bluuebunny/crossref_metadata_2025 huggingface dataset:
IκB kinase 2 but not NF-κB–inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction
Authors: Andreakos Evangelos , Smith Clive , Monaco Claudia , Brennan Fionula M. , Foxwell Brian M. , Feldmann Marc
Published: January 2003

Although dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activation is central to that process, as overexpression of IκBα blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-κB–inducing components, NF-κB–inducing kinase (NIK), and IκB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell–derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)–induced NF-κB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity.
Distinguishable live erythroid and myeloid cells in β-globin ECFP x lysozyme EGFP mice
Authors: Heck Susanne , Ermakova Olga , Iwasaki Hiromi , Akashi Koichi , Sun Chiao-Wang , Ryan Thomas M. , Townes Tim , Graf Thomas
Published: January 2003

We previously described a mouse line that contains green myelomonocytic cells due to the knock-in of enhanced green fluorescence protein (EGFP) into the lysozyme M gene.1 We have now created a transgenic line with fluorescent erythroid cells using a β-globin locus control region driving the enhanced cyan fluorescence protein (ECFP) gene. These mice exhibit cyan fluorescent cells specifically in the erythroid compartment and in megakaryocyte-erythroid progenitors. Crossing the animals with lysozyme EGFP mice yielded a line in which live erythroid and myeloid cells can readily be distinguished by fluorescence microscopy and by fluorescence-activated cell-sorter scanner. This cross allowed unambiguous identification of unstained mixed erythroid-myeloid colonies for the first time. The new mouse lines should become useful tools to dissect the branching between erythroid and myelomonocytic cells during in vitro differentiation of definitive multipotent progenitors.
LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3
Authors: Senga Takeshi , Iwamoto Shotaro , Yoshida Tsunehiko , Yokota Takashi , Adachi Koichi , Azuma Eiichi , Hamaguchi Michinari , Iwamoto Takashi
Published: January 2003

G-protein–coupled receptors (GPCRs) transduce the signal of a wide variety of chemokines, cytokines, neurotransmitters, hormones, odorants, and others to regulate the biologic homeostasis, including hematopoiesis and immunity. Here we report the molecular cloning of leukocyte-specific STAT-induced GPCR (LSSIG), which is a novel murine orphan GPCR with the highest homology to human GPR43. The mRNA expression of LSSIG was clearly induced in M1 leukemia cells during the leukemia inhibitory factor (LIF)–induced differentiation to macrophages, and the induction was evidently signal transducers and activators of transcription 3 (STAT3)–dependent. GPR43 expression was also strongly induced in HL-60 and U937 leukemia cells during the differentiation to monocytes. Further analysis showed that the expression of both LSSIG and GPR43 is highly restricted in hematopoietic tissues. Cytokine-stimulation induced LSSIG and GPR43 in bone marrow cells, and monocytes and neutrophils, respectively. These results suggest that LSSIG and GPR43 might play pivotal roles in differentiation and immune response of monocytes and granulocytes.
Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies
Authors: Wang Zhiqing , Zhang Yana , Liu Haichao , Salati Emanuela , Chiriva-Internati Maurizio , Lim Seah H.
Published: January 2003

Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription–polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation betweenSPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.
IL-15 enhances survival and function of HIV-specific CD8+ T cells
Authors: Mueller Yvonne M. , Bojczuk Paul M. , Halstead E. Scott , Kim Alfred H. J. , Witek James , Altman John D. , Katsikis Peter D.
Published: January 2003

HIV-specific CD8+ T cells are prone to undergo apoptosis, and this may affect their ability to control HIV infection. Because CD8-mediated immune responses play a key role in controlling HIV infection, enhancing the survival and effector function of HIV-specific CD8+ T cells may augment their ability to control HIV virus. We show here that interleukin 15 (IL-15) potently inhibits spontaneous and CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. IL-15 inhibits apoptosis in both CD45RA−CD62L− and CD45RA+CD62L− effector memory subpopulations of these cells. Furthermore, IL-15 greatly enhances the survival of HIV-specific CD8+ T cells in long-term cultures. Finally, IL-15 directly enhances activation, interferon γ (IFNγ) production, and direct ex vivo cytotoxicity of HIV-specific CD8+ T cells. Thus, IL-15 potently enhances the survival and effector function of HIV-specific CD8+ T cells and, therefore, may prove useful in augmenting the antiviral function of these cells.
A CD45 minigene restores regulated isoform expression and immune function in CD45-deficient mice: therapeutic implications for human CD45-null severe combined immunodeficiency
Authors: Virts Elizabeth L. , Diago Oscar , Raschke William C.
Published: January 2003

