Biomedical subjects

W J Simpson

Publications and source records attributed to W J Simpson.

At least 37 records · Page 2Linked to original sources

PubMed1991

Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma.

From 1975 to 1982, 32 patients with a diagnosis of anaplastic carcinoma of the thyroid were entered into a protocol of hyperfractionated accelerated radiotherapy. The tumor dose was 30-45 Gy at 1 Gy per fraction given 4 times a day at 3-h intervals. The results were disappointing with a median survival of less than 6 months. Two patients developed radiation myelopathy at 8 and 13 months, total spinal cord dose being 39.9 and 48.3 Gy, respectively. The risk of spinal cord damage was much higher than expected. The possible radiobiological causes and clinical implications are discussed.

Carcinoma↗

PubMed1991

Antibody to a 39-kilodalton Borrelia burgdorferi antigen (P39) as a marker for infection in experimentally and naturally inoculated animals.

Borrelia burgdorferi expresses a conserved, species-specific 39-kDa protein (P39) that can stimulate antibodies during human infection. To confirm that anti-P39 antibodies are produced consistently in animals exposed to infectious spirochetes, white-footed mice, Peromyscus leucopus, and laboratory white mice, Mus musculus (strain BALB/c), were experimentally inoculated with either infectious or noninfectious B. burgdorferi and the antibody response to P39 was determined by immunoblot at 21 days postinoculation. All mice inoculated with approximately 10(7) infectious B. burgdorferi produced anti-P39 antibodies and were cultured positive for this spirochete. Mice inoculated with similar numbers of inactivated or viable noninfectious B. burgdorferi still producing P39 did not induce anti-P39 antibodies. By contrast, putative antiflagellin antibodies were detected in less than 18% of the infected animals, which supports the notion that antibody reactive with flagellin may not be reliable as a marker for B. burgdorferi exposure as was originally thought. Mice infected with B. burgdorferi following exposure to ticks (Ixodes dammini) produced anti-P39 antibodies no later than 7 days postinfection, indicating that P39 is an effective immunogen in natural infections. Notably, anti-P39 antibodies were the predominant B. burgdorferi reactive antibodies detected early in the infection. Our results indicate that anti-P39 antibodies are produced in response to an active infection and are therefore reliable markers for infection in experimentally and naturally inoculated animals.

Animals↗

PubMed1991

Molecular and immunological analysis of a polymorphic periplasmic protein of Borrelia burgdorferi.

Borrelia burgdorferi is the causative agent of Lyme disease, a tick-borne spirochetosis with a worldwide prevalence. To assist the categorization and typing of fresh isolates from global foci, we have identified a unique species-specific periplasmic protein (P22-A) conserved among all North American and European isolates examined. The gene encoding this antigen was cloned, and the recombinant was used to screen serum collected from experimentally infected animals. Although antibodies were detected in all infected animals at 21 days after inoculation with live, low-passage spirochetes, the response was stronger in other animals that were inoculated with inactivated and lysed bacteria. This result, along with the immune electron microscopy data, suggests P22-A is concentrated in the periplasmic space. The P22-A antigens exhibited size heterogeneity among different isolates, ranging between 20 and 23 kDa, but as a group the P22-A antigens appeared to retain antigenic homogeneity. Thus, P22-A can serve as a structural marker for characterizing new isolates of B. burgdorferi and may prove useful in future serological assays with a mixture of B. burgdorferi-specific antigens.

Animals↗

PubMed1991

Changes in antigenic reactivity of Borrelia burgdorferi, the Lyme disease spirochete, during persistent infection in mice.

Adult laboratory mice, Mus musculus, were shown to be suitable experimental animals for studying infectivity, persistent infection, and in vivo antigenic changes of Borrelia burgdorferi. Sixteen mice were inoculated intraperitoneally with a low-passage culture of an uncloned strain of B. burgdorferi and 16 months later spirochetes were reisolated from the urinary bladder of 15 (94%) of the mice. Spirochetes recovered from the urinary bladder of one persistently infected mouse were tested for infectivity and found to be infectious when passaged into four laboratory mice. Western blot analysis of immune serum from each of the persistently infected mice demonstrated that spirochetes used to infect the mice reacted differently when compared with the spirochetes subsequently reisolated from the mice, demonstrating for the first time that changes in antigenic reactivity had occurred in the spirochete populations during persistent infection.

