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INTRODUCTION: Chronic dyspnoea that remains unexplained after resting pulmonary function and cardiovascular testing is a common problem in clinical practice. The aim of this study was to determine the utility of cardiopulmonary exercise testing (CPET) in the diagnosis of unexplained dyspnoea. METHODS: This retrospective single-centre study included consecutive patients with dyspnoea who had normal resting cardiopulmonary examinations (including chest X-ray, electrocardiography, pulmonary function tests [PFTs], and cardiac ultrasound). CPET was performed using a cycle ergometer with analysis of blood gases. The results were interpreted as being most likely due to one of the six pathophysiological mechanisms shown below. Consensus required agreement between at least three of the authors. RESULTS: Of the 194 patients included (median age 53 years, sex-ratio (M:F) 0.83, mean body mass index 27.3±5.36kg/m2), 32% of the test profiles were compatible with deconditioning, 20% with inappropriate hyperventilation (without gas exchange abnormalities), 18% with disorders of gas exchange, 13% with sub-maximal CPET, 9% with cardiovascular anomalies, and 8% with normal CPET. Of the patients with gas exchange abnormalities, the most common causes were bronchiectasis (6), emphysema (6), recent pneumonia (2), and diffuse interstitial pneumonitis (2). Ten of the patients with cardiovascular abnormalities had chronotropic insufficiencies, 5 had excessive tension responses, and 3 had disorders of rhythm or repolarisation. CONCLUSIONS: CPET may greatly facilitate the diagnosis of unexplained dyspnoea. More than 50% of the dyspnoea cases examined here were due to deconditioning or hyperventilation syndrome and would benefit from a simple pulmonary rehabilitation program.

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Cardiopulmonary exercise testing (CPET) is the most comprehensive investigation for understanding the mechanisms responsible for dyspnea in patients with chronic respiratory disease. The two observations presented here illustrate how CPET can contribute to the management of patients with interstitial lung diseases. A 60-year-old woman had been followed for 20 years for non-progressive pulmonary sarcoidosis, untreated for many years. CPET led to the diagnosis of an atrial septal defect. A 76-year-old man was treated for idiopathic pulmonary fibrosis. Before pulmonary rehabilitation, CPET was performed which revealed significant aortic valve stenosis, which had been to that point asymptomatic. In these two observations, CPET determined the presence of an associated disease, distinct from the interstitial lung disease.

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Pasteurellosis is an infection caused by inoculation usually through bites or scratches. Pasteurella multocida is involved in 50 to 60% of cases. Cats are the main vectors of the pathogen. Immunodepression increases the risk of systemic disease. We report a case of Pasteurella multocida pneumonia in an 81-year-old patient who had no cutaneous portal of entry. The patient had a past medical history of rectal neoplasia and prostate neoplasia treated with brachytherapy and hormonal therapy respectively. He had an environmental risk factor (the presence of a cat at home). The diagnosis was confirmed by repeated blood cultures. Antimicrobial therapy resulted in clinical, biological and radiological improvement. This case report raises the question of a possible pathogenesis different from the commonly described "inoculation".

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The purpose of this study was to test the capacity of the ectomycorrhizal (ECM) fungus, Scleroderma bermudense, to alleviate saline stress in seagrape (Coccoloba uvifera L.) seedlings. Plants were grown over a range (0, 200, 350 and 500 mM) of NaCl levels for 12 weeks, after 4 weeks of non-saline pre-treatment under greenhouse conditions. Growth and mineral nutrition of the seagrape seedlings were stimulated by S. bermudense regardless of salt stress. Although ECM colonization was reduced with increasing NaCl levels, ECM dependency of seagrape seedlings increased. Tissues of ECM plants had significantly increased concentrations of P and K but lower Na and Cl concentrations than those of non-ECM plants. Higher K concentrations in the leaves of ECM plants suggested a higher osmoregulating capacity of these plants. Moreover, the water status of ECM plants was improved despite their higher evaporative leaf surface. The results suggest that the reduction in Na and Cl uptake together with a concomitant increase in P and K absorption and a higher water status in ECM plants may be important salt-alleviating mechanisms for seagrape seedlings growing in saline soils.

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Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 micromol/L) than in the sensitive (0.2-0.25 micromol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC(50) for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL.

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CD40 ligand (CD40L)/CD40 interactions play a central role in T-cell-dependent B-cell activation as previously shown by in vitro studies, the phenotype of CD40L knockout mice and the defective expression of CD40L in patients who have X-linked immunodeficiency with hyper-IgM. The distribution of CD40 in cells other than of myeloid and lymphoid lineages has suggested additional functions for this receptor/ligand couple. Here we show that CD40L stimulates myelopoiesis with a noticeable effect on megakaryocytopoiesis in cocultures of hematopoietic progenitor cells and bone marrow stromal cells. These results suggest a mechanism by which T-cell or platelet-associated or soluble CD40L may regulate myelopoiesis. (Blood. 2000;95:3758-3764)

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An increasing number of methods are being described to detect apoptotic cells. However, attempts to detect apoptotic cells in clinical samples are rarely successful. A hypothesis is that apoptotic cells are cleared from the circulation by phagocytosis before they become detectable by conventional morphological or cytometric methods. Using LR73 adhering cells as phagocytes in a model of in vitro phagocytosis, we found that phagocytosis of daunorubicin (DNR)-treated U937, HL60, or K562 leukemia cell lines occurred prior to phosphatidylserine externalization, DNA hydrolysis, chromatin condensation, nuclear fragmentation, or mitochondrial potential alteration. Moreover DNR-treated K562 cells were eliminated by phagocytes while apoptosis was never observed by any of the above methods. By contrast, using a fluorometric batch analysis assay to detect caspase activity in ceramide- or DNR-treated cells (fluorogenic substrate for caspase), we found that caspase activity increased in apoptosis-committed cells before they were detected by flow cytometry or recognized by phagocytes. Similarly a caspase activity increase was detected in circulating mononuclear cells of luekemic patients 15 h after the beginning of anthracyclin treatment. We suggest that recent findings on enzymatic events (caspase activation) occurring in the early events of apoptosis must now allow the development of new markers for apoptosis, irrespective of the morphological features or internucleosomal fragmentation which are late events in apoptosis.