Transgenic mice have been generated that carry a CD45 minigene under control of the human leukocyte function-associated antigen (LFA-1, CD11a) promoter. CD45-null mice carrying the transgene exhibit the lymphocyte lineage-specific isoform expression patterns of wild-type mice. Furthermore, these mice have normal thymocyte development and peripheral T-cell numbers. The proliferative ability of T cells in response to mitogens and antigen also is regained, as is B-cell responsiveness to anti-IgM. The antibody response to antigen is also restored and is similar to that of normal mice. Therefore, introduction of a functional CD45 minigene is sufficient to overcome the principal severe combined immunodeficiency (SCID)–associated defects and represents a potential route to a gene therapy for human CD45-deficent SCID.
Efficacy of 2-chlorodeoxyadenosine in refractory factor VIII inhibitors in persons without hemophilia
Authors: Sallah Sabah , Wan Jim Y.
Published: January 2003

The authors examined the efficacy of 2-chlorodeoxyadenosine (2-CDA) in the treatment of refractory inhibitors to factor VIII in persons without hemophilia. The drug was administered to 6 patients at a dose of 0.1 mg/kg as a 24-hour continuous infusion for a total of 7 days each cycle. An average of 3 immunosuppressive regimens per patient had been administered prior to enrollment in this study. The median inhibitor titer against human and porcine factor VIII before treatment with 2-CDA was 31 Bethesda units (BUs) and 9 BU, respectively. The median inhibitor titer against human and porcine factor VIII after treatment was 3.5 BU and 1.5 BU, respectively. The median time to reach nadir inhibitor titer in this study was 137 days, whereas the median time to reach a 50% increase in factor VIII was 117 days. No major toxicity was observed in any patient in this study. Patients with acquired inhibitors to factor VIII refractory to conventional immunosuppressive therapy may respond favorably to 2-CDA.
MIP-1α and MIP-1β differentially mediate mucosal and systemic adaptive immunity
Authors: Lillard James W. , Singh Udai P. , Boyaka Prosper N. , Singh Shailesh , Taub Dennis D. , McGhee Jerry R.
Published: January 2003

Macrophage inflammatory protein-1α (MIP-1α) and MIP-1β are distinct but highly homologous CC chemokines produced by a variety of host cells in response to various external stimuli and share affinity for CCR5. To better elucidate the role of these CC chemokines in adaptive immunity, we have characterized the affects of MIP-1α and MIP-1β on cellular and humoral immune responses. MIP-1α stimulated strong antigen (Ag)–specific serum immunoglobulin G (IgG) and IgM responses, while MIP-1β promoted lower IgG and IgM but higher serum IgA and IgE antibody (Ab) responses. MIP-1α elevated Ag-specific IgG1 and IgG2b followed by IgG2a and IgG3 subclass responses, while MIP-1β only stimulated IgG1 and IgG2b subclasses. Correspondingly, MIP-1β produced higher titers of Ag-specific mucosal secretory IgA Ab levels when compared with MIP-1α. Splenic T cells from MIP-1α– or MIP-1β–treated mice displayed higher Ag-specific Th1 (interferon-γ [IFN-γ]) as well as selective Th2 (interleukin-5 [IL-5] and IL-6) cytokine responses than did T cells from control groups. Interestingly, mucosally derived T cells from MIP-1β–treated mice displayed higher levels of IL-4 and IL-6 compared with MIP-1α–treated mice. However, MIP-1α effectively enhanced Ag-specific cell-mediated immune responses. In correlation with their selective effects on humoral and cellular immune responses, these chemokines also differentially attract CD4+ versus CD8+ T cells and modulate CD40, CD80, and CD86 expressed by B220+ cells as well as CD28, 4-1BB, and gp39 expression by CD4+ and CD8+ T cells in a dose-dependent fashion. Taken together, these studies suggest that these CC chemokines differentially enhance mucosal and serum humoral as well as cellular immune responses.
A site involving the “hybrid” and PSI homology domains of GPIIIa (β3-integrin subunit) is a common target for antibodies associated with quinine-induced immune thrombocytopenia
Authors: Peterson Julie A. , Nyree Contessa E. , Newman Peter J. , Aster Richard H.
Published: January 2003

Drug-dependent antibodies (DDAbs) can cause the precipitous destruction of platelets if a patient is exposed to the drug for which the antibodies are specific. The molecular character of the epitopes recognized is poorly understood, and the mechanism by which drugs promote tight binding of these antibodies to platelet glycoproteins without linking covalently to protein or antibody is not yet known. We studied a group of quinine-dependent antibodies that react with human glycoprotein IIIa (GPIIIa; β3-integrin subunit) but fail to recognize rat GPIIIa, despite close homology between the 2 proteins. By characterizing reactions of these antibodies with human/rat GPIIIa chimeras and selected GPIIIa mutants, we found that each of 3 quinine-dependent antibodies requires a 17-amino acid sequence in the newly recognized “hybrid” and PSI homology domains of GPIIIa for drug-dependent binding. Disulfide bonds are required to stabilize the target epitope. Monoclonal antibody AP3, which blocks the binding of these DDAbs to GPIIIa, was found to require a more limited stretch of the same peptide for its reaction with the glycoprotein. The findings suggest this region of GPIIIa may be a favored target for quinine-dependent antibodies and may provide a basis for further studies to elucidate the molecular basis of glycoprotein–drug–antibody interaction.
Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive
Authors: Bosga-Bouwer Anneke G. , van Imhoff Gustaaf W. , Boonstra Ronald , van der Veen Anneke , Haralambieva Eugenia , van den Berg Anke , de Jong Bauke , Krause Vanessa , Palmer Martin C. , Coupland Robert , Kluin Philip M. , van den Berg Eva , Poppema Sibrand
Published: January 2003

