Host immune response in immunodeficient mice against infection with Cryptosporidium parvum

Immunantwort von immundefizienten Mäusen gegenüber Infektionen mit Cryptosporidium parvum. Cryptosporidium parvum ist ein intrazellulärer, protozoischer Krankheitserreger, der im immunkompromittierten Wirt zu lebensbedrohender Enteritis führen kann. CD4+ T-Zellen und Interferon (IFN)-γ spielen wesentliche Rollen bei der Wirtsimmunantwort gegen die Infektion. Dennoch sind die Effektormechanismen, die zur Resistenz führen nur wenig verstanden. In dieser Studie wurde die Immunantwort von IFN-γ- und Interleukin (IL)-12-Defektmäusen parallel zu Wildtypmäusen analysiert. Die Ergebnisse identifizierten IFN-γ als Schlüsselzytokin bei der natürlichen und erworbenen Immunität während der Erst- und Folgeinfektion mit C. parvum. Tumornekrosefaktor (TNF)-α ist möglicherweise ein Induktor der frühen IFN-γ-Antwort in IL-12 Knockout-Mäusen. Weiterhin tragen offenbar sowohl Th1- als auch Th2-Zytokine zur Überwindung der Primärinfektion bei, die ersten mehr als die letztgenannten. Zytokingene waren am Ort der Infektion (Ileum) dramatisch verändert, nicht aber in den lokalen Lymphknoten und der Milz. Nach Folgeinfektion ergab sich in Abwesenheit von IFN-γ eine signifikante Erhöhung der Th2-Zytokine IL-5 and IL-13. Die Ergebnisse zeigten weiterhin, dass das Th1-Zytokin IL-18 zur Resistenz gegenüber C. parvum beiträgt, möglicherweise durch verschiedene Immunfunktionen, wie der Regulation von Serum-IFN-γ während der Infektion und/oder der Erhaltung der Homeostase der Th1/Th2-Zytokine durch Regulation der Th2-Zytokine. Weiterhin zeigten diese Untersuchungen den Transfer von Resistenz gegenüber C. parvum von infizierten auf naïve Mäuse mittels stimulierter intraepithelialer Lymphozyten und CD4+ T-Zellen. Diese Ergebnisse weisen auf die Gegenwart von C. parvum-spezifischen CD4+ T-Zellen in anderen lymphatischen Geweben neben der Darmmukosa hin. Eine Stimulation der Spendertiere durch Infektion war notwendig für eine übertragbare schützende Immunität. Dennoch konnte die übertragene Immunität nicht die Infektion der Empfängertiere vollständig verhindern; eine Verdopplung der Spenderzellen führte zu keinem besseren Ergebnis. Weiterhin ergab der Transfer von CD4+ und CD8+ T-Zellen (Pan-T-Zellen) keinen erhöhten Schutz der naiven Empfängertiere als der alleinige Transfer von CD4+ T-Zellen. Dies weist auf die fehlende Bedeutung der CD8+ T-Zellen beim Schutz vor C. parvum-Infektion hin.

Untersuchungen zur antitumoralen Wirkungsweise eines bispezifischen MCSP-CD3 Antikörpers in vitro und im humanisierten Tumormausmodell

