Case report: appearance of uterine cervical lymphoma on MRI: a case report and review of the literature.

We present the appearances on CT and MRI of a case of non-Hodgkin's lymphoma (NHL) of uterine cervix. A 41-year-old woman presented with a short history of urinary symptoms and menorrhagia. Previous cervical smears were normal. Clinically, the cervix was replaced by a huge ulcerating mass. Biopsy showed malignant high grade B-cell NHL. T(2) weighted MRI of the pelvis showed a 12 cm intermediate signal mass replacing the cervix, with infiltration of the vagina and left parametrium, and bilateral internal iliac lymphadenopathy. Whole body CT imaging showed lymphoma in the kidneys and pancreas, the latter associated with biliary obstruction. The patient is in complete remission 7 months post chemotherapy, radiotherapy and stenting of biliary stricture. The success of the cervical cancer screening programme has lead to a reduction in the number of cases of advanced cervical carcinoma and the presence of an unusually large homogeneous cervical tumour, with relatively scant necrosis should prompt suspicion of a less common histology such as NHL.

Functional domains of yeast plasmid-encoded Rep proteins.

Both of the Saccharomyces cerevisiae 2 microm circle-encoded Rep1 and Rep2 proteins are required for efficient distribution of the plasmid to daughter cells during cellular division. In this study two-hybrid and in vitro protein interaction assays demonstrate that the first 129 amino acids of Rep1 are sufficient for self-association and for interaction with Rep2. Deletion of the first 76 amino acids of Rep1 abolished the Rep1-Rep2 interaction but still allowed some self-association, suggesting that different but overlapping domains specify these interactions. Amino- or carboxy-terminally truncated Rep1 fusion proteins were unable to complement defective segregation of a 2 microm-based stability vector with rep1 deleted, supporting the idea of the requirement of Rep protein interaction for plasmid segregation but indicating a separate required function for the carboxy-terminal portion of Rep1. The results of in vitro baiting assays suggest that Rep2 contains two nonoverlapping domains, both of which are capable of mediating Rep2 self-association. The amino-terminal domain interacts with Rep1, while the carboxy-terminal domain was shown by Southwestern analysis to have DNA-binding activity. The overlapping Rep1 and Rep2 interaction domains in Rep1, and the ability of Rep2 to interact with Rep1, Rep2, and DNA, suggest a model in which the Rep proteins polymerize along the 2 microm circle plasmid stability locus, forming a structure that mediates plasmid segregation. In this model, competition between Rep1 and Rep2 for association with Rep1 determines the formation or disassembly of the segregation complex.

The assessment of irradiated bladder carcinoma using dynamic contrast-enhanced MR imaging.

AIM: To evaluate the role of dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) in distinguishing residual or recurrent tumour from radiation change in patients with bladder carcinoma. MATERIALS AND METHODS: Forty patients with biopsy proven bladder carcinoma were imaged before and at 4 and 12 months after radiotherapy (XRT) using conventional and dynamic contrast-enhanced magnetic resonance imaging at 0.5 Tesla. An enhancement of >1.54 times above baseline at 80 s post-contrast injection proved a reliable indicator of tumour before radiotherapy and was therefore applied to the assessment of patients after XRT. Conventional MR images and dynamic enhancement profiles (DEPs) from the site of previous tumour were scored by three radiologists for the presence of tumour at 4 and 12 months after XRT. Findings were compared with cystoscopic biopsy. RESULTS: Dynamic contrast-enhanced magnetic resonance imaging had negative predictive values of 100% and 93% for tumour recurrence at 4 and 12 months, respectively. The positive predictive values, sensitivity and specificity were 48, 100 and 48% at 4 months and 50, 80 and +76% at 12 months post XRT, respectively. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging may prove reliable in excluding the presence of persistent or recurrent tumour up to 12 months after XRT.

ETn insertion in the mouse Adcy1 gene: transcriptional and phylogenetic analyses.