Chromosomal translocations involving t(14;18)(q32;q21) and the chromosome 3q27 region are common in B-cell non-Hodgkin lymphoma of germinal center cell origin. Grade 3B follicular lymphoma (FL), consisting almost exclusively of centroblasts, is a distinct subgroup of follicular lymphomas that has more in common clinically with the aggressive diffuse large B-cell lymphomas than with their indolent FL grade 1 and 2 counterparts. We studied the cytogenetic and molecular genetic aberrations by classic cytogenetics, polymerase chain reaction, Southern blot hybridization, and fluorescence in situ hybridization, with special emphasis on t(14;18), affecting bcl-2, and 3q27 rearrangement, affecting bcl-6, in 32 cases of FL grade 3B. Three distinctive subgroups were identified based upon the existence of breakpoint 3q27, a translocation t(14;18), or the absence of both. Group I involved a t(14;18) and no 3q27 aberrations (n = 13); group II was without a t(14;18) and without 3q27 aberrations (n = 9), but had other cytogenetic aberrations; and group III was without a t(14;18) but with aberrations involving 3q27 (n = 10). None of the FL grade 3B cases harbored both a t(14;18) and 3q27 aberration. These results, in particular the finding of a mutual exclusiveness of bcl-2 and bcl-6 rearrangement, indicate at least 3 different pathways of oncogenesis in FL grade 3B. FL grade 3B with bcl-2 rearrangement probably is part of the same entity as the other follicular lymphomas (1, 2, 3A), whereas the cases with 3q27 abnormalities or other unrelated translocations are more closely related to the majority of diffuse large-cell lymphomas of germinal center cell origin.
Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia
Authors: Fuhler Gwenny M. , Drayer A. Lyndsay , Vellenga Edo
Published: January 2003

Neutrophils from patients with myelodysplastic syndrome (MDS) show a disturbed differentiation pattern and are generally dysfunctional. To study these defects in more detail, we investigated reactive-oxygen species (ROS) production and F-actin polymerization in neutrophils from MDS patients and healthy controls and the involvement of N-formyl-L-methionyl-L-lucyl-L-phenylaline (fMLP) and granulocyte macrophage–colony-stimulating factor (GM-CSF)–stimulated signal transduction pathways. Following fMLP stimulation, similar levels of respiratory burst, F-actin polymerization, and activation of the small GTPase Rac2 were demonstrated in MDS and normal neutrophils. However, GM-CSF and G-CSF priming of ROS production were significantly decreased in MDS patients. We subsequently investigated the signal transduction pathways involved in ROS generation and demonstrated that fMLP-stimulated ROS production was inhibited by the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002, but not by the MAPK/ERK kinase (MEK) inhibitor U0126. In contrast, ROS production induced by fMLP stimulation of GM-CSF–primed cells was inhibited by LY294002 and U0126. This coincides with enhanced protein kinase B (PKB/Akt) phosphorylation that was PI3K dependent and enhanced extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation that was PI3K independent. We demonstrated higher protein levels of the PI3K subunit p110 in neutrophils from MDS patients and found that though the fMLP-induced phosphorylation of PKB/Akt and ERK1/2 could also be enhanced by pretreatment with GM-CSF in these patients, the degree and kinetics of PKB/Akt and ERK1/2 phosphorylation were significantly disturbed. These defects were observed despite a normal GM-CSF–induced signal transducer and activator of transcription 5 (STAT5) phosphorylation. Our results indicate that the reduced priming of neutrophil ROS production in MDS patients might be caused by a disturbed convergence of the fMLP and GM-CSF signaling routes.
Dynamics of GPIIb/IIIa-mediated platelet-platelet interactions in platelet adhesion/thrombus formation on collagen in vitro as revealed by videomicroscopy
Authors: Patel Dipti , Väänänen Heikki , Jiroušková Markéta , Hoffmann Thomas , Bodian Carol , Coller Barry S.
Published: January 2003

The conventional description of platelet interactions with collagen-coated surfaces in vitro, based on serial static measurements, is that platelets first adhere and spread to form a monolayer and then recruit additional layers of platelets. To obtain dynamic information, we studied gravity-driven platelet deposition in vitro on purified type 1 collagen by video phase-contrast microscopy at 22°C. With untreated human and wild-type mouse platelets, soon after the initial adhesion of a small number of “vanguard” platelets, “follower” platelets attached to the spread-out vanguard platelets. Follower platelets then adhered to and spread onto nearby collagen or over the vanguard platelets. Thus, thrombi formed as a concerted process rather than as sequential processes. Treatment of human platelets with monoclonal antibody (mAb) 7E3 (anti–GPIIb/IIIa (αIIbβ3) + αVβ3) or tirofiban (anti–GPIIb/IIIa) did not prevent platelet adhesion but nearly eliminated the deposition of follower platelets onto vanguard platelets and platelet thrombi. Similar results were obtained with Glanzmann thrombasthenia platelets. Wild-type mouse platelets in the presence of mAb 1B5 (anti–GPIIb/IIIa) and platelets from β3-null mice behaved like human platelets in the presence of 7E3 or tirofiban. Deposition patterns of untreated human and wild-type mouse platelets were consistent with random distributions under a Poisson model, but those obtained with 7E3- and tirofiban-treated human platelets, 1B5-treated mouse platelets, or β3-null platelets demonstrated a more uniform deposition than predicted. Thus, in this model system, absence or blockade of GPIIb/IIIa receptors interferes with thrombus formation and alters the pattern of platelet deposition.
Treatment of community-acquired lower respiratory tract infections in adults
Authors: Örtqvist Å.
Published: January 2003

