Hepatitis B immunisation: problems and practicalities in a primary school.
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Child↗
Biomedical subjects
R Carter
Publications and source records attributed to R Carter.
A potential role for c-jun in cell cycle progression through late G1 and S.
When the level of c-jun mRNA was analyzed in WI-38 human fibroblasts exciting short- and long-term quiescence, two peaks of c-jun mRNA accumulation were found. The first occurred one hour after stimulation and lasted three to five hours, whereas the second occurred at the G1/S border and was coupled to the time of entry to S phase rather than to the time of stimulation. The early peak is well documented and in agreement with the proposed role of c-Jun/AP-1 in mediating cellular responses to receptor-generated signals. The later peak, however, has not been previously reported. Additional follow-up studies showed that late G1/S expression was not solely a phenomenon of cells existing a quiescent state, nor was it restricted only to human cells. Gel retardation studies confirmed that there is AP-1 specific DNA binding activity in nuclear extracts isolated in late G1 and S phase, and that this AP-1 binding activity is due to the presence of Jun protein. An anti-Fos antibody was able to significantly decrease AB-1 binding activity in early G1 extracts, but had no effect on extracts isolated in late G1 and S phase, indicating that the complexes observed in late G1 and S phase are clearly different from those seen in early G1. These studies are among the first to suggest a functional dissociation of c-Jun from c-Fos. Our results identify a new, previously unreported role for c-Jun/AP-1 in regulation of cell cycle progression and mammalian cell growth.
Animals↗
Catheterisation: your urethra in their hands.
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Clinical Competence↗
Sequence coding for a sexual stage specific protein of Plasmodium falciparum.
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Amino Acid Sequence↗
Target antigens of transmission blocking immunity of Plasmodium vivax malaria. Characterization and polymorphism in natural parasite isolates.
A panel of 20 anti-Plasmodium vivax female gamete mAb has been established and was characterized with respect to their transmission-blocking properties in membrane-feeding experiments and their target Ag identified. Seven mAb suppressed the infectivity of P. vivax parasites to Anopheles tesselatus mosquitoes. The m.w. of the Ag recognized by these mAb were ascertained by SDS-PAGE and Western blots. Three sets of polypeptides of low Mr--20, 24, and a doublet of 37/42 kDa--have been defined as target Ag of transmission-blocking antibodies of P. vivax. All epitopes of these target Ag were found to be dependent on the tertiary conformational structure of the Ag. Polymorphism of target Ag of transmission-blocking immunity was investigated in over 30 natural isolates of P. vivax in Sri Lanka based on the reactivity of a mAb with an isolate as assessed by the indirect immunofluorescent test with the use of live extracellular female gametes, and in Western blots with the use of extracted gametes. The functional consequences of antigenic polymorphism on immunity was investigated in transmission-blocking assays by using membrane-feeding experiments. A majority of target Ag of transmission-blocking immunity were found to be polymorphic, exhibiting size as well as epitope polymorphism. Results indicate that failure of a mAb to affect the infectivity of a parasite isolate of P. vivax to mosquitoes can be caused by polymorphism of the target Ag among isolates.
Animals↗
Tumor cells exhibit deregulation of the cell cycle histone gene promoter factor HiNF-D.
Cell cycle-regulated gene expression is essential for normal cell growth and development and loss of stringent growth control is associated with the acquisition of the transformed phenotype. The selective synthesis of histone proteins during the S phase of the cell cycle is required to render cells competent for the ordered packaging of replicating DNA into chromatin. Regulation of H4 histone gene transcription requires the proliferation-specific promoter binding factor HiNF-D. In normal diploid cells, HiNF-D binding activity is regulated during the cell cycle; nuclear protein extracts prepared from normal cells in S phase contain distinct and measurable HiNF-D binding activity, while this activity is barely detectable in G1 phase cells. In contrast, in tumor-derived or transformed cell lines, HiNF-D binding activity is constitutively elevated throughout the cell cycle and declines only with the onset of differentiation. The change from cell cycle-mediated to constitutive interaction of HiNF-D with the promoter of a cell growth-controlled gene is consistent with, and may be functionally related to, the loss of stringent cell growth regulation associated with neoplastic transformation.
Animals↗
Human T cell proliferative responses to Plasmodium vivax antigens: evidence of immunosuppression following prolonged exposure to endemic malaria.
Human T cell proliferative responses, of 33 adult Sri Lankans convalescing from Plasmodium vivax infections, to several P. vivax antigens (i.e. a soluble extract of asexual erythrocytic stage parasites and two cloned antigens that are potential vaccine candidates PV200 and GAM-1) were assessed. The peripheral blood mononuclear cell proliferative responses to the soluble extract of P. vivax, as assessed by studying both the proportion of responders and the degree of the response, were significantly lower in a group of individuals resident in a malaria endemic area in Sri Lanka than in another group that did not have a life-long exposure to malaria but had acquired the disease on a visit to an endemic region. Individuals of both groups responded equally well to mitogen. The responses to a non-malarial antigen such as purified protein derivative of tuberculin were only marginally lower in residents of the malaria-endemic region. These findings suggest that exposure to endemic P. vivax malaria leads to a specific immunosuppression to P. vivax antigens. Immunosuppression of a much lower degree was evident to a non-malarial antigen.