Early retrotransposons (ETn) are murine transposable elements, bearing some structural similarity to integrated proviruses, and can be insertional mutagens. We have recently identified the causative mutation of the barrelless (Adcy1brl) phenotype as an integration of a 5.7-kb ETn in an intron of the adenylyl cyclase type I (Adcy1) gene. In the present study, Northern blot analysis shows that the ETn insertion results in loss of the normal Adcy1 transcript, a finding consistent with the loss-of-function Adcy1brl mutation, and generation of shorter transcripts. These aberrant transcripts are the products of abnormal RNA splicing and termination owing to the inserted sequence, and transcription initiation within the 3' long terminal repeat (LTR) of the ETn. The DNA sequences of the LTRs were compared in phylogenetic analyses with LTRs from 22 other ETn-related sequences. Three distinct families of ETn sequences can be identified on the basis of their LTRs. The ETn found in Adcy1brl is a member of a family that includes all classified ETn elements known to have recently transposed. Further, of the four known solitary (solo) LTRs, we have identified two that show evidence of recombination between LTRs from different ETn families.

Malaria control in East Africa: the Kampala Conference and the Pare-Taveta Scheme: a meeting of common and high ground.

The 1950 Malaria Conference in Equatorial Africa, held in Kampala, Uganda, has been remembered primarily for its decision to control malaria '...by modern methods as soon as feasible, whatever the original degree of endemicity, and without awaiting the outcome of further experiments.' This decision was far from conclusive and, indeed, reflects only one side of the argument which brought two groups of malariologists into direct opposition on the wisdom of malaria control in equatorial Africa, using modern methods such as DDT. Through an examination of the unpublished verbatim transcript of the Kampala Conference, we are able to document the 'furious debates' which took place at Kampala in 1950. We highlight, in particular, the adamant concerns expressed by some of the delegates that intervention in areas of high malaria transmission might lead to a loss of naturally acquired immunity which, in turn, could give rise to a resurgence of malaria, should the control strategies fail to be sustained. As we show, this concern had been expressed by a number of malariologists working in East Africa in the first half of the twentieth century, but it was only with the advent of DDT, as a residual insecticide, that the implications of wide-spread control, in the absence of any knowledge of the long-term consequences, became a serious possibility. While the Kampala Conference gave the 'go ahead' to control malaria in Africa without awaiting the outcome of 'further experiments', a number of participants insisted that a field trial should be set up to evaluate the impact of malaria on areas of high transmission both before and after spraying: to this end, a field trial in Pare-Taveta was carried out in 1954-59. In this paper we look at the Kampala Conference for its scientific debates and the Pare-Taveta Scheme for its field applications. In the final part of the paper, we address a number of questions raised at Kampala which have, once more, become contentious issues, following the recent successful trials of ITBNs. We believe that an understanding of the historical foundations of these issues should provide an important component of the new WHO campaign to Roll Back Malaria.

Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain.

Niemann-Pick type II disease is an autosomal recessive disorder characterized by a defect in intracellular trafficking of sterols. We have determined the intron/exon boundaries of eight exons from the conserved 3' portion of NPC1, the gene associated with most cases of the disease. SSCP analyses were designed for these exons and were used to identify the majority of mutations in 13 apparently unrelated families. Thirteen mutations were found, accounting for 19 of the 26 alleles. These mutations included eight different missense mutations (including one reported by Greer et al. [1998]), one 4-bp and two 2-bp deletions that generate premature stop codons, and two intronic mutations that are predicted to alter splicing. Two of the missense mutations were present in predicted transmembrane (TM) domains. Clustering of these and other reported NPC1 mutations in the carboxy-terminal third of the protein indicates that screening of these exons, by means of the SSCP analyses reported here, will detect most mutations. The carboxy-terminal half of the Npc1 protein shares amino acid similarity with the TM domains of the morphogen receptor Patched, with the largest stretch of unrelated sequence lying between two putative TM spans. Alignment of this portion of the human Npc1 protein sequence with Npc1-related sequences from mouse, yeast, nematode, and a plant, Arabidopsis, revealed conserved cysteine residues that may coordinate the structure of this domain. That 7 of a total of 13 NPC1 missense mutations are concentrated in this single Npc1-specific domain suggests that integrity of this region is particularly critical for normal functioning of the protein.