Community-acquired lower respiratory tract infection (LRTI) is a common cause of acute illness in adults. The spectrum of disease ranges from a mild mucosal colonisation or infection, acute bronchitis or acute exacerbation of chronic bronchitis/chronic obstructive pulmonary disease (AE-CB/COPD), to an overwhelming parenchymal infection with the patient presenting with severe community-acquired pneumonia (CAP).

Although the great majority of LRTIs are self-limiting viral infections, CAP is most often a bacterial disease with a substantial mortality. Thus, antibiotic treatment is rarely indicated for acute bronchitis and is only indicated for the more severe cases of AE-CB/COPD, but it is nearly always indicated for CAP, for which a delay in treatment may increase the risk of a fatal outcome. It may be difficult to differentiate between a viral and a bacterial LRTI, or between bronchitis/AE-CB/COPD and CAP. This may be one reason why antibiotics are prescribed to more than two-thirds of patients with LRTIs in Europe and the USA. Considering the worldwide development of antibiotic resistance, this is not an acceptable situation.

Since an empirical approach is nearly always necessary in the management of LRTI, greater emphasis must be placed on the decision of whether or not to prescribe an antibiotic at all. This decision should be based on an assessment of the severity of the disease, including underlying risk factors, and on markers for bacterial/parenchymal/invasive LRTI. The choice of empirical therapy must be based on the same data together with epidemiological information. The choice of antibiotic must always coverStreptococcus pneumoniae, which remains the main pathogen of morbidity and mortality in CAP. In hospital, attempts should be made to obtain an aetiological diagnosis in order to be able to switch to a specific treatment or to evaluate a failure of empirical therapy.

Several guidelines for the management of community-acquired pneumonia have been published during the last 10 yrs. Some reports indicate that the implementation of such guidelines has resulted in lowered costs, length of stay in hospital and mortality. However, the results from these studies are not consistent and the evidence is still weak.
Tuberculosis therapy: past, present and future
Authors: Iseman M.D.
Published: January 2003

The major historical landmarks of tuberculosis (TB) therapy include: the discovery of effective medications (streptomycin and para-aminosalicylic acid) in 1944; the revelation of “triple therapy” (streptomycin, para-aminosalicylic acid and isoniazid) in 1952, which assured cure; recognition in the 1970s that isoniazid and rifampin could reduce the duration of treatment from 18 to 9 months; and the observation in the 1980s that adding pyrazinamide to these drugs allowed cures in only 6 months.

To combat noncompliance, intermittent regimens, twice or thrice weekly, have been proven to cure even far-advanced TB in as few as 62–78 encounters over 26 weeks.

However, these regimens are not sufficiently short or convenient to facilitate effective treatment in resource-poor countries. Therefore, drug-resistant strains have emerged to threaten TB control in various areas of the world, including India, China, Russia and the former Soviet Union. For these reasons, it is vital that new medications are developed to shorten the duration of therapy, increase the dosing interval of intermittent regimens and replace agents lost to resistance. Other special considerations include identifying optimal therapy for persons with acquired immune deficiency syndrome, particularly noting the problems of drug/drug interactions for those receiving antiretroviral treatment.

Finally, the Alchemist's Dream of tuberculosis should be pursued: modulating the immune response to shorten treatment and/or overcome drug resistance.
Comparative mycobacterial genomics as a tool for drug target and antigen discovery
Authors: Cole S.T.
Published: January 2003

Genomics and the associated downstream technologies are generating vast data sets that provide new opportunities for understanding and combating both infectious and genetic diseases in humans.

The genomic approach has been applied to tuberculosis, a major cause of transmissible morbidity and mortality, with notable success. Complete genome sequences are now available for three members of theMycobacterium tuberculosiscomplex and the related intracellular pathogenM. leprae.

Many of the predictions generatedin silicoby genomics have been validated through functional analysis, including studies of the transcriptome and proteome, and led to the identification of essential genes. Knowledge of the latter defines potential targets for new and existing drugs and their specificity can be assessed by comparative genomics with the host or other pathogens. Genomics is also furthering tuberculosis vaccine development by pinpointing potentially antigenic proteins as well as providing better diagnostic tools to detect infection.
Exacerbations of chronic obstructive pulmonary disease: when are bacteria important?
Authors: Miravitlles M.
Published: January 2003

The progressive course of chronic obstructive pulmonary disease (COPD) is often aggravated by exacerbations, the majority of them produced by bronchial infection. Frequent exacerbations have been demonstrated to have a negative impact on quality of life and pulmonary function in patients with COPD, particularly in active smokers. Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic lung disease.

