Towards more accurate 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in Active and Latent Tuberculosis

Tuberculosis is one of the leading causes of death worldwide. Although the disease is curable and preventable, it is under-diagnosed in many parts of the world. Positron emission tomography (PET) imaging using 18 F-FDG in TB can localise disease sites and extent of disease. 18F-FDG accumulates in immune cells which participate in inflammation and granuloma formation, such as activated macrophages and lymphocytes. Therefore, FDG PET/CT scanning is now being evaluated for its usefulness in diagnosis of EPTB, and monitoring response to treatment. FDG PET/CT imaging is positive and has high sensitivity in active TB, complementing conventional radiologic imaging (X-ray, CT, MRI) in the diagnosis of primary pulmonary, extrapulmonary and post-primary or miliary TB. FDG PET/CT has low specificity when it is used for solitary pulmonary nodule characterization and its ability to differentiate TB from malignancy is limited in this setting. Dual point imaging has been proposed as a way to overcome this limitation. FDG PET/CT can reliably differentiate active from inactive disease and there is promising evidence that it can contribute to response assessment to treatment with impact on patients' management. FDG PET/CT has been found positive in cases of latent TB infection and its ability for early identification of activation is being currently explored. More studies are needed to establish the method's utility in recognizing multidrug-resistant TB cases. Furthermore, other PET radiotracers might prove useful in the functional imaging of TB infection in the future

Adenovirus DNA in Guthrie cards from children who develop acute lymphoblastic leukaemia (ALL)

Aims: The aim of this thesis was to increase understanding of how molecular processes influence the development and risk assessment of childhood leukemia. Studies I and II investigates whether a specific virus infection in utero could be involved in a “first hit” in leukemogenesis. Studies III and IV examine whether alterations in protein expression from cell cycle regulating genes may predict a relapse in children with myeloid malignancies undergoing hematopoietic stem cell transplantation (HSCT). Background: Genetic alterations, analyzed at time of diagnosis in children who develop leukemia, have been traced back to neonatal dried blood spots (DBS). This suggests that the majority of chromosome translocations occur in utero during fetal hematopoiesis, generating a “first hit”. A “second hit” is then required to generate a leukemic clone. Today, experiments in vitro, animal models, and clinical observations have revealed that several viruses are oncogenic and capable of initiating a genetic alteration. Smith M postulated the theory that an in utero infection might be the “first hit”, causing genetic aberrations that could later lead to the development of the leukemic clone, which is supported by the early age of onset and space-time clustering data, based on time, place of birth, and diagnosis. Leukemia develops as a result of hematopoietic or lymphoid tissue with uncontrolled cell division. Normally cell division is controlled by the cell cycle, the network of which is complex with numerous regulating proteins both up and down stream, but also containing several feedback loops. The important regulators of this process are tumor suppressor genes, essential for normal cell proliferation and differentiation as well as for controlling DNA integrity. Errors in these genes or their protein expression affect the ability of the cell to check for DNA damage, thus tumors may occur. Proteins from these genes could serve as prognostic markers and predict relapse. Methods: In studies I and II we investigated neonatal DBS by PCR for the presence of adenovirus DNA (243 samples) and the three newly discovered polyomaviruses (50 samples) from children who later developed leukemia but also from controls (486 and 100 samples respectively). In studies III and IV we explored the expression of one (p53) respectively four (p53, p21, p16 and PTEN) cell cycle regulating proteins in bone marrow at diagnosis as well as pre and post HSCT in myeloid malignancies in children. We retrospectively collected clinical data and bone marrow samples from 33 children diagnosed with chronic myeloid malignancies (MDS, JMML and CML), 34 children diagnosed with AML as well as 55 controls. The samples were prepared by tissue micro array (TMA) as well as immunohistochemistry and examined for protein expression in a light microscope. Results: In study I we detected adenovirus DNA in only two patients who later developed leukemia, but in none of the controls. In study II all the samples were negative for KIPyV, WUPyV and MCPyV DNA in both patients and controls. In study III we found an overexpression of p53 protein at diagnosis that significantly predicted relapse after HSCT in children with rare chronic myeloid malignancies. In study IV a significantly higher p53 expression was found in the relapse compared to the non-relapse group at six months post HSCT in children with AML, suggesting that p53 may be used as prognostic markers for predicting a relapse. In addition, the calculated cut off level for p53 at diagnosis (study III) and at six months (study IV) post HSCT was approximately 20%, which indicates that a p53 expression over 20% may predict relapse in children with myeloid malignancies. Conclusion: Although we did not find an association between adenoviruses or the three newly discovered polyomaviruses and the development of childhood leukemia, a virus could still be involved in this process; the virus may have escaped detection, other new viruses could be involved or a virus could precipitate the “second hit”. We suggest that evaluation of p53 protein expression may be used as a supplement to regular prognostic markers both pre and post HSCT. To further evaluate this, a prospective multicenter study has been started

