measurements with the fractional concentration of nitric oxide in exhaled air (FE,NO).

Thirty-two steroid-naïve asthmatics, 24 steroid-treated asthmatics (16 patients with allergic rhinitis, nine patients with cystic fibrosis), and 30 nonsmoking healthy controls were included. CO measurements with the NDIR analyser were performed simultaneously with nitric oxide (NO) analysis (chemiluminescence technique). After 15 s of breath-hold, single-breath exhalations over 10 s were performed at two flow rates and end-tidal plateau concentrations were registered. An electrochemical CO sensor was used independently with an exhalation to residual volume, after a 15 s breath-hold.

None of the two CO analysers gave a significant increase inFE,COin the groups of patients with inflammatory airway disorders compared to controls.FE,NOwas significantly elevated in steroid-naïve asthmatics and subjects with allergic rhinitis, but not in steroid-treated asthmatics and subjects with cystic fibrosis. Reducing exhalation flow rate by 50% gave a two-fold increase inFE,NO, whileFE,COwas unaffected. A significant increase was seen inFE,CO, but not inFE,NO, when comparing with and without a 10 s breath-hold.

In conclusion, the fractional concentration of carbon monoxide in expired gas was not increased in any of the patient groups, while the fractional concentration of nitric oxide in expired gas was significantly elevated in patients with steroid-naïve asthma and allergic rhinitis. Moreover, carbon monoxide was unaffected by flow rate but increased with breath-hold, suggesting an origin in the alveoli rather than the conducting airways.
Rhinovirus infection in nonasthmatic subjects: effects on intrapulmonary airways
Authors: de Kluijver J. , Grünberg K. , Sont J.K. , Hoogeveen M. , van Schadewijk W.A.A.M. , de Klerk E.P.A. , Dick C.R. , van Krieken J.H.J.M. , Sterk P.J.
Published: October 2002

The common cold is a highly prevalent, uncomplicated upper airway disease. However, rhinovirus (RV) infection can lead to exacerbation of asthma, with worsening in airway hyperresponsiveness and bronchial inflammation. The current authors questioned whether such involvement of the intrapulmonary airways is disease specific.

Twelve nonatopic, healthy subjects (forced expiratory volume in one second (FEV1) >80% predicted, provocation concentration causing a 20% fall in FEV1(PC20) >8 mg·mL−1) were experimentally infected with RV16. Next to PC20and the maximal response to methacholine (MFEV1and MV′40p), the numbers of mucosal inflammatory cells and epithelial intercellular adhesion molecule (ICAM)‐1 expression in bronchial biopsies were assessed before and 6 days after RV16 inoculation.

RV16 infection induced a small but consistent increase in maximal airway narrowing, without a change in PC20. There was a significant increase in bronchial epithelial ICAM‐1 expression after RV16, whereas inflammatory cell counts did not change. Nevertheless, the change in the number of submucosal CD3+ cells was correlated with the change in MV′40p.

In conclusion, rhinovirus infection in normal subjects induces a limited, but significant increase in maximal airway narrowing, which is associated with changes in bronchial T‐cell numbers. Together with the upregulation of bronchial epithelial intercellular adhesion molecule‐1, these findings indicate that, even in healthy subjects, rhinovirus infection affects the intrapulmonary airways.
The bidirectional capacity of bacterial antigens to modulate allergy and asthma
Authors: Renz H. , Herz U.
Published: October 2002

In recent decades, the prevalence of allergic diseases including bronchial asthma, hay fever and atopic dermatitis, has risen steadily in high-income countries. The underlying mechanisms for this phenomenon remain largely unknown. Since the natural mutation rate is low, altered environmental and lifestyle conditions are thought to play an important role.

Epidemiological and clinical studies have provided indirect evidence that infections may prevent the development of atopy and atopic disease. This is referred to as the “hygiene hypothesis”. According to the hygiene hypothesis, viral and/or bacterial infections could inhibit the T-helper (Th)-2 immune response associated with atopic reactions by stimulating a Th-1 response involved in defence of bacterial infections and delayed-type hypersensitivity reactions.