Linkage disequilibrium mapping of the Nova Scotia variant of Niemann-Pick disease.

Niemann-Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13-cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232-235) recently demonstrated that one of these ESTs is the Niemann-Pick type C (NPCI) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097-->T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1-cM (1.3-1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5-cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.

The value of specialist oncological radiology review of cross-sectional imaging.

AIM: To determine whether specialist oncological radiology review of outside cross-sectional imaging affects patient management. MATERIALS AND METHODS: Five hundred and twenty-six patients attending a regional oncology centre had review of outside cross-sectional imaging over a 1-year period. The number of examinations per patient, time interval between examination and review request, and examination technical adequacy were recorded in each case. More detailed evaluation of 124 patients included comparison of outside and review reports for major differences in interpretation by a medical oncologist who also evaluated the effect of the review on patient management. Examinations resulting in major report discrepancies were subjected to independent radiological adjudication. RESULTS: Eighty-one percent of examinations were reviewed within 3 months of being performed and 94% were considered technically adequate. The hard copy images provided were incomplete in 33% of cases and a calibration rule was absent in 9%. There was a major difference in interpretation in 34% of examinations, the most common cause being differences in interpretation of lymphadenopathy (52%), particularly in the mediastinum (19%). Other problems identified were the failure to record disease dimensions and absence of specific information on key organs in the outside reports. Specialist radiology review changed radiological staging in 19% of patients, affected management in 7% of patients and resulted in a change in treatment in 4%. There was no correlation between management change and any particular tumour type. In 27% of cases, treatment decisions had been made before the review was requested. CONCLUSION: Specialist oncological radiology review of outside cross-sectional imaging changed radiological staging in 19% of cases but had little impact on patient management. Oncological cross-sectional imaging techniques in the North West of England are of high quality, probably helped by recent RCR guidelines.

The malariology centenary.

The year 1898 was one of the most significant years in the history of malariology. One hundred years later scientists gathered at the Accademia Nazionale dei Lincei, Rome, to commemorate the Malariology Centenary. This paper provides a short overview of some of the key developments and discoveries in malaria research which took place at the end of the 19th century. The major contributions of Alphonse Laveran, Patrick Manson, Ronald Ross, Battista Grassi and a number of scientists of the Italian School of Malariology to the understanding of the transmission of malaria by Anopheles mosquitoes are described. This paper also highlights the importance of an historical perspective in furthering our understanding of the 'Malaria Challenge after One Hundred Years of Malariology'.

A LINE2 repetitive DNA sequence from the cichlid fish, Oreochromis niloticus: sequence analysis and chromosomal distribution.

We report the cloning and characterization of a long interspersed nucleotide element (LINE) from a cichlid fish, Oreochromis niloticus, and show the distribution of this element, called CiLINE2 for cichlid LINE2, in the chromosomes of this species. The identification of an open reading frame in CiLINE2 with amino acid sequence similarity to reverse transcriptases encoded by LINE-like elements in Caenorhabditis elegans, Platemys spixii, Schistosoma mansoni, Gallus gallus (CRI), Drosophila melanogaster (I factor), and Homo sapiens (LINE2), as well as the structure of the element, suggest it is a member of this family of non-long terminal repeat-containing retrotransposons. Search of a DNA sequence database identified sequences similar to CiLINE2 in four other fish species (Haplotaxodon microlepis, Oreochromis mossambicus, Pseudotropheus zebra, and Fugu rubripes). Southern blot hybridization experiments revealed the presence of sequences similar to CiLINE2 in all Tilapiini species analyzed from the genera Oreochromis, Tilapia, and Sarotherodon, and gave an estimated copy number of about 5500 for the haploid genome of O. niloticus. Fluorescent in situ hybridization showed that CiLINE2 sequences were organized in small clusters dispersed over all chromosomes of O. niloticus, with a higher concentration near chromosome ends. Furthermore, the long arm of chromosome 1 was strikingly enriched with this sequence. The distribution of LINE2-related elements might underlie the difference in chromosome banding patterns observed between cold-blooded vertebrates and mammals.