Adenovirus DNA is detected at increased frequency in Guthrie cards from children who develop acute lymphoblastic leukaemia

Epidemiological evidence suggests that childhood acute lymphoblastic leukaemia (ALL) may be initiated by an in infection in utero. Adenovirus DNA was detected in 13 of 49 neonatal blood spots from ALL patients but only in 3 of 47 controls (P=0.012) suggesting a correlation between prenatal adenovirus infection and the development of AL

Studies on human polyomavirus infection in immunosuppressed patients with polyoma related tumors

Polyomaviruses are potentially oncogenic viruses, found in humans, in other mammals and in birds all over the world. The polyomaviruses that have been observed in humans are BK virus (BKV) and JC virus (JCV) as well as the primate polyomavirus Simian Virus 40 (SV40). BKV and JCV persistent latent in humans, but are not believed do not cause any disease or symptoms in immunocompetent individuals. However, in immunosuppressed individuals, e.g in bone marrow transplanted (BMT) patients BKV has been reported to be associated with hemorrhagic cystitis (HC), and in HIV positive patients JCV has been shown to cause progressive multifocal leukoencephalopathy (PML). SV40 is believed to have been transferred to humans via contaminated polio vaccine 195561, and recent studies have detected fragments of SV40 DNA in malignant mesotheliomas (MM), brain tumors and osteosarcomas. However, the reported frequency varies widely between different studies and countries. 'Me aim of the present study was to further investigate human polyomavirus infections in immunosuppressed patients and in patients with polyoma virus related tumors. In BMT patients with late onset HC, BKV is excreted in the urine, but all BMT patients with BK viruria do not develop HC. To investigate if primary BKV infection transmitted from donor to recipient during BMT could cause HC we investigated anti BKV serum titers in BMT recipients and their donors. We also sequenced the non coding control region (NCCR) and the VP1 region of BKV from BMT patients to search for mutations correlated to the development of HC. Primary BKV infection was not the major cause of HC in BMT patients since all patients had anti BKV antibody titers before BMT. However, after BMT significantly more patients with HC had serological changes compared to patients without HC. BKV with C to G mutations in the NCCR Sp1 binding site was significantly over represented in BMT patients with HC. However, when we by Real Time PCR investigated if these mutations resulted in a higher BKV load in the urine of affected patients, we found that this was not the case. To study if human polyomavirus reactivation was related to graft cold ischemia time and if this could cause graft rejections in renal transplant (RTX) patients, we analyzed urine samples by PCR from RTX patients for presence of BKV or JCV and in parallel we examined their files for graft rejection. Reactivation of BKV or JCV was not correlated to the length of the cold ischemia time or to complications after RTX, such as rejection. JCV can be detected by PCR in the cerebrospinal fluid (CSF) of patients with PML. To investigate if JCV is present in CSF during other central nervous system (CNS) infections or in Multiple Sclerosis (MS) patients, we analyzed CSF samples by PCR from patients with other vital CNS infections and MS. JCV was not detected by PCR in CSF from patients with HSV-1 encephalitis, enteroviral meningitis, nonenteroviral meningitis or during MS. Thus, detection of JCV by PCR in CSF is indicative for PML. In order to investigate if SV40 or human polyomaviruses were present in Swedish malignant mesotheliomas (MM), and possibly related to the distribution of early batches of SV40 contaminated polio vaccine, we analyzed Swedish MM samples for SV40 by PCR. SV40 was present in only 10% of the Swedish MM (from three men hom 1905-1953), which was less than that reported, 40-69% in Italy and the USA. This indicates that SV40 contaminated polio vaccine not was distributed widely in Sweden even before 1958

A Note on ‘What Drives Share Prices in the Middle East?’

There are several hypotheses suggesting that some properties of oil prices make it interesting to focus on the predictive ability of oil prices for stock returns. This paper reviews some models recently used in the literature and selects the most suitable one for measuring the relationships and/or linkages of oil prices to the stock markets of the selected five oil producing countries in the Middle East. In particular, the paper uses two methodologies to test for the presence of a co integrating relationship between the two variables and an unobserved components model to find a relationship between the two variables. The results rejects convincingly that there is no linkage between the prices of oil and the stock market prices in these oil-based economies