HLA effects in malaria: increased parasite-killing immunity or reduced immunopathology?
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Journal Article↗
Biomedical subjects
R Carter
Publications and source records attributed to R Carter.
Clinical correlation of high activity dynamic hepatic scintigraphy in patients with colorectal cancer.
The hepatic perfusion index, the ratio of hepatic arterial to total liver blood flow, was measured in 50 consecutive patients with colorectal cancer using radiolabelled colloid with high administered activity. In patients with proven liver metastases the diagnostic sensitivity of the HPI was 96% and the predictive value of a negative test was 92%. Dynamic hepatic scintigraphy is of value in the management of patients with colorectal cancer.
Colorectal Neoplasms↗
The combination of degradable starch microspheres and angiotensin II in the manipulation of drug delivery in an animal model of colorectal metastasis.
Both biodegradable emboli and pharmacological agents can enhance regional therapy for hepatic targeting. Using a rat model with similar haemodynamic characteristics to human colorectal liver tumour and a radio-labelled marker of similar molecular weight to Adriamycin, we have combined the two approaches to see if the effect was addictive. Following induction of liver tumour in male hooded rats by intrahepatic injection of HSN sarcoma cells, the relative distribution of marker, 99mTc methylene diphosphonate (MDP), was studied in three groups given the following by injection into the hepatic artery. (1) Saline (Control) + MDP; (2) Degradable Starch Microspheres (DSM) + MDP; and (3) Angiotensin II + DSM + MDP. Both Degradable Starch Microspheres alone (P less than 0.001) and Degradable Starch Microspheres + Angiotensin II (P = 0.003) significantly increased the retention of marker in liver and tumour at 1 min following injection, with a 12-fold improvement over controls, but the tumour:liver ratio was unaltered. By 90 min the MDP levels in normal hepatic parenchyma had returned to control values. There was relatively less washout with significant retention in tumour tissue in both DSM (P = 0.03) and combination treated animals (P = 0.001), with a significantly improved (P = 0.001) tumour to liver ratio (5.22:1) in combination treated animal relative to those treated with DSM alone.
Angiotensin II↗
Reflections on the International Medical Society of Paraplegia and management of paraplegia.
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History, 20th Century↗
Use of the Terumo SteriCell for the processing of bone marrow and peripheral blood stem cells.
The SteriCell cell processing instrument is a good choice for a stem cell processing laboratory that is of sufficient size that they cannot share an apheresis machine with the blood bank. It is a laboratory instrument, with no facility for patient connection. Because of its minimal size and weight, it is easily stored in a cramped laboratory. Its automated programs are appropriate for processing of bone marrow and peripheral blood stem cells, and it is quite easy to learn how to use (in our laboratory, most individuals have been completely facile with the SteriCell after fewer than six processings). Based on reported results from other instruments, the SteriCell provides cell yields that are comparable to competing instruments. Service (provided by Haemonetics) has been satisfactory, and support from Terumo has been excellent. We can recommend this instrument to any other laboratory.
Automation↗
Pathology of squamous carcinomas of the head and neck.
Recent publications have been critically reviewed to illustrate some of the newer approaches that may eventually provide more precise prognostic information from tumor biopsies. Examples include changes in expression of various surface antigens, DNA ploidy, and alterations at the level of molecular genetics, eg, gene amplification. Other molecular changes in tumor tissue, such as point mutations and loss of normal tumor suppressor genes, are also giving clues to underlying carcinogenic mechanisms.
Aneuploidy↗
Tumour necrosis factor-dependent parasite-killing effects during paroxysms in non-immune Plasmodium vivax malaria patients.