In particular, the prenatal period and early childhood are considered to be critical for the establishment and maintenance of a normal Th-1/Th-2 balance. On the other hand, several studies suggested that infections exacerbate established allergic diseases,e.g.bronchial asthma, airway hyperresponsiveness and atopic dermatitis. Therefore, viral and/or microbial infections and/or their products may have bidirectional effects on the development of allergy and asthma.

This review will focus on recent findings related to the interaction between allergic disorders and infectious diseases, with the main emphasis on bacterial infections.
Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane
Authors: Mercier F.J. , Naline E. , Bardou M. , Georges O. , Denjean A. , Benhamou D. , Advenier C.
Published: October 2002

Volatile anaesthetics relax airway smooth musclein vitro. The amount of relaxation might depend on the type and concentration of volatile anaesthetics, the calibre and precontraction level of the bronchi, and also on the species considered. These effects were investigated on isolated human bronchi.

Isometric relaxations produced by halothane, isoflurane and desflurane bubbled on human bronchial rings precontracted with carbachol were recorded and compared with time controls.

Volatile anaesthetics induced a concentration-dependent relaxation at 0.66, 1.33 and 2 minimum alveolar concentration (MAC). The relaxation was greater in mildly (carbachol 3×10−7 M) than in highly (carbachol 2×10−6 M) precontracted bronchi. Halothane was more potent in relaxing distal as compared to proximal bronchi; this differential effect was less pronounced with isoflurane and not observed with desflurane. While the three volatile anaesthetics induced similar relaxation on proximal bronchi, halothane was significantly more potent than desflurane on distal bronchi, with isoflurane being intermediate. The relaxation induced by 1.33 MAC of halothane, isoflurane and desflurane on moderately precontracted distal bronchi (carbachol 1×10−6 M) was attenuated by pretreatment with glibenclamide 1×10−5 M.

In conclusion, halothane, isoflurane and desflurane exert direct but differential relaxant effects on human isolated bronchial smooth muscle. This may provide supplemental bronchodilation during anaesthesia. Although adenosine triphosphate-sensitive K+channels are involved in these relaxant effects, they are unlikely to explain the observed differences between the three volatile anaesthetics.
Sepsis and hyperoxia effects on the pulmonary surfactant system in wild-type and iNOS knockout mice
Authors: Bailey T.C. , Cavanagh C. , Mehta S. , Lewis J.F. , Veldhuizen R.A.W.
Published: October 2002

Alterations of pulmonary surfactant and increases in inducible nitric oxide synthase (iNOS) have been implicated in the pathophysiology of acute lung injury. It was hypothesised that these two observations are related and that alterations of the endogenous surfactant, due to either sepsis or hyperoxia, would be reduced in mice lacking the iNOS gene compared to wild-type mice.

Wild-type and iNOS (−/−) mice were randomised into sham or sepsis, and in a separate experiment animals were randomised to normoxia or hyperoxia exposure for 48 h. Lungs were lavaged and analysed for total surfactant levels and surfactant subfractions (large (LA) and small (SA) aggregates).

Both sepsis groups had decreased SA compared to sham groups with no significant difference between the two genotypes. Mice exposed to hyperoxia had a decreased amount of total surfactant when compared to normoxia controls and there was no significant difference between the two genotypes.

It is concluded that inducible nitric oxide synthase does not influence the amount of pulmonary surfactant or surfactant subfractions recovered in lavage after 18 h of sepsis or 48 h of hyperoxia.
Pertechnegas lung clearance in different forms of interstitial lung disease
Authors: Thomeer M.J. , Dehaes B. , Mortelmans L. , Demedts M.
Published: October 2002

Interstitial lung diseases (ILD) are characterized by an acute or chronic inflammation of the alveolar capillary membrane, which affects the permeability of this membrane. A possible way to measure the permeability of the membrane is by radionuclide aerosol imaging. Pertechnegas, a gas composed of technetium-labelled carbon particles, has recently been proposed as a new ventilation agent to measure this lung clearance.