Evidence indicates that the number of patients with pathogenic bacteria in respiratory secretions and the bronchial bacterial load increase during exacerbations. Furthermore, the local inflammatory response of the host parallels the increase in bacterial load. From these observations, it can be speculated that, for symptoms of acute exacerbation to appear, there must be a minimum bacterial load in the airways,i.e.a threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may vary from patient to patient owing to different modifying factors. Some of these factors may be the recognised risk factors for relapse, such as increasing age, impairment of lung function, comorbid conditions or frequent exacerbations in the past.

Relapse rates after ambulatory treatment of acute exacerbation of COPD may be as high as 20–25% of cases. Relapses are associated with significant mordibity and increased costs.

A number of unanswered questions remain regarding exacerbations of chronic obstructive pulmonary disease. These include the role of viral infection, the importance of residual bacterial colonisation and the impact of new antibiotics on the treatment of exacerbations.
Bacteriological evidence of antibiotic failure in pneumococcal lower respiratory tract infections
Authors: Klugman K.P.
Published: January 2003

The global pandemic of antimicrobial resistance, particularly in the pneumococcus, has had a major impact on the management of community-acquired pneumonia.

A number of prospective and retrospective studies have analysed the impact of penicillin resistance on clinical outcome in pneumonia. Pharmacodynamic principles predicting success when the antibiotic dose exceeds the minimum inhibitory concentration (MIC) for 40–50% of the dosing interval have proved remarkably accurate. There is no evidence of bacteriological failure of penicillins active against resistant strains. There is a single report of the failure of the less active agent, ticarcillin. High dose oral and intravenous amoxicillin should treat strains with MICs ≤4 µg·mL−1, as should high doses of intravenous penicillin, ceftriaxone and cefotaxime. Strains of pneumococci resistant to these agents at an MIC ≥8 µg·mL−1are rare at the present time. Most other cephalosporins are less active and should not be used empirically for drug-resistantStreptococcus pneumoniae. Bacteriological failures of cefazolin, cefuroxime and ceftazidime have been reported.

There is increasing evidence of bacteriologically confirmed macrolide failure of pneumonia therapy at MICs ≥4 µg·mL−1. The molecular basis of the resistance is irrelevant if the MIC is in that range or higher. Double mutants in theparCandgyrAgenes lead to fluoroquinolone resistance that has been found to cause bacteriological failure of the fluoroquinolones, particularly levofloxacin and ciprofloxacin, in the management of pneumonia and exacerbations of chronic bronchitis. Two mutations in these genes can greatly increase the MICs of all the marketed fluoroquinolones, and raise the prospect of failure of therapy even with the more active ones. However, demonstration of bacteriological failure of gatifloxacin or moxifloxicin has not yet been reported.

High dose, active β‐lactams or fluoroquinolones with enhanced activity against Gram positive pathogens remain the drugs of choice for the management of community-acquired pneumonia caused by the drug-resistant pneumococcus.
Pyogenic bacterial lower respiratory tract infection in human immunodeficiency virus-infected patients
Authors: Mayaud C. , Parrot A. , Cadranel J.
Published: January 2003

In human immunodeficiency virus (HIV)-infected patients, bacterial lower respiratory tract infections are the most frequent respiratory diseases. They are frequently the first clinical manifestation of HIV infection.

The incidence and severity of bacterial lower respiratory tract infections increase with the degree of immunosuppression. At the acquired immune deficiency syndrome (AIDS) stage, the responsible bacteria and clinical presentation may be atypical. Bacterial pneumonia may be fatal, particularly in AIDS patients, and its occurrence is predictive of a reduced survival time.

Pneumococcal vaccine is recommended in patients with a CD4 T‐lymphocyte count of >200 cells·mm−3and cotrimoxazole (trimethoprim/sulfamethoxazole) in patients with a CD4 T‐lymphocyte count of <200 cells·mm−3. Unfortunately, such prophylaxis remains insufficiently prescribed and its protective effect is limited.

Highly active antiretroviral treatment has dramatically reduced the incidence of lower respiratory tract infection due toPseudomonasaeruginosaand opportunistic bacteria. In contrast, successful highly active antiretroviral therapy slightly decreased the risk of bacterial pneumonia due to usual bacteria, even in patients on successful highly active antiretroviral therapy.
Molecular epidemiology of tuberculosis
Authors: Burgos M.V. , Pym A.S.
Published: January 2003

Despite the almost 50 yrs since the introduction of curative antituberculosis drugs,Mycobacterium tuberculosiscontinues to exert an enormous toll on world health, and tuberculosis remains the world's leading cause of death due to a single infectious agent. This has stimulated research efforts into finding new tools to tackle the continuing tuberculosis pandemic.