Plasmodium vivax malaria infections in non-immune individuals manifest as periodic clinical episodes of fever with chills and rigors known as paroxysms. We have demonstrated that in non-immune patients the period of paroxysm is associated with the transient presence of plasma factors which kill gametocytes, the intra-erythrocytic sexual stages of the malaria parasite which transmit the infection from humans to mosquito, rendering them non-infectious to mosquitoes. Gametocyte killing in paroxysm plasma is mediated by tumour necrosis factor (TNF) acting in conjunction with other essential serum factor(s). Plasma TNF levels were elevated during a paroxysm. In semi-immune individuals from a P. vivax-endemic area clinical symptoms of malaria are mild and the parasite killing factors are not induced during paroxysm. Serum TNF levels were correspondingly lower in endemic patients during a paroxysm. Human peripheral blood mononuclear cells (PBMC) can be stimulated in vitro by extracts of P. vivax blood stage parasites to produce TNF and associated parasite killing factor(s), thus simulating in vitro the events that occur during a paroxysm, this being the release of parasite exo-antigens by rupturing schizonts and the subsequent induction of PBMC to produce TNF and other parasite-killing factors. We were able to show that convalescent serum from P. vivax semi-immune individuals block the induction of TNF and parasite-killing factors by malaria antigens in vitro, presumably through antibodies that neutralize parasite exo-antigens. Thus, individuals living in malaria-endemic areas appear to acquire clinical immunity to malaria by avoiding their induction during infection; we have shown that one such mechanism is the neutralization of parasite exo-antigens that induce the production of parasite killing factors.
Animals↗
Anti-circumsporozoite protein antibodies measure age related exposure to malaria in Kataragama, Sri Lanka.
Antibodies to two peptides DDAAD and (NANP)40 representing the repetitive sequence of circumsporozoite antigens (CS protein) of P. vivax and P. falciparum respectively were measured in a cohort of 149 and 107 individuals respectively at four, 6 monthly blood surveys performed on residents of Kataragama, a P. vivax malaria endemic region in southern Sri Lanka. The prevalence of antibodies to the CS protein of both species was relatively low being less than 20% to either peptide in the population as a whole, this being consistent with the low entomological inoculation rates in the area. A marked age related prevalence pattern was evident, with the prevalence of antibodies increasing with age to reach between 25 to 30% in the 25-50 year age group in both P. vivax and P. falciparum. The population had had a life long exposure to P. vivax malaria but not to P. falciparum, an epidemic of which occurred in this region a few months prior to the beginning of this study. Nevertheless, the age-related prevalence of these antibodies was identical with respect to the two species. This suggests that the age-related prevalence pattern reflected differences in inoculation rates between the age groups due to differences in exposure to inoculation rather than an age acquired response resulting from a cumulative experience over several years. An analysis of antibody prevalence in individuals showed first, that sporozoite inoculations must have been clustered rather than homogeneously distributed in the population and secondly, that sero-conversion did not correlate with malaria infections in these individuals.
Adolescent↗
Transmission blocking immunity to human Plasmodium vivax malaria in an endemic population in Kataragama, Sri Lanka.
Serum effects on gametocyte infectivity, that is, transmission blocking/enhancing immunity, were measured in the sera of 196 acute Plasmodium vivax patients who were residents of a malaria region in Kataragama, southern Sri Lanka. Direct mosquito feedings were also performed on 170 of these patients. Sera of about 48% of patients suppressed gametocyte infectivity significantly (by more than 75%) and of a smaller proportion (12%) had pronounced infectivity enhancing effects. Transmission immunity did not increase with age of patients, rather, immunity tended to be higher in younger patients. Data suggest that immunity levels are boosted by reinfections only if they occur within a period of 4 months from the previous infection, i.e., that immune memory for boosting does not last beyond 4 months. Enhancing effects in the sera of patients correlated with the absence of gametocytes at the time of investigation suggesting that enhancement occurs early during the course of a blood infection, and blocking later, when serum antibodies reach higher levels. The blocking and enhancing effects of serum appears to depend not only on the antibody concentration in serum, but also on the intrinsic infectivity of the parasite isolate against which it is tested: thus, infectivity enhancing effects were potentiated by low intrinsic infectivities of the parasite isolate. The direct infectivity of patients to mosquitoes correlated with transmission immunity indicating that transmission immunity is an influential factor determining infectivity of malaria patients.