Animals↗

PubMed1991

Factors influencing the antigenic reactivity of Borrelia burgdorferi, the Lyme disease spirochete.

The immunologic reactivity of some antigens of low passage Borrelia burgdorferi varied with the temperature at which it was cultivated in vitro, with long-term cultivation in vitro, and following passage in white-footed mice, Peromyscus leucopus. The low passaged uncloned strain Sh-2-82 had either more antigens or antigens which were more immunoreactive when grown at various temperatures from 28-39 degrees C. The influence of temperatures was less evident, however with a higher passage of the same strain. Immune sera from white-footed mice experimentally infected with the spirochete were more reactive with antigens of the inoculum than with antigens of spirochetes reisolated later. The antigenicity of the Lyme borreliosis spirochete is becoming more complex and this may relate to the complex life cycle that includes tick and mammalian hosts.

Animals↗

PubMed1990

Results of a screening program for C-cell disease (medullary thyroid cancer and C-cell hyperplasia).

In the authors' Medullary Screening Clinic, medullary thyroid cancer (MTC) or C-cell hyperplasia (CCH) has been identified in 26 relatives of 12 apparently "sporadic" patients from 56 families in which calcitonin (CT) testing has been performed. The interpretation of stimulated test results was sometimes difficult: elevated basal levels without a significant increase after the injection of secretagogues; basal levels in the normal range with considerable increases after stimulation but not exceeding two or three times the upper limit of normal; elevated basal or stimulated CT levels that slowly decreased to normal or near-normal levels over relatively short periods of time. The latter results suggest the possibility of CCH disappearing spontaneously in some patients.

Adolescent↗

PubMed1990

Analysis of supercoiled circular plasmids in infectious and non-infectious Borrelia burgdorferi.

Linear plasmids are widely distributed in isolates of Borrelia burgdorferi, but the prevalence of supercoiled circular (SC) plasmids has not been clearly established. Enriching for SC plasmids on ethidium bromide density-gradients revealed that a low passage of strain Sh-2-82 of B. burgdorferi has at least six SC plasmids (8.4, 8.8, 20, 26, 29 and 51 kb). In addition, several of the SC plasmids were observed by electron microscopy to form concatenated structures. Because of the high incidence of coupled SC plasmids and the effect of such structures on plasmid mobility, we suggest that they could be mistaken for a single DNA species having a high molecular weight when total DNA from B. burgdorferi is examined by agarose-gel electrophoresis. Of the six SC plasmids in strain Sh-2-82, four could still be detected after two years of continuous in vitro passaging in BSK II medium. The two SC plasmids lost after a maximum of 20 passages, pBBC1 (8.4 kb) and pBBC2 (8.8 kb), shared a high degree of DNA sequence similarity, suggesting that their apparent instability may be a unique feature of these closely related plasmids. Two higher passaged variants of strain Sh-2-82, P20 and P202, were shown by hybridization to lack pBBC1 and pBBC2 sequences and were unable to infect the white-footed mouse, Peromyscus leucopus. However, six of 14 unrelated isolates that infected this rodent and Syrian hamsters also lacked pBBC1 and pBBC2 sequences. None of five unrelated but highly passaged non-infectious isolates carried either pBBC1 or pBBC2 sequences. These data indicate that pBBC1 and pBBC2 do not encode constitutively expressed proteins required for infectivity in our experimental system. Nevertheless, eight of the 13 infectious strains examined did carry pBBC1 and/or pBBC2, indicating that these two closely related plasmids can be detected in a wide range of unrelated isolates of B. burgdorferi.

Animals↗

PubMed1990

Borrelia burgdorferi contains repeated DNA sequences that are species specific and plasmid associated.