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In order to prevent the occurrence of major hypothermia during liver transplantation, with its deleterious effects on intraoperative cardiovascular activity and on postoperative graft functioning, this study evaluated the benefit of an oesophageal rewarmer, used during surgery, in addition to the usual methods of warming (OR temperature at 22 degrees C, rewarming of fluids and blood, heating mattress, heat and moisture exchanger). We compared 10 patients with an oesophageal rewarmer (OeR group) to 10 patients without (Control group). The anaesthetic procedure was similar in all cases. Rectal (RT) and pulmonary artery (PT) temperatures were recorded during the three phases of surgery (pre-anhepatic, anhepatic, postanhepatic phase) and their time course was analysed with non-parametric tests. The two groups were comparable with regard to duration of surgery, blood and fluid requirements and veno-venous bypass flow rate. The RT decreased similarly in both groups, but was significantly higher in the OeR group at peritoneum closure (P < 0.01). The PT was higher in the OeR group after onset of venous shunting (P < 0.05) and during the third phase of surgery (P < 0.01). Three incidents (one leakage and two herniations of the latex tube) occurred, without detrimental effects on the patients. It is concluded that the oesophageal heat exchanger allows better rewarming after revascularization of the graft, but is unable to prevent cardiac hypothermia at unclamping.

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Allogeneic immunocompetent T cells injected into chicken embryos induce a graft-versus-host reaction (GVHR) whose most prominent manifestation is splenic hyperplasia. The highly inbred CC and CB strains of chickens used here are, respectively, homozygous for the B4 or B12 MHC haplotypes. By means of a panel of immunological reagents, including alloantisera and monoclonal antibodies against public domains of the T-cell receptor, CD4, CD8, and the inducible interleukin-2-receptor light chain (CD25), it is shown that the bulk of cells in the enlarged spleen are of host origin and do not express markers typical of mature T or B lymphocytes. Among recipient splenocytes, the quantitatively most important population consists of TCR alpha beta-TCR gamma delta- CD4-CD8+CD25+ (TCR0) lymphocytes. Donor cells encountered in the spleen prevalently exhibit a TCR alpha beta+CD4+CD8-CD25+ phenotype and proliferate in vivo. The data demonstrate that nonspecific host and potentially specific donor-derived cellular elements contribute to splenomegaly.

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Using histocompatible chicken strains B14 and B19, we demonstrate that the capacity to induce a GVH-R in an embryo could be induced precociously by the reaction itself. While naive chickens display this capacity around 3 to 4 weeks posthatching, embryos engrafted with adult allogeneic cells at E13 or E8 became endowed with this capacity at E20 and E15, respectively. Furthermore, this acceleration could be obtained by serial transfer of splenic cells through a sequence of three embryos undergoing the GVH-R. The highest efficiency in transfer was realized by regularly alternating the MHC haplotype at each transfer. It is concluded that the original cells from the adult donor may be partially responsible for the transfer, but that cells from the successive embryos are also certainly involved. Thus, maturation of the embryonic immune system appears accelerated by a GVH-R.

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Three strains of MHC homozygous chickens were used to study the ontogeny of the GVH-R. It was found that this function of the immune system was acquired with a delay in animals raised in germ-free conditions. In our previous work, we had shown that, contrary to expectation, bursal cells were capable of mounting a GVH-R against embryos, and actually were particularly efficient in this regard when compared to spleen cells. The present experiments have disclosed that splenomegaly induction may be dissociated from the toxic effect that bursal cells also exert on recipient embryos.

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Allogeneic cells inoculated into immunologically immature chick embryos induce a Graft-Versus-Host Reaction (GVH-R), one of the manifestations of which is splenic enlargement. Splenomegaly varies with the composition of allogeneic cell suspensions, route of inoculation and age of recipient embryos at inoculation and autopsy. We have compared the splenomegaly induced by lymphoid cells from spleen or bursa of Fabricius with that induced by peripheral blood lymphocytes, after these cell preparations were either grafted on the chorioallantoic membrane (CAM) at 9 or 13 days or injected intravenously at 13 days. We confirm our previous findings that bursa cells grafted on the 9-day CAM induced splenomegaly as efficiently as other cell preparations. On the other hand, bursa cells did not mediate such an effect after they were injected at 13 days. On the whole, a hierarchy of decreasing efficiency is observed from PBL to spleen and finally to bursal cells. It appears that, as the recipient embryo ages, this hierarchy becomes more marked.

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Allogeneic bursal fragments or bursal cells (B 14 or B 19), grafted on the chorioallantois, induce splenomegaly in the recipient embryo (B 14 or B 19). This splenomegaly compares to that instigated by spleen cells. Syngeneic bursal grafts do not result in spleen enlargement. The reaction is thus caused by the MHC difference of the two lines used. We conclude that B cells may have a role in initiating the GVH-R.

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