Adolescent↗
The role of cytokines in Plasmodium vivax malaria.
The cytokine tumor necrosis factor and other as yet unidentified factor(s) which together mediate the killing of intraerythrocytic malaria parasites are transiently elevated in sera during paroxysms in human Plasmodium vivax infections in non-immunes. These factors which included TNF and parasite killing factor(s) are associated with the clinical disease in malaria to the extent that their transient presence in infection sera coincided with paroxysms, the the most pronounced clinical disturbances of P. vivax malaria and secondly because their levels were markedly lower in paroxysm sera of semi-immune patients who were resident of an endemic area. Further, a close parallel was obtained between serum TNF levels and changes in body temperature that occur during a P. vivax paroxysm in non-immune patients, suggesting a causative role for TNF in the fever in malaria. P. vivax rarely if ever cause complicated clinical syndromes. Nevertheless serum TNF levels reached in acutely ill P. vivax patients were as high as in patients suffering from cerebral complications of P. falciparum malaria as reported in studies from the Gambia. Cytokine profiles and other changes accompanying clinical disease in P. vivax and P. falciparum malaria are compared in this paper with a view to discussing the potential role of cytokines in the causation of disease in malaria.
Fever↗
Characterization of a Plasmodium falciparium mutant that has deleted the majority of the gametocyte-specific Pf11-1 locus.
We identified a gametocyte-specific protein of Plasmodium falciparum called Pf11-1 and provide experimental evidence that this molecule is involved in the emergence of gametes of the infected erythrocyte (gametogenesis). A mutant parasite clone, which has deleted over 90% of the Pf11-1 gene locus, was an important control to establish the gametocyte-specific expression of the Pf11-1. Molecular analysis of the Pf11-1 deletion indicates that it is presumably due to a chromosome breakage with subsequent 'healing' by the addition of telomeric heptanucleotides. Moreover, similar DNA rearrangements are observed in most of the laboratory isolates during asexual propagation in vitro.
Animals↗
Transmission immunity in malaria: reflections on the underlying immune mechanisms during natural infections and following artificial immunization.
Malaria transmission-blocking immunity has been studied in natural malarial infections in man, during infections in animals and following artificial immunization of animals with sexual stage malaria parasites. Effective immunity, which prevents infectivity of a malarial infection to mosquitoes, has been observed under all of these circumstances. Two general types of effector mechanism have been identified. One is an antibody mediated mechanism which acts against the extracellular sexual stages of the parasite within the midgut of a blood feeding mosquito. The other is a cytokine mediated mechanism which inactivates the gametocytes of the parasites while still in the circulation of the vertebrate host. Both effects have been observed during natural infections and following artificial immunization. The basis of induction of transmission-blocking immunity, including the nature of the memory for such immunity, however, may be very different in different host/parasite systems and during natural infection or following artificial immunization. Following artificial immunization a strong immune memory for transmission blocking immunity has been observed in animal systems. By contrast, following natural infections in man immune memory for transmission blocking immunity has been found to be weak and short lived if it occurs at all. It is suggested that the immunogens which induce natural transmission blocking immunity may be CD4+ independent.
Animals↗
Exercise training in patients with chronic obstructive pulmonary disease.