Borrelia burgdorferi, the causative agent of Lyme borreliosis, contains linear and supercoiled circular (SC) plasmids. Because SC plasmids are present in multiple copies, these plasmids were examined for species-specific sequences that could serve as high-copy-number target DNAs for a diagnostic probe. Three EcoRI fragments (4.3, 4.2, and 3.5 kilobase pairs [kb]) that hybridized with multiple DNA fragments from B. burgdorferi were identified and cloned from a SC plasmid-enriched fraction. The 4.2- and 3.5-kb fragments were similar in that they hybridized with each other and with similar-sized EcoRI fragments from two unrelated strains of B. burgdorferi. The 4.3-kb fragment did not hybridize with the other two cloned sequences. Both types of sequences hybridized with most of the SC plasmids in seven B. burgdorferi isolates, whereas only a single 49-kb linear plasmid, found in two of the seven strains tested, hybridized with the cloned sequences. None of the cloned sequences hybridized with chromosomal DNA from B. burgdorferi or with total DNA or SC plasmids from Borrelia hermsii, B. turicatae, B. coriaceae, B. parkeri, or B. anserina. These data indicate that the repeated DNA sequences described in this study appear to be plasmid associated and specific to B. burgdorferi. Heteroduplexes formed from the 4.2- and 3.5-kb fragments showed that hybridizing regions in each fragment comprise a 1.8-kb conserved region that is adjacent to a 1.5-kb region that exhibits greater sequence variability. The sequence divergence seen in the variable region is likely the result of genetic drift and may mean that these regions represent closely related genes that encode functionally similar but antigenically distinct proteins.

Animals↗

PubMed1990

Coregulation of type 12 M protein and streptococcal C5a peptidase genes in group A streptococci: evidence for a virulence regulon controlled by the virR locus.

Group A streptococci express at least two surface-associated virulence factors, the antiphagocytic M protein and the antichemotactic streptococcal C5a peptidase (SCP). Preliminary evidence suggested that the biosynthesis of these two proteins is coordinately controlled and subject to simultaneous phase variation. To explore this possibility further, a series of phase-switching and phase-locked M- variants were assayed for SCP by enzyme-linked immunosorbent assay inhibition and for SCP-specific mRNA by dot blot hybridization. All M- cultures produced diminished amounts of SCP antigen and specific mRNA, whereas revertants produced quantities equivalent to those of the wild-type M+ culture. A phase-locked strain that harbors a deletion in a region upstream of the M12 and SCP genes, termed the virR locus, failed to produce SCP antigen or SCP-specific transcripts. The SCP-specific transcript produced by M+ bacteria was shown by Northern (RNA) blot hybridization to be 4 kilobases in size, distinguishing it from the transcript which encodes M protein. These data demonstrate that phase switching of both SCP and M12 proteins is at the transcriptional level and that expression is under the control of the upstream virR locus. We propose that the genetic determinants of these proteins and of colony morphology comprise a virulence regulon.

Adhesins, Bacterial↗

PubMed1990

Reactivity of human Lyme borreliosis sera with a 39-kilodalton antigen specific to Borrelia burgdorferi.

Borrelia burgdorferi is the causative agent of Lyme borreliosis, a spirochetal illness with a variety of acute clinical manifestations that may lead to debilitating neurological and arthritic complications. Diagnosis is difficult because symptoms mimic a variety of unrelated clinical conditions, spirochetes cannot always be isolated from infected patients, and current serological tests are frequently inconclusive because of the presence of cross-reacting non-B. burgdorferi antibodies. To identify antigens specific to B. burgdorferi that could be used in the serodiagnosis of Lyme borreliosis, we screened a Borrelia DNA expression library in Escherichia coli for antigens reactive with human Lyme borreliosis sera. One clone carried a 6.3-kilobase EcoRI chromosomal fragment (pSPR33), which encoded two species-specific antigens with molecular masses of 28 (P28) and 39 (P39) kilodaltons (kDa). These two antigens were immunologically distinct from OspA, OspB, and the 41-kDa flagellin. Ninety-four serum specimens from patients having Lyme borreliosis were tested for reactivity with P39. All of 33 the serum specimens with immunofluorescence assay titers of greater than or equal to 1:256, 13 of 17 serum specimens with titers of 1:128, and 14 of 44 serum specimens with titers of less than or equal to 1:64 reacted with P39. Notably, many sera reactive to P39 did not appear to react with the 41-kDa flagellin. Therefore, antibody to P39 could be mistaken for antibody to the 41-kDa flagellin in tests of human sera by Western blot (immunoblot). Twenty-five control serum specimens, which included sera from syphilitic, relapsing fever, and amyotrophic lateral sclerosis patients as well as from 10 normal individuals, did not react to P39. Our data suggest that P39 may be a useful antigen for the serological confirmation of Lyme borreliosis.

Animals↗

PubMed1990

Recombinant capsular antigen (fraction 1) from Yersinia pestis induces a protective antibody response in BALB/c mice.