One of the few successes to date has been the development of a new discipline, molecular epidemiology. This has added a further dimension to the classical epidemiology of tuberculosis and enhanced understanding of howM. tuberculosiscontinues to be successfully transmitted within populations. In the process, inadequacies in tuberculosis control programmes have been identified, helping accumulate resources for their improvement.

Other technologies, based on knowledge of the complete genome sequence ofM. tuberculosis, which will provide newer tools for probing the epidemiology of tuberculosis, are now emerging. In spite of these advances, tuberculosis continues to remain a devastating infectious disease, disproportionately impacting on the world's poorest countries.

The future challenge for molecular epidemiology is to provide better understanding of the transmission dynamics of tuberculosis in these settings and to stimulate the implementation of control measures on a more global scale.
Strategies against multidrug-resistant tuberculosis
Authors: Loddenkemper R. , Sagebiel D. , Brendel A.
Published: January 2003

The rise of multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis showing resistance to at least isoniazid and rifampicin, is a serious threat to tuberculosis control in some high prevalence countries and may have some impact on low prevalence regions as well.

The World Health Organization estimates that 50 million people worldwide are infected with MDR-TB, and that, in the year 2000, 273,000 (3.1%) MDR-TB cases were among the 8.7 million new tuberculosis cases. In 1998, the highest MDR-TB rates among new cases and the highest combined (new and previously treated cases) MDR-TB rates were found in Estonia (14.1 and 18.1%), Henan province in China (10.8 and 15.1%), Latvia (9.0 and 12.0%), and Ivanovo Oblast (9.0 and 12.3%) and Tomsk Oblast (6.5 and 13.7%) in the Russian Federation. The risk factors for MDR-TB are previous treatment or relapse, originating from “hot spot” areas, a history of imprisonment, homelessness and possibly also human immunodeficiency virus.

The treatment of multidrug-resistant tuberculosis is difficult due to side-effects and a treatment duration of up to 3 yrs, which is expensive and often unsuccessful. Therefore, strategies for the treatment and prevention of multidrug-resistant tuberculosis are urgently required. This requires functioning tuberculosis control programmes (directly observed treatment short course), and, in some high prevalence countries, the introduction of second-line drugs on the basis of appropriate susceptibility testing (directly observed treatment short course-Plus). Only the future will show whether this “ticking time bomb” can be defused.
Community-acquired pneumonia in Europe: causative pathogens and resistance patterns
Authors: Woodhead M.
Published: January 2003

Community-acquired pneumonia (CAP) is a common condition affecting about 1/1,000 of the adult population per year. It occurs when bacteria enter the alveolar spaces of the lung initiating an inflammatory response which leads to the clinical features of cough, sputum production, breathlessness and sometimes chest pain and haemoptysis.

At the end of the last century the causal relationship between bacteria and pneumonia was established and many of the early discoveries about the causes of CAP were made in Europe. Some 41 different prospective studies have established that ∼10 different microbial pathogens regularly cause CAP with occasional cases due to other rarer causes. The frequency of these organisms in Europe is similar in most countries, but there are some geographic differences. Differences in frequency are also apparent according to illness severity. It is generally recognised thatStreptococcus pneumoniaeis the most important causal bacterium in all countries.

A relatively recent development has been the appearance and spread, in some of the common causative bacteria, of resistance to commonly used antibiotics to which they were once sensitive. The frequency of such resistance does vary markedly between European countries.

However, published data is often difficult to interpret. The reasons for this are that the frequency of resistance varies according to the age of the patient, the site of the sample, the clinical diagnosis, the use of prior antibiotics and the influence of special groupse.g.those with cystic fibrosis. The impact ofin vitroantibiotic resistance on clinical outcome is still poorly understood, but recent studies are helping to clarify this issue and will be discussed.
The birth and development of the forced expiratory manoeuvre: a tribute to Robert Tiffeneau (1910-1961)
Authors: Yernault JC
Published: January 2003

The forced expiratory manoeuvre was first described by Tiffeneau and Pinelli working in Paris (France), in December 1947, who proposed measurement of the "pulmonary capacity usable on exercise" (capacite pulmonaire utilisable a l'effort) (CPUE), the maximal volume expelled in one second after a deep inspiration. It was intended to replace the measurement of the maximum breathing capacity, a difficult and tiring manoeuvre. A similar approach was later followed in the USA by Gaensler, who proposed the "timed vital capacity" in 1951. The name CPUE was changed to "volume expiratoire maximum seconde" (VEMS) by a group of European experts, who met in Paris on February 13, 1954, whereas the expression "forced expiratory volume" was adopted by the British Thoracic Society in 1957. Despite numerous attempts to examine the forced expiration in a different manner, the VEMS and/or forced expiratory volume in one second (FEV1) remain, after 50 yrs the main variables used daily by the respiratory physician. Although primarily a pharmacologist, Robert Tiffeneau (1910-1961) undoubtedly deserves to figure among the pioneers of respiratory medicine.
Pleural disease during treatment with bromocriptine in patients previously exposed to asbestos
Authors: Hillerdal G , Lee J , Blomkvist A , Rask-Andersen A , Uddenfeldt M , Koyi H , Rasmussen E
Published: January 2003