Most patients with chronic obstructive pulmonary disease (COPD) demonstrate positive responses to exercise conditioning. Dyspnea is reduced and work tolerance is extended with little or no change in pulmonary function noted. Possible explanations for the increased ability to better tolerate exercise and activities of daily living (ADL) after training include: 1) psychological encouragement, 2) improvements in mechanical efficiency, 3) improved cardiovascular conditioning, 4) improved muscle function, 5) biochemical adaptations responsible for reducing glucose utilization, 6) desensitization to dyspnea, and 7) contributions from better self-care. However, not all patients respond positively to exercise conditioning. This may represent differences in patient selection, training approaches, and/or comorbidity issues commonly seen in patients with COPD. Alternatively, the answer may reside in devising an optimal training intensity, duration, and frequency combination for patients with COPD. This is not an easy matter because of the diversity of patients categorized as COPD. We have reviewed these issues from the available data and presented areas where additional research is warranted. What is needed at present is a series of well-controlled studies that focus on identifying and improving training responses in patients with COPD. Secondary to this issue is the long term epidemiologic surveillance of trained patients to document sustained effects.
Dyspnea↗
Stone in the middle gallbladder.
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Adult↗
Increased airways reactivity after smoke inhalation.
13 fire victims who required treatment after smoke inhalation underwent lung function assessment within 3 days of injury and 3 months later. Initial airways hyperreactivity improved over this period, but FEV1 and airways specific conductance did not change significantly. There was a strong correlation between exposure carboxyhaemoglobin concentration (an indicator of smoke exposure) and initial airways specific conductance (r + 0.79; p = 0.006). Airways obstruction after smoke inhalation in house fires may be more common and more persistent than is generally recognised. Early lung function tests would allow the incidence of pulmonary complications after smoke inhalation and the potential benefits of early use of inhaled antiinflammatory drugs to be assessed.
Adult↗
Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.
Malaria infection crisis, at which the parasitemia drops precipitously and the parasite loses infectivity to the mosquito vector, occurs in many natural malaria systems, and has not been explained. We demonstrate that in a simian malaria parasite (Plasmodium cynomolgi in its natural host, the toque monkey), the loss of infectivity during crisis is due to the death of circulating intraerythrocytic gametocytes mediated by crisis serum. These parasite-killing effects in crisis serum are due to the presence in the serum of cytokines tumor necrosis factor and interferon gamma, which are produced by the host as a result of the malaria infection. The killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified factor(s) in the crisis serum.
Animals↗
Growth-associated gene expression is not constant in cells traversing G-1 after exiting mitosis.
Analysis of gene expression following stimulation of growth-arrested cells has been the main approach for identification of growth-associated genes. Since the activation of these gene sequences is dependent on both the stimulatory agent and the state of quiescence of the cell, the activation and role of the same genes may be entirely different in non-growth arrested, actively proliferating cells. We have addressed the question of growth-associated gene expression during active growth by analyzing gene expression during G-1 of cells which have just exited mitosis without first leaving the cell cycle. We were able to isolate, by a non-inductive, drug free system, a population of highly synchronized Swiss 3T3 cells within mitosis (greater than 90%) in numbers sufficient to determine the pattern of expression of a large number of representative growth-associated genes. Our results show that after replating the mitotic cells into conditioned medium: (1) growth-associated gene expression is not constant during G-1 of actively proliferating cells, and (2) while a number of genes (e.g., JE, c-myc, ODC, p53, and histone) exhibited patterns of expression similar to that reported in the quiescent systems, others (e.g., nur-77, vimentin, calcyclin) exhibited patterns which were completely different. From these results, we can begin to construct a temporal map of G-1 progression during active growth.
Animals↗
Translocation (14;19) in acute biphenotypic leukemia.
Translocation (14;19)(q32;q13.1) is an acquired chromosomal rearrangement that has been associated with chronic lymphocytic leukemia of B-cell phenotype frequently progressing to lymphoma. Molecular analysis suggests that the translocation involves the immunoglobulin heavy chain gene on chromosome 14 and the BCL3 oncogene on chromosome 19. We present the first case of t(14;19) in a patient with acute leukemia. Correlation of detailed cytogenetic and molecular genetic studies, cell surface marker analysis, cytochemistry, and electron microscopy indicated that the leukemic cells were biophenotypic, with characteristics consistent with both myeloid and B-lineage lymphoid differentiation.
Adult↗