FISH mapping and inter-Alu fingerprinting define the YAC contig map around the centromeric region of human chromosome 18.

Previous reports concerning the location of D18S44 with respect to the centromere have been ambiguous. Also, it has not been possible, based on formerly reported markers, to show that contigs WC18.0 and WC18.1 overlap. However, the data presented here definitively show, using FISH technology, that D18S44 (located on WC18.0) maps to proximal 18q. Furthermore, inter-Alu fingerprinting shows a clear overlap between WC18.0 and WC18.1, thereby establishing a complete contig between D18S44 and markers from WC18.1.

Bitter-sweet solutions for malaria: exploring natural remedies from the past.

This paper explores "a wonderful cure" for malaria used successfully by Robert Talbor, an apothecary's apprentice in the English marshes, to treat Essex smugglers and European Royalty in the seventeenth century. The basis of this cure is identified as "quinquina" from the bark of the South American Cinchona tree. The story of Robert Talbor and his secret remedy for malaria opens up a set of intriguing questions about the early history of "quinquina", the subsequent development of quinine, the use of higher plants for antimalarial drugs, including the Chinese plant Artemisia annua L., and the value of unlocking the secrets of the past in our search for strategies to control malaria.

Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex.

The somatosensory (SI) cortex of mice displays a patterned, nonuniform distribution of neurons in layer IV called the 'barrelfield' (ref. 1). Thalamocortical afferents (TCAs) that terminate in layer IV are segregated such that each barrel, a readily visible cylindrical array of neurons surrounding a cell-sparse center, represents a distinct receptive field. TCA arbors are confined to the barrel hollow and synapse on barrel-wall neurons whose dendrites are oriented toward the center of the barrel. Mice homozygous for the barrelless (brl) mutation, which occurred spontaneously in ICR stock at Université de Lausanne (Switzerland), fail to develop this patterned distribution of neurons, but still display normal topological organization of the SI cortex. Despite the absence of barrels and the overlapping zones of TCA arborization, the size of individual whisker representations, as judged by 2-deoxyglucose uptake, is similar to that of wild-type mice. We identified adenylyl cyclase type I (Adcy1) as the gene disrupted in brl mutant mice by fine mapping of proximal chromosome 11, enzyme assay, mutation analysis and examination of mice homozygous for a targeted disruption of Adcy1. These results provide the first evidence for involvement of cAMP signalling pathways in pattern formation of the brain.

The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1.

Niemann-Pick type D (NPD) disease is a progressive neurodegenerative disorder characterized by the accumulation of tissue cholesterol and sphingomyelin. This disorder is relatively common in southwestern Nova Scotia, because of a founder effect. Our previous studies, using classic linkage analysis of this large extended kindred, defined the critical gene region to a 13-cM chromosome segment between D18S40 and D18S66. A recently isolated gene from this region, NPC1, is mutated in the majority of patients with Niemann-Pick type C disease. We have identified a point mutation within this gene (G3097-->T; Gly992-->Trp) that shows complete linkage disequilibrium with NPD, confirming that NPD is an allelic variant of NPC1.

The telomere-associated DNA from human chromosome 20p contains a pseudotelomere structure and shares sequences with the subtelomeric regions of 4q and 18p.