Humanes MCSP ist ein gut charakterisiertes Tumorantigen, das auf der Mehrzahl aller malignen Melanome hoch exprimiert wird, und stellt somit eine gute Zielstruktur für immuntherapeutische Ansätze dar. rnInnerhalb der vorliegenden Arbeit wurden die Wirkmechanismen eines neuen bispezifischen Antikörpers, der gegen humanes MCSP und CD3 auf T-Zellen gerichtet ist, in vitro und im humanisierten Tumormausmodell in vivo untersucht. In humanen T Zellkokulturen induzierte der bispezifische MCSP-CD3 Antikörper in Gegenwart MCSP-positiver Melanomzellen konzentrationsabhängige T-Zellaktivierung, Sekretion von Zytokinen und effiziente Tumorzelllyse durch CD4- und CD8-positive T-Zellen. Die induzierte Lyse war hierbei unabhängig von der T-Zellrezeptorspezifität sowie kostimulatorischen Molekülen und allein abhängig von der Expression des Tumorantigens sowie CD3 auf den T-Zellen. Wie hier diskutiert, liegt es nahe, dass die Freisetzung lytischer Moleküle (Perforin und Granzym-B) durch CD8- und auch CD4 positiver T-Zellen den Hauptmechanismus in der Lyse der Melanomzellen darstellt. rnUm die Wirksamkeit in vivo testen zu können, wurde ein humanisiertes Tumormausmodell etabliert. Die Injektion humaner hämatopoetischer Stammzellen in neugeborene Rag2-/-gc-/- Mäuse führte zur Entwicklung funktioneller T-Zellen im murinen Thymus, welche lymphatische Organe besiedelten. In vitro induzierten die T-Zellen humanisierter Mäuse in Anwesenheit des bispezifischen MCSP-CD3 Antikörpers ebenfalls konzentrationsabhängige Lyse der Melanomzellen. Wie hier gezeigt, induzierte die Injektion humaner Melanomzellen in humanisierte Mäuse keine messbare Abstoβungsreaktion. Unter Behandlung mit MCSP-CD3 wurde zwar eine erhöhte Anzahl humaner T-Zellen im Tumorgewebe nachgewiesen, jedoch verfügte die verwendete Melanomzelllinie über eine geringe basale T Zellinfiltration, geringe Vaskularisierung und ein noduläres Wachstumsverhalten. Wie innerhalb dieser Arbeit diskutiert, kann durch die Kombination mit Therapien, die eine erhöhte T-Zellinfiltration in das Tumorgewebe ermöglichen, die Wirksamkeit von bispezifischen Antikörpern möglicherweise gesteigert werden. rn

Erkennung der alpha-Kette des GM-CSF-Rezeptors (CSF2RA) durch einen HLA-unabhängigen alpha:beta-T-Zellrezeptor