The clearance by pertechnegas in the four most common forms of ILD (eight patients with connective tissue disease, 10 with hypersensitivity pneumonitis, nine with idiopathic interstitial pneumonia and 10 with sarcoidosis) was measured and compared with 10 nonactive smoking controls. Because forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusing capacity of the lung (DL,CO) are used in the assessment of functional severity of the ILD, the pertechnegas clearance was correlated with these lung-function indices.

It was found that the time to half clearance of pertechnegas of the lung is significantly decreased in idiopathic interstitial pneumonia (p<0.0001), hypersensitivity pneumonitis (p=0.0005) and connective tissue disease (p=0.002) but not in sarcoidosis when compared with 10 nonsmoking controls. A significant correlation is also found between time to half clearance and FVC (r=0.76; p<0.0001), TLC (r=0.63; p<0.0001) andDL,CO(r=0.75; p<0.0001) for all groups together. For all subjects as a group, the time to half clearance is shorter in the upper lung zones than in the lower zones (p<0.0001) and the ratio between both zones is not significantly different between the different types of disease.

These results indicate that pertechnegas clearance is increased in idiopathic interstitial pneumonia, hypersensitivity pneumonitis and connective tissue disease, but not in sarcoidosis and is related to the functional severity of the disease.
A portable forced oscillation device for respiratory home monitoring
Authors: Rigau J. , Farré R. , Roca J. , Marco S. , Herms A. , Navajas D.
Published: October 2002

The increase in the prevalence of chronic respiratory diseases has resulted in a rise in health services provided at home. The forced oscillation technique (FOT) proves to be a useful tool when it is desired to assess lung function noninvasively, and particularly for patients in whom spirometry cannot be applied. As no portable FOT device is currently available, the aim of this study was to design and test a portable FOT system for ambulatory and home care applications.

The system devised is based on a microprocessor, which allows online computation of respiratory resistance (Rrs) and reactance (Xrs) and reliability indices. The portable device was compared with a conventional FOT system by using signals from 14 patients with chronic respiratory disease.

This device has the same computation capabilities and flexibility as conventional FOT systems and meets the requirements for home application.Rrs(14.2±6.0 cmH2O·s·L−1, mean±sd) andXrs(−5.3±2.7 cmH2O·s·L−1) measured at 5 Hz by the portable system virtually coincided with those computed with the reference conventional FOT system: mean differences±sd were 0.074±0.025 and 0.005±0.009 cmH2O·s·L−1, respectively.

This portable forced oscillation technique device could be a useful tool for monitoring respiratory mechanics in ambulatory and home care applications.
Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease
Authors: Polosa R.
Published: October 2002

Adenosine administration by inhalation elicits concentration-related bronchoconstriction in subjects with asthma and chronic obstructive pulmonary disease (COPD). The mechanisms of adenosine-induced bronchoconstriction appear to involve a selective interaction with activated mast cells with subsequent release of preformed and newly-formed mediators. Further evidence linking adenosine signalling to asthma and COPD comes from the finding that many cell types that play important roles in the exacerbation of these conditions express adenosine receptors and demonstrate relevant effects through stimulation of these receptors.

Therefore, blockade of these receptors may be a valuable approach to the treatment of asthma and chronic obstructive pulmonary disease. Promising adenosine-receptor targets for novel therapeutics of asthma and chronic obstructive pulmonary disease have recently been identified in a number of inflammatory cell types, including mast cells, eosinophils, lymphocytes, neutrophils, and macrophages. The recent characterisation of the A2Breceptors indicates the human lung mast cell as one of the most strategic cellular targets.