The human chromosome 20p telomere has been cloned on a yeast artificial chromosome (YAC). The telomere-associated DNA contains an interstitial tract of (TTAGGG)n telomeric repeats 60 kb in from the chromosome end. Frequent truncation of the YAC clone was observed due to resolution of the internal telomeric array into a telomere. The 20p internal telomeric repeat tract is flanked on its centromeric side by telomere-associated repeated sequences that have previously been found adjacent to terminal telomeric repeat arrays. The pseudotelomere structure of the 20p subtelomeric region is similar to the structure of some yeast subtelomeric regions where these sequences act as substrates for recombinational repair of chromosome ends that have lost their terminal telomeric repeat arrays. Sequences flanking the telomeric end of the internal (TTAGGG)n repeat array on 20p are found adjacent to three other subtelomeric (TTAGGG)n tracts on 4q, 18p, and an unknown chromosome end, respectively. These shared sequences provide evidence of exchange between nonhomologous chromosomes in humans.

What is the value of the lateral chest radiograph in the follow-up thoracic lymphoma?

Lateral chest radiography in the investigation of thoracic lymphoma remains a feature of the current literature. This study assessed what information the lateral chest radiograph (CXR) adds in the follow-up of such patients. Eighty-eight patients with known lymphoma who had a CXR and thoracic CT within the same 4-week period were assessed. Five radiologists scored eight mediastinal and hilar nodal groups and eight extramediastinal regions on the frontal CXR as normal, equivocal or definitely abnormal (denoted 0, 1 and 2, respectively). This was repeated 1 week later with a combination of frontal and lateral films. Results were compared with the findings on CT which were scored similarly using accepted criteria for the presence of lymphadenopathy. Where the lateral CXR caused a change in score at any site, this change was compared with CT to determine the effect on diagnostic accuracy. For four of the five observers, the lateral film made no significant difference in diagnostic accuracy in the assessment of mediastinal lymph nodes. A fifth observer derived a small benefit from the addition of the lateral film, although almost 30 % of this was accounted for by changing from a wrong to an equivocal diagnosis. The lateral film did cause a small increase in the detection of pleuro-parenchymal lung lesions, although none of these were clinically significant. We conclude that routine lateral chest radiography is unhelpful in the follow-up of patients with lymphoma.

MR angiography and MR imaging of symptomatic vascular malformations.

PURPOSE: To define the appearance of peripheral vascular malformations at magnetic resonance angiography (MRA) and assess the role of magnetic resonance imaging (MRI) and MRA in the investigation of these lesions. PATIENTS AND METHODS: Fourteen patients (aged 8-51 years) with clinical evidence of a vascular malformation were referred for MRI and MRA, performed on a 0.5T GE Vectra superconducting system (International General Electric, Slough, UK). Multisection T1-weighted spin-echo and T2-weighted fast spin-echo pulse sequences were performed, with an inversion recovery fast spin-echo sequence in two cases. Two-dimensional time of flight (2-D TOF) and/or 2-D phase contrast (PC) MRA was performed in 13 cases. Eleven patients had digital subtraction angiography (DSA) using a Phillips Integris V3000 digital angiographic unit. The findings at MRA and MRI were compared with the catheter angiograms, and the effective diagnostic input of MRA and MRI was determined. RESULTS: MRA demonstrated major feeding vessels and multiple intra-lesional vessels in relation to the high flow lesions, features absent in the low flow lesions. However, small feeding vessels to the AVMs were not clearly identified. MRI gave a clear demonstration of the anatomical extent of all lesions. AVMs (n = 6) and venous malformations (n = 6) were reliably distinguished, the former containing multiple serpentine signal voids on T1- and T2-weighted imaging, the latter being hyperintense to fat on T2-weighted images. Two other high-flow lesions diagnosed clinically as vascular malformations appeared solid on MRI, and were diagnosed histologically as a carotid body tumour and an angiomyolipoma. CONCLUSION: Although 2-D TOF MRA can distinguish AVMs from venous malformations, the technique adds little extra practical information to the diagnostic process, and cannot compete with catheter angiography for the detailed demonstration of AVM feeding vessels. These lesions can also be characterized using spin-echo sequences, though the primary role of MRI is to demonstrate their anatomical extent.