Aus dem tumorreaktiven T-Zellrepertoire der Melanompatientin Ma-Mel-86/INTH, bei der im Verlauf Lymphknotenmetastasen HLA-Klasse I-negativer Tumorzellen auftraten, wurden durch Stimulation mit autologen Tumorzellen CD8+ T-Zellklone isoliert und expandiert, die auf Melanomzellen der Patientin CSF2RA (engl. GM-CSF receptor alpha chain) in HLA-unabhängiger Weise erkannten. Aus einem der T-Zellklone wurde ein CSF2RA-reaktiver α:β-T-Zellrezeptor (TCR, engl. T-cell receptor) kloniert (Bezeichnung: TCR-1A.3/46). Die α-Kette des TCR enthielt die Domänen TRAV14/DV4*01, TRAJ48*01 und TRAC*01, die β-Kette die Domänen TRBV10-3*01, TRBD2*01, TRBJ2-7*01 und TRBC2*01. Durch Austausch der humanen konstanten gegen die homologen murinen Domänen wurde der TCR optimiert (Bezeichnung: cTCR-1A.3/46) und hinsichtlich seiner Expression und Funktionalität nach retroviralem Transfer in humane PBMC (engl. peripheral blood mononuclear cells) im 51Chromfreisetzungstest, im IFN-γ-ELISpot-Assay und in einem Degranulations-Assay validiert. TCR-transgene T-Zellen lysierten nicht nur spezifisch die HLA-defizienten, CSF2RA+ Melanomlinien des Modells Ma-Mel-86, sondern erkannten auch Zelllinien verschiedener Spezies nach Transfektion von CSF2RA sowie Monozyten, Granulozyten, dendritische Zellen und ein breites Spektrum hämatologischer Malignome myeloiden Ursprungs ungeachtet deren HLA-Phänotypen. Lymphatische Zellen sowie CD34+ Blutstammzellen wurden in In vitro-Untersuchungen nicht erkannt. Der Zusatz von GM-CSF zu Zellen, die CSF2RA und CSF2RB exprimierten, inhibierte die Erkennung durch TCR-transgene PBMC, während die Koexpression der α- und der ß-Kette des GM-CSF-Rezeptors alleine keinen negativen Effekt auf die Erkennung hatte. Daraus war zu schließen, dass CSF2RA präferentiell freistehend und weniger nach Integration in den heteromultimerischen GM-CSF-Rezeptor-Komplex erkannt wurde. In der zweidimensionalen Collier-de-Perles-Visualisierung der IMGT-Datenbank (engl. International immunogenetics information system) wies der CSF2RA-reaktive TCR-1A.3/46 im Vergleich zu TCR von konventionellen, HLA-restringierten T-Zellen keine Besonderheiten auf. Darüber hinaus waren auch die von den HLA-unabhängigen T-Zellen exprimierten CD8-Moleküle identisch zu den CD8-Molekülen HLA-abhängiger CTL (engl. cytotoxic T lymphocytes). Die Präsenz von CD8-Molekülen förderte die HLA-unabhängige Erkennung von CSF2RA, schien aber dafür nicht zwingend erforderlich zu sein, da Antikörper gegen CD8 die Erkennung zu ca. 65 % blockierten und TCR-transgene CD4+ T-Zellen im Vergleich zu TCR-transduzierten CD8+ T-Zellen eine deutlich verringerte, aber noch erhaltene Funktionalität aufwiesen. Es ist derzeit nicht klar, ob HLA-unabhängige T-Zellen gegen CSF2RA im peripheren Blut der Patientin vorkamen, weil sie der im Tiermodell postulierten Thymusselektion MHC-unabhängiger TCR (Tikhonova et al., Immunity 36:79, 2012) entkommen waren, oder weil ein ursprünglich gegen einen HLA-Peptid-Komplex gerichteter TCR eine HLA-unabhängige Kreuzreaktivität aufwies. CSF2RA verbessert die Glucoseutilisation in malignen Zellen, und es wurden ihm embryotrophe Eigenschaften zugeschrieben (Spielholz et al., Blood 85:973, 1995; Sjöblom et al., Biol. Reprod. 67:1817, 2002). Damit kann CSF2RA malignes Wachstum fördern und ist somit ein potentielles Zielmolekül für die Immuntherapie. Seine HLA-unabhängige Erkennung würde sowohl die HLA-Vielfalt als auch den HLA-Verlust als typische Limitationen der T-Zellimmuntherapie umgehen. Zur Überprüfung der In vivo-Spezifität des HLA-unabhängigen TCR gegen CSF2RA und damit zum Ausschluss relevanter off-tumor-/on-target- bzw. off-tumor-/off-target-Effekte ist jedoch eine Testung in einem präklinischen Tiermodell erforderlich.

Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis

In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions. Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.

Critical roles for Rac GTPases in T-cell migration to and within lymph nodes

Naive T cells continuously recirculate between secondary lymphoid tissue via the blood and lymphatic systems, a process that maximizes the chances of an encounter between a T cell and its cognate antigen. This recirculation depends on signals from chemokine receptors, integrins, and the sphingosine-1-phosphate receptor. The authors of previous studies in other cell types have shown that Rac GTPases transduce signals leading to cell migration and adhesion; however, their roles in T cells are unknown. By using both 3-dimensional intravital and in vitro approaches, we show that Rac1- and Rac2-deficient T cells have multiple defects in this recirculation process. Rac-deficient T cells home very inefficiently to lymph nodes and the white pulp of the spleen, show reduced interstitial migration within lymph node parenchyma, and are defective in egress from lymph nodes. These mutant T cells show defective chemokine-induced chemotaxis, chemokinesis, and adhesion to integrin ligands. They have reduced lateral motility on endothelial cells and transmigrate in-efficiently. These multiple defects stem from critical roles for Rac1 and Rac2 in transducing chemokine and sphingosine-1-phosphate receptor 1 signals leading to motility and adhesion.

Advantages of preoperative hybrid SPECT/CT in detection of sentinel lymph nodes in cutaneous head and neck malignancies

There is some controversy around the value of sentinel lymph node excision (SLNE). Especially SLNE of cutaneous head and neck malignancies has been debated intensively, in part because of the complexity of the lymphatic drainage in this region associated with potential high morbidity. In order to improve preoperative three-dimensional mapping of sentinel lymph nodes (SLN), in the head and neck region, by means of hybrid single photon emission computed tomography/computed tomography (SPECT/CT) is gaining significance. Our study seeks to identify the potential medical and economic advantages of preoperative SPECT/CT in direct comparison to standard SLNE without SPECT/CT in patients with cutaneous head and neck malignancies.