Bromocriptine, which is used in the treatment of Parkinson's disease, can cause adverse pleuropulmonary reactions. Exposure to asbestos can result in similar lesions. Fifteen patients with former exposure to asbestos, who developed pleural fibrosis after treatment with bromocriptine, were observed independently in Sweden (11 patients) and Australia (four patients). The patients complained of malaise, often associated with weight loss, dyspnoea, and a disturbing cough. Laboratory values included increased erythrocyte sedimentation rate and a low haemoglobin level. Lung function tests showed a restrictive lung function defect. Chest radiographs showed bilateral pleural fibrosis, with small amounts of fluid in some cases. Soon after bromocriptine was withdrawn, the patients improved clinically, and the laboratory values returned to normal. However, in most cases, pleural fibrosis and a restrictive lung function defect persisted to some extent. In conclusion, in patients who develop pleuropulmonary fibrosis whilst being treated with bromocriptine, former exposure to asbestos should be investigated. Conversely, when pleural changes develop in a patient on bromocriptine and with prior exposure to asbestos, the possible causative role of the drug should be discussed. Special follow-up may be indicated when bromocriptine is planned in a patient with previous asbestos exposure, and if symptoms or signs of pleural fibrosis develop, bromocriptine withdrawal should be considered.
The CD4/CD8 ratio in BAL fluid is highly variable in sarcoidosis
Authors: Kantrow SP , Meyer KC , Kidd P , Raghu G
Published: January 2003

Patients with pulmonary sarcoidosis frequently have increased numbers of lymphocytes and a high ratio of CD4+ to CD8+ T-lymphocytes (CD4/CD8 ratio) in bronchoalveolar lavage (BAL) fluid. Some investigators have suggested that these parameters can be used to distinguish sarcoidosis from other types of interstitial lung disease with a high degree of reliability. However, we hypothesized that the BAL CD4/CD8 ratio measured during the initial diagnostic evaluation of patients with biopsy-proven sarcoidosis is highly variable. BAL lymphocytes were analysed via flow cytometry to determine the CD4/CD8 ratio in a population of 86 patients with histological and clinical evidence of sarcoidosis, who underwent BAL as part of their initial diagnostic evaluation. In these patients, the CD4/CD8 ratio ranged 0.5-37.3, with a median value of 3.35 (mean 6.49). The CD4/CD8 ratio was greater than 4 in only 36 (42%) subjects. Ten patients (12%) had a CD4/CD8 ratio less than 1. The distribution of CD4/CD8 ratios was similar in the presence or absence of BAL lymphocytosis. In conclusion, the CD4/CD8 ratio in bronchoalveolar lavage fluid is highly variable in biopsy-proven sarcoidosis. Bronchoalveolar lavage lymphocyte subset determination is a diagnostic test with low sensitivity for this disease.
Bronchoscopic diagnosis of sarcoidosis
Authors: Leonard C , Tormey VJ , O'Keane C , Burke CM
Published: January 2003

Transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA) of mediastinal lymph nodes and bronchoalveolar lavage (BAL) are routinely performed at fibreoptic bronchoscopy. Up to the present time, no data have been available on the efficacy of performing all three of these procedures simultaneously in the bronchoscopic work-up of sarcoidosis. A prospective study was undertaken to compare the diagnostic yield from TBLB, TBNA and BAL in patients presenting with clinical and radiological features typical of sarcoidosis. Thirteen consecutive patients with clinical and radiological features consistent with stage I and II sarcoidosis underwent bronchoscopy with TBLB, TBNA and BAL. Noncaseating granulomata (stain and culture negative for tuberculosis bacilli and fungi) were found in seven of the 13 patients by TBLB, and in six of the 13 patients by TBNA (of which four patients had negative TBLB). Eight of the 13 patients had classical "sarcoid" BAL findings, i.e. >12% lymphocytes, and high CD4+:CD8+ lymphocyte ratio. Combining TBLB, TBNA and BAL gave a diagnostic sensitivity of 100% (12 out of 12 patients) for sarcoidosis. The remaining patient had nondiagnostic bronchoscopic studies and mediastinoscopy biopsy showed a non-Hodgkin's lymphoma. Our data suggest that performing simultaneous transbronchial lung biopsy, transbronchial needle aspiration and bronchoalveolar lavage produces optimal results in the diagnosis of sarcoidosis.
Propeptide levels of type III and type I procollagen in the serum and bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis
Authors: Lammi L , Kinnula V , Lahde S , Risteli J , Paakko P , Lakari E , Ryhanen L
Published: January 2003