Yersinia pestis produces a glycoprotein capsule, the biosynthesis of which appears to be temperature dependent. The fraction I (F1) component of this capsule is specific to Y. pestis and the detection of F1 antibodies is the basis for several serological tests. We report the cloning of the F1 gene and its expression in Escherichia coli using the phagemid vector lambda ZAPII and a F1-specific monoclonal antibody. The recombinant F1 antigen had a molecular weight of 17 kDa, which proved to be identical to that of the F1 antigen produced by Y. pestis. The recombinant cells produced F1 antigen at 37 degrees C but only minimal amounts at 27 degrees C, suggesting that the genetic features affected by temperature in Y. pestis may be operating in the E. coli clone. It is not known if their similar molecular weights reflect the glycosylated nature of both proteins. F1 antigen purified from the E. coli recombinant induced a protective immune response in BALB/c mice challenged with up to 10(5) virulent Y. pestis. The resistance of immunized mice to plague infection correlated with high titers of F1 antibody. The cloned gene expresses an immunogenically competent F1 antigen suitable for use in plague serodiagnostics and vaccine development.

Animals↗

PubMed1990

Radioiodine and radiotherapy in the management of thyroid cancers.

Radioiodine is an important adjuvant treatment in the management of resectable papillary and follicular thyroid cancers in all patients except those with the best prognostic features. External radiation is also an important adjuvant therapy in these patients, especially those with tumors that extend beyond the thyroid gland and invade the trachea, esophagus, nerves, and blood vessels; it is especially important in treating patients whose tumors do not concentrate radioiodine. Radioiodine may be curative in patients with microscopic distant metastases demonstrated by radioiodine scanning. Even unresectable primary papillary and follicular cancers may be eradicated by combined therapy with radioiodine and radiotherapy. Radioiodine plays no significant role in the treatment of medullary or anaplastic thyroid cancers, but external radiation may eradicate microscopic thyroid bed or nodal disease when persistent disease is indicated by elevated calcitonin levels in medullary thyroid cancer patients. Anaplastic thyroid cancers are usually unresectable and are not eradicated by conventional radiotherapy or by any of the novel radiation techniques, with or without chemotherapy. In all types of thyroid cancer, external radiotherapy may produce beneficial palliative results in patients with distant metastases, but the use of radioiodine should always be explored in papillary and follicular thyroid cancer patients.

Adenocarcinoma↗

PubMed1989

Antibody response in white-footed mice (Peromyscus leucopus) experimentally infected with the Lyme disease spirochete (Borrelia burgdorferi).

White-footed mice (Peromyscus leucopus), the primary reservoir for Borrelia burgdorferi in the northern midwest and northeastern United States, were experimentally inoculated with an infectious strain or a noninfectious strain of the Lyme disease spirochete and examined for their specific antibody response with the enzyme-linked immunosorbent assay and Western blot (immunoblot) analysis. Immunoglobulin M (IgM) anti-B. burgdorferi antibodies were detected in mice 1 to 2 days after inoculation with either the infectious or noninfectious strain of spirochetes and peaked on days 4 and 5. Mice inoculated with the infectious strain of spirochete had a secondary increase in IgM 21 days after inoculation. Mice also produced both IgG1 and IgG2 antibodies beginning 5 to 7 days after inoculation and they increased in titer until 84 days after inoculation when the experiment was terminated. Western blot analysis of sequential plasma samples from mice inoculated with the infectious strain of spirochete demonstrated the development of IgM, IgG1, and IgG2 antibodies to numerous spirochetal antigens, whereas mice inoculated with the noninfectious strain had reduced blot patterns with antibodies reactive primarily to the 31,000-kilodalton outer surface protein A. Persistent spirochetal infection in some mice, in spite of a strong and diverse antibody response, deserves further investigation.

Animals↗

PubMed1989

Identification of Borrelia burgdorferi and B. hermsii using DNA hybridization probes.