Super extended versus extended pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer: a comparative study

There is evidence from retrospective studies that radical cystectomy with extended pelvic lymph node dissection provides better staging and outcomes than limited lymph node dissection. However, the optimal limits of extended lymph node dissection remain unclear. We compared oncological outcomes at 2 cystectomy centers where 2 different extended lymph node dissection templates are practiced to determine whether removing lymphatic tissue up to the inferior mesenteric artery confers an additional survival advantage.

Intra-tumoral budding in preoperative biopsy specimens predicts lymph node and distant metastasis in patients with colorectal cancer

Tumor budding, a histological hallmark of epithelial-mesenchymal transition in colorectal cancer, is a parameter of tumor progression and according to the International Union Against Cancer/American Joint Committee on Cancer an 'additional' prognostic factor. The current definition of tumor budding is reserved for the invasive tumor front of colorectal cancer (so called peri-tumoral budding), but tumor buds can also be observed in small preoperative biopsy specimens. Whereas the prognostic value of peri-tumoral budding assessed in resection specimens has found wide acceptance, the value of budding in preoperative biopsies, which normally do not encompass the invasive tumor margin and hence can be called intra-tumoral budding, has not been systematically investigated yet. Therefore, the aim of this study is to assess the predictive value of intra-tumoral budding for lymph node and distant metastasis in preoperative biopsies. Preoperative biopsy samples and consecutive resection specimens from 72 patients with pathological information on TNM stage, vascular, lymphatic and perineural invasion, and tumor border configuration were used to evaluate intra-tumoral budding and peri-tumoral budding. Both parameters were scored semiquantitatively as 'high' (detectable at low power magnification × 2.5) and 'low' (occasional budding at intermediate magnification × 10, difficult to find or absent). In biopsy samples high intra-tumoral budding was observed in 12/72 patients (17%) and associated with high peri-tumoral budding in the corresponding resection specimens (P=0.008). Additionally, there was a correlation between high intra-tumoral budding and lymph node metastasis (P=0.034), distant metastasis (P=0.007) and higher tumor grade (P=0.025). Peri-tumoral budding was associated with higher N stage (P=0.004), vascular (P=0.046) and lymphatic invasion (P=0.019) as well as with an infiltrating tumor border (P<0.001), reflecting the predictive power of peri-tumoral budding for tumor progression. High intra-tumoral budding in preoperative biopsy samples of colorectal cancer patients predicts high peri-tumoral budding at the invasive margin and lymph node metastasis in the corresponding resection specimens as well as distant metastasis.

Virological and pathological findings in Bluetongue virus serotype 8 infected sheep

Twenty-seven sheep of the four most common Swiss breeds and the English breed Poll Dorset were experimentally infected with a northern European field strain of bluetongue virus serotype 8 (BTV-8). Animals of all breeds developed clinical signs, viremia and pathological lesions, demonstrating that BTV-8 is fully capable of replicating and inducing bluetongue disease (BT) in the investigated sheep. Necropsy performed between 10 and 16 days post-infectionem (d.p.i.) revealed BT-typical hemorrhages, effusions, edema, erosions and activation of lymphatic tissues. Hemorrhages on the base of the Arteria pulmonalis and the left Musculus papillaris subauricularis were frequently present. Histology confirmed the macroscopical findings. Using a score system, clinical manifestation and pathology were found to be significantly related. Furthermore, clinical signs and fever were shown to be indicative for the concurrent presence of high amounts of viral ribonucleic acid (RNA) in blood. Spleen, lung, lymph nodes and tonsils from all animals were analyzed regarding viral RNA loads and infectivity using real-time reverse transcriptase PCR (rRT-PCR) and virus isolation in cell culture, respectively. The highest amount of viral RNA was detected in spleen and lung and rRT-PCR revealed to be a more sensitive method for virus detection compared to virus isolation. A long-term follow-up was performed with three sheep showing that BTV-8 viral RNA in blood was present up to 133 d.p.i. and in certain tissues even on 151 d.p.i. No significant breed-related differences were observed concerning clinicopathological picture and viremia, and the Swiss sheep were as susceptible to BTV-8 infection as Poll Dorset sheep, demonstrating a remarkably high virulence of BTV-8 for indigenous sheep breeds.