No single test is available to reliably assess the activity or prognosis of pulmonary sarcoidosis. In this study, we have evaluated two procollagen markers, aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) in serum and bronchoalveolar lavage fluid (BALF) and compared them to other disease markers of pulmonary sarcoidosis, such as serum level of angiotensin converting enzyme (S-ACE) or serum interleukin-2 receptor (S-IL-2R). Bronchoalveolar lavage was performed in 40 sarcoidosis patients without (stages 0-I) and 20 patients with lung parenchymal involvement (stages II-III), as well as in 17 controls. Serum (S)- and BALF-PIIINP and PICP, S-ACE, S-IL-2R, BALF-albumin, BALF-lymphocytes and mast cells were determined in these patients. BALF-PIIINP was clearly and S-PIIINP slightly elevated in sarcoidosis compared to the controls. Similarly BALF-PICP, but not S-PICP, was significantly higher in sarcoidosis. BALF-PIIINP, but not BALF-PICP correlated with S-ACE and S-IL-2R levels. Patients with lung parenchymal disease had higher S-ACE and BALF-PIIINP, but neither S-IL-2R, S-PIIINP nor S- or BALF-PICP were elevated. S-PIIINP and S-IL-2R but not S-ACE were higher in symptomatic than nonsymptomatic patients. Symptomatic patients with parenchymal disease had elevated BALF-PIIINP whereas in the symptomatic nonparenchymal group S-PIIINP was elevated. In conclusion, this is the first study to evaluate carboxyterminal propeptide of type I procollagen in sarcoidosis and showed elevated levels in bronchoalveolar lavage fluid. In contrast to the levels of bronchoalveolar lavage fluid aminoterminal propeptide of type III procollagen, levels of carboxyterminal propeptide of type I procollagen did not correlate with serum level of angiotensin converting enzyme and serum interleukin-2 receptor levels, suggesting that carboxyterminal propeptide of type I procollagen may be less suitable disease marker in sarcoidosis than aminoterminal propeptide of type III procollagen. However, the role of carboxyterminal propeptide of type I procollagen as an indicator of fibrogenesis must be further studied.
Proteoglycans in granulomatous lung diseases
Authors: Bensadoun ES , Burke AK , Hogg JC , Roberts CR
Published: January 2003

In nongranulomatous fibrotic lung conditions, we have recently shown that early collagen synthesis by myofibroblasts occurs in an extracellular matrix rich in the proteoglycan versican. We hypothesized that versican is associated with the process of collagen synthesis resulting from chronic inflammation. In this study, we examined the localization of proteoglycans and collagen in the granulomatous lung conditions, sarcoidosis, extrinsic allergic alveolitis (EAA) and tuberculosis (TB). Tissue from individuals with sarcoidosis (n=6), EAA (n=4) and TB (n=2) was examined for glycosaminoglycans and collagen using histochemistry, and for versican, decorin, biglycan, hyaluronan, type I procollagen and alpha-smooth muscle actin using immunohistochemistry. The results showed that in sarcoidosis, EAA and TB, the rim of connective tissue surrounding granulomas contained glycosaminoglycans and collagen, and that glycosaminoglycan staining corresponded to localization of versican. Versican-rich zones contained myofibroblasts that stained intracellularly for type I procollagen. Hyaluronan was found diffusely throughout the matrix. Decorin was localized intracellularly in the epithelioid cells of granulomas and some myofibroblasts. We conclude that the deposition of versican is specific to the early remodelling process in both granulomatous and nongranulomatous lung diseases. In both forms of lung fibrosis, regardless of the nature of the driving inflammatory process, collagen synthesis takes place in a versican-rich provisional matrix. These results suggest that versican may influence the progression of the repair process following many different types of lung injury.
Efficacy of transbronchial biopsy in pulmonary vaculitides
Authors: Schnabel A , Holl-Ulrich K , Dalhoff K , Reuter M , Gross WL
Published: January 2003

This study was performed to determine the value of transbronchial biopsy (TBB) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides and mild-to-moderate pulmonary involvement. Included in the study were 19 patients with Wegener's granulomatosis (WG) and six patients with Churg-Strauss syndrome (CSS) with evidence of active pulmonary disease but without gross parenchymal lesions accessible by radiologically guided biopsy. All of the patients had undergone staging examinations which included TBB taken from peripheral lung tissue and from any focal tracheobronchial lesions. Any suspicious lesion in the upper respiratory tract was biopsied by an otolaryngologist and the number of positive biopsies was compared with that of TBB. In the WG patients, only two out of 17 biopsies of alveolar tissue yielded histopathological findings supporting the diagnosis of WG. In five WG patients, ulcerative or exophytic airway lesions were found whose histopathologies were invariably positive. Otolaryngological examination revealed abnormal findings in 19 WG patients and biopsies from these sites yielded positive results in 13 instances. In CSS, TBB produced a diagnostically helpful histopathology in four of six cases and biopsies from the upper respiratory tract were positive in five out of six cases. We conclude that transbronchial biopsies of alveolar tissue are seldom positive in Wegener's granulomatosis patients with mild-to-moderate pulmonary disease unless they are taken from grossly abnormal lung areas. Conversely, ulcerative, exophytic or stenotic tracheobronchial lesions had a high rate of positive findings. These results further suggest that the upper rather than the lower respiratory tract should be the biopsy site of first choice in Wegener's granulomatosis. In Churg-Strauss syndrome, the upper and lower respiratory tract seem to yield a roughly equal number of positive biopsies.