Fragments of plasmid DNA from Borrelia burgdorferi and B. hermsii were cloned and tested for specificity as hybridization probes to identify these two species of pathogenic spirochetes. Three fragments from the 49-kilobase-pair linear plasmid of B. burgdorferi were tested: a 500-base-pair (bp) HindIII fragment (probe 49A), a 445-bp PstI-HindIII fragment (probe 3G), and a 320-bp HindIII fragment (probe 16H). When hybridized to purified DNA or whole spirochetes, all of the probes distinguished B. burgdorferi from the other species examined, including B. hermsii, B. parkeri, B. turicatae, B. coriaceae, B. crocidurae, and B. anserina. Probe 49A was the most useful, however, hybridizing with all strains of B. burgdorferi originating from both North America and Europe while not cross-hybridizing with B. hermsii. A 790-bp HindIII fragment of B. hermsii DNA hybridized with DNA and whole spirochetes of this species and also with B. parkeri, confirming the close relatedness of these two species. These probes provide a new method of identifying these Borrelia species once the organisms have been grown in culture.

Animals↗

PubMed1988

Papillary and follicular thyroid cancer: impact of treatment in 1578 patients.

We report the experience from 13 Canadian radiotherapy centres concerning the treatment and outcome for 1074 papillary and 504 follicular thyroid cancer patients followed for 4-24 years. Surgical resection was carried out in almost all patients; there was no correlation between the type of operation and recurrence or survival. Treatment with external irradiation (201 patients) radioiodine (214 patients), or both (107 patients) was used more often in poor prognosis patients than in those with good prognostic factors, and was effective in reducing local recurrences and improving survival, especially in patients with microscopic residual disease postoperatively. Treatment complications were common but rarely fatal. Thyroid cancer was the cause of death in over half of the papillary cancer deaths and in two-thirds of the follicular cancer deaths.

Adenocarcinoma↗

PubMed1988

Squamous cell carcinoma of the thyroid gland.

We present the clinical manifestations and details of treatment and outcome for eight patients with squamous cell cancer arising in the thyroid gland, which is a rare entity. All patients had advanced disease, with primary tumors invading adjacent structures (the trachea, esophagus, and major vessels). In two patients, pulmonary metastases were also present. Six patients died 6 months or less after diagnosis, five from the effects of local disease. Transient palliation was obtained in four patients who underwent partial excision (three patients) and radical radiotherapy (one patient). Two patients remained free of disease at last follow-up more than 4 years after gross total tumor resection and radical radiotherapy and were presumably cured. One patient treated by partial resection and radical radiotherapy died from other causes 17 months later. His disease status was unknown. Complete excision with postoperative radiotherapy may be curative, and debulking followed by external irradiation may provide short-term palliation. Patients with unresectable tumors are best managed by supportive measures only unless a truly effective chemotherapeutic regimen is developed for squamous cell cancer of the head and neck.

Adult↗

PubMed1988

The role of surgery in the management of thyroid lymphoma.

The role of surgery in the management of patients with primary lymphoma of the thyroid gland has been addressed after review of 61 patients treated at Princess Margaret Hospital between 1958 and August 1982, 46 of whom had clinical stage I and II disease confined to the thyroid gland or lymph nodes or both above the diaphragm. Postoperative radiation therapy was used in 34 patients, radiation therapy and chemotherapy in 11 patients, and chemotherapy alone in 1 patient. Analysis of disease progression, local relapse, and distant disease recurrence indicated that postoperative residual disease bulk predicted strongly for both local and distant disease progression. Overall cause-specific survival was 59% at 5 years, with a relapse-free rate of 46% at 5 years. Of those with less than 2.5 cm of residual disease after surgery, 80% achieved lifelong local disease control compared with 40% for those with residual disease in excess of 2.5 cm after surgery. Distant relapse rates were 7% and 23% for those with less than 2.5 cm and greater than 2.5 cm after surgery, respectively. The long-term survival rate for those with disease progression during this period was approximately 10%, with a median survival expectancy of 18 months. It is suggested that those patients without an antecedent cytologically based diagnosis of lymphoma undergo biopsy and removal of operable tumor without compromise of parathyroid glands, recurrent laryngeal nerves, or appearance. Those patients with an existing cytologic diagnosis of lymphoma and bulky and/or inoperable tumor may be more effectively managed with a combined chemotherapy-radiation therapy program.

Antineoplastic Agents↗

PubMed1987

Tuberculosis infection in cattle and badgers in an area of Staffordshire.

The recent history of tuberculosis infection in cattle in Staffordshire is described, showing how a problem area in the north of the county was identified. The subsequent culture of Mycobacterium bovis from badger faeces and a badger carcase is reported together with the operations to remove badgers from the area.

Animals↗