Intratumoral budding is preoperative biopsies predicts local and distant metastasis in colorectal cancer patients

Objective: In 2011, the term “intratumoral budding, ITB” was used to describe the presence of tumor buds within the main tumor body and was correlated to worse clinical outcome in colorectal cancer patients. Here, we further elucidate the potential clinical role of ITB in pre-operative biopsies using pan-cytokeratin stained tissues and a quantitative scoring system. Method: 139 pre-operative biopsies from patients with colorectal cancer underwent immunohistochemistry for pancytokeratin (AE1/AE3). ITB were counted in the area of densest budding (40×) and classified as high-grade when >10 buds/HPF were observed based on receiver operating characteristic (ROC) curve analysis. Results: High-grade ITB occurred in 26.6 % of cases and was associated with right-sided tumor location (p=0.0356), more advanced pT (p=0.0198) and pN (p<0.0001) classifications, distant metastasis (p=0.0164), higher tumor grade (p=0.0037) and lymphatic invasion (p=0.0445). The specificity and positive predictive value for lymph node metastasis was 86.7 % and 75.6 %, respectively. Disease-free survival was significantly worse in patients with high-grade ITB (5-year survival=25 %) in comparison to patients with low-grade ITB (5-year survival=55 %) (p=0.0157). Conclusion: The assessment of ITB in pre-operative biopsies is predictive of local and distant metastasis in corresponding resections and should be considered in daily management of colorectal cancer patients.

Sensitivity and specificity of fluorescence microlymphography for detecting lymphedema of the lower extremity

Fluorescence microlymphography (FML) is used to visualize the lymphatic capillaries. A maximum spread of the fluorescence dye of ≥ 12 mm has been suggested for the diagnosis of lymphedema. However, data on sensitivity and specificity are lacking. The aim of this study was to investigate the accuracy of FML for diagnosing lymphedema in patients with leg swelling. Patients with lower extremity swelling were clinically assessed and separated into lymphedema and non-lymphatic edema groups. FML was studied in all affected legs and the maximum spread of lymphatic capillaries was measured. Test accuracy and receiver operator characteristic (ROC) analysis was performed to assess possible threshold values that predict lymphedema. Between March 2008 and August 2011 a total of 171 patients (184 legs) with a median age of 43.5 (IQR 24, 54) years were assessed. Of those, 94 (51.1%) legs were diagnosed with lymphedema. The sensitivity, specificity, positive and negative likelihood ratio and positive and negative predictive value were 87%, 64%, 2.45, 0.20, 72% and 83% for the 12-mm cut-off level and 79%, 83%, 4.72, 0.26, 83% and 79% for the 14-mm cut-off level, respectively. The area under the ROC curve was 0.82 (95% CI: 0.76, 0.88). Sensitivity was higher in the secondary versus primary lymphedema (95.0% vs 74.3%, p = 0.045). No major adverse events were observed. In conclusion, FML is a simple and safe technique for detecting lymphedema in patients with leg swelling. A cut-off level of ≥ 14-mm maximum spread has a high sensitivity and high specificity of detecting lymphedema and should be chosen.

Postural effects on interstitial fluid pressure in humans

BACKGROUND: Direct assessment of the effect of postural changes on interstitial fluid pressure (IFP) in the human skin under physiological conditions is important for the understanding of mechanisms involved in diseases resulting in lower limb edema. Previous techniques to measure IFP had limitations of being invasive, and acute measurements were not possible. Here we describe the effect of postural changes on IFP in the skin of the foot using the minimally invasive servonulling technique. RESULTS: Measurements were performed in 12 healthy subjects. IFP (means +/- SD) was significantly higher in the sitting (5.1 +/- 2.9 mm Hg) than in the supine position (-0.3 +/- 3.6 mm Hg, p = 0.04) when measured in the sitting position first. The difference between the sitting and the supine position was not significant when measurements were taken in the supine position first [from 1.0 +/- 4.3 (supine) to 3.6 +/- 6.7 mm Hg (sitting), p = 0.46]. Spontaneous low-frequency pressure fluctuations occurred in 58% of the recordings during sitting, which was almost twice as frequent as in the supine position (33%; p = 0.001), while no effects on lymphatic capillary network extension were observed (p = 0.12). CONCLUSION: Using the servonulling micropressure system, postural effects on IFP can be directly assessed. IFP is higher in the sitting position, but differences are influenced by the time in the upright position.

Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer

BACKGROUND AND PURPOSE: This is the first study investigating neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with chemotherapy in patients with breast cancer. The goal was to evaluate the type of surgical treatment, histopathologic response, side effects, local control, and survival. PATIENTS AND METHODS: 53 patients, who could not be treated with breast-conserving surgery due to initial tumor size (36/53) or due to an unfavorable breast-tumor ratio (17/53), were analyzed retrospectively. All but one were in an intermediate/high-risk group (St. Gallen criteria). The patients received a neoadjuvant protocol consisting of systemic chemotherapy combined with fractionated HDR brachytherapy (2 x 5 Gy/day, total dose 30 Gy). In cases, where breast-conserving surgery was performed, patients received additional external-beam radiotherapy (EBRT, 1.8 Gy/day, total dose 50.4 Gy). In patients, who underwent mastectomy but showed an initial tumor size of T3/T4 and/or more than three infiltrated lymph nodes, EBRT was also performed. RESULTS: In 30/53 patients (56.6%) breast-conserving surgery could be performed. The overall histopathologic response rate was 96.2% with a complete remission in 28.3% of patients. 49/53 patients were evaluable for follow-up. After a median of 58 months (45-72 months), one patient showed a mild fibrosis of the breast tissue, three patients had mild to moderate lymphatic edema of the arm. 6/49 (12.2%) patients died of distant metastases, 4/49 (8.2%) were alive with disease, and 39/49 (79.6%) were free from disease. Local recurrence was observed in only one case (2%) 40 months after primary therapy. After mastectomy, this patient is currently free from disease. CONCLUSION: The combination of interstitial HDR brachytherapy and chemotherapy is a well-tolerated and effective neoadjuvant treatment in patients with breast cancer. Compared to EBRT, treatment time is short. Postoperative EBRT of the whole breast -- if necessary -- is still possible after neoadjuvant brachytherapy. Even though the number of patients does not permit definite conclusions, the results are promising regarding survival and the very low rate of local recurrences.

Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

AIMS: To investigate the relationship between extremely low frequency magnetic field (ELF-MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. METHODS: 20,141 Swiss railway employees with 464,129 person-years of follow-up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 muT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 muT). In addition, individual cumulative exposure was calculated from on-site measurements and modelling of past exposures. RESULTS: The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non-Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. CONCLUSIONS: Some evidence of an exposure-response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours.

Demographic characteristics of patients with extrapulmonary tuberculosis in Germany

The aim of the present study was to determine the demographics of patients with extrapulmonary tuberculosis in Germany. Data on 26,302 tuberculosis cases from a national survey carried out during the period 1996-2000 were analysed. The crude proportion of tuberculosis patients with extrapulmonary manifestations was 21.6%. Extrapulmonary tuberculosis was most likely among females, children aged <15 yrs and persons originating from Africa and Asia. Females tended to be more likely to have any form of extrapulmonary tuberculosis than males, except pleural tuberculosis. The strength of this association was strongest in the age range 25-64 yrs and less pronounced amongst the oldest patients. Children were particularly prone to the development of lymphatic and meningeal tuberculosis, whereas the likelihood of genitourinary tuberculosis increased with increasing age. Asian and African patients were generally more likely than persons from other areas to have lymphatic, osteoarticular, meningeal and miliary tuberculosis. The analysis shows important differences, by age, sex and origin, in the likelihood of a tuberculosis patient presenting with extrapulmonary tuberculosis. Since the relative contribution of the foreign-born to tuberculosis in low-prevalence countries is rising, extrapulmonary tuberculosis must be taken into account more often in the differential diagnostic work-up of these patients, particularly among those originating from Asia and Africa.