Adolescent↗
Evidence that density-dependent growth arrest is a two-stage process in WI-38 cells.
It was the goal of this study to determine whether during long-term quiescence WI-38 cells gradually lose labile components which then need to be resynthesized before a stimulated cell can progress through G-1 and enter S. The metabolic and molecular status of WI-38 cells was systematically analyzed as they entered and were maintained for an extended period of time in a state of density-dependent growth arrest. Our results indicate that growth arrest in WI-38 cells can be divided into two stages. The first, which we call "early" growth arrest, occurs during the first 7-10 days following cessation of DNA synthesis and mitosis. It is characterized by few biochemical changes compared to actively proliferating cells. During this period of early growth arrest cells do not exhibit a prolongation of the prereplicative stage following serum stimulation. In contrast, WI-38 cells growth arrested for 10-20 days exhibit a number of changes at the molecular and biochemical level (i.e., a twofold decrease in total protein and total RNA content, and decreased levels of most proteins, but an increased amount of fibronectin and collagen). Also, quiescent WI-38 cells stimulated at any time during "later" or "deep" growth arrest do exhibit a prolonged prereplicative phase. Although changes were also observed in the patterns of expression of ten representative growth-associated genes (i.e., histone H-3, p53, c-Ha-ras, 2A9/calcyclin, 4F1/vimentin, LDL-receptor, insulin receptor, collagen, and fibronectin), these occurred mostly at the time when the cells ceased synthesis of DNA and mitosis and became quiescent. No changes in the steady-state levels of the growth-associated transcripts analyzed occurred while the cells were maintained in the growth-arrested state. Thus, these experiments show that although WI-38 cells do cease to incorporate thymidine and divide under crowded culture conditions, the "quiescent" cells continue to undergo changes, are metabolically active, and certainly do not grossly deteriorate.
Blotting, Western↗
Plasmodium cynomolgi: serum-mediated blocking and enhancement of infectivity to mosquitoes during infections in the natural host, Macaca sinica.
The infectivity of Plasmodium cynomolgi in its natural host, the toque monkey, Macaca sinica, to Anopheles tessellatus mosquitoes was studied in relation to the evolution of anti-sexual-stage immunity in the host during the course of a blood-induced infection. The effects of serum on the infectivity of gametocytes and the intrinsic infectivity of gametocytes to mosquitoes on each day were assessed in membrane feeding experiments. Mosquitoes were also directly fed on the animal on each day. Our results demonstrate that during the very early patent period, before the peak of gametocytemia, the infection serum enhanced the infectivity of gametocytes up to two to three times above their infectivity in normal monkey serum. Subsequently, serum drawn post-peak of parasitemia ceased to enhance, and began to suppress, infectivity. After 2-3 months, long after parasitemias ceased patency, the serum no longer suppressed and between 3 and 4 months the serum again tended to enhance gamete infectivity before losing any significant effect. Serum infectivity enhancing effects were consistent with low indirect immunofluorescence test antibody titers against blood stage parasites first during the very early days of a blood infection before reaching blocking levels, and again during convalescence when antibodies were declining. The serum infectivity blocking effects on gametocytes were seen at the peak of antibody titers from about Days 9 to 23 of an infection. From 78 to 95% of the total infectivity of the parasite to mosquitoes during an infection occurred when infectivity enhancing activity was present in the serum. Hence, the infectivity of the parasite to mosquitoes was largely dependent on infectivity enhancing antibodies in host serum.
Animals↗
Human immune responses against sexual stages of malaria parasites: considerations for malaria vaccines.
Studies on the natural immune responses to the sexual stages of malaria parasites have been reviewed in the context of human malaria transmission-blocking vaccines. Antibodies against the sexual stages of the malaria parasite, gametocytes and gametes, are readily evoked by natural malaria infections. These antibodies that suppress infectivity at high concentrations can, at low concentrations, enhance the development of the parasite in the mosquito; however, because enhancing antibodies are prevalent during natural malaria infections, it is likely that a vaccine would rapidly boost these antibodies to blocking levels. The immunogenicity of sexual stage antigens appears to be constrained in the human host, probably due to T epitope polymorphism and MHC restriction in humans. These constraints apply mainly to those antigens that are sensitive targets of host immunity such as the gamete surface antigens and not to internal gamete antigens, indicating that antigenic polymorphism may have evolved in response to immune selection pressure. Evidence for immunosuppression of the host by exposure to endemic malaria is presented and its consequences on vaccine development are discussed.
Animals↗
Anti-parasite effects of cytokines in malaria.
Cytokines induced during natural malaria infections, e.g., at crisis of a blood infection of Plasmodium cynomolgi, and during clinical paroxysms in human Plasmodium vivax infections, mediate killing of intra-erythrocytic blood stage malaria parasites. These cytokines, TNF and IFN-gamma, require additional, yet unidentified complementary factors that are present in "crisis" and "paroxysm" serum to kill intra-erythrocytic blood stage parasites. In contrast, cytokines, (mainly IFN-gamma) are able to effect killing of intra-hepatic stages of the parasite by themselves independent of serum complementary factors, suggesting that the mechanisms of killing may be different with respect to the two parasite stages. Cytokines also appear to be critical intermediates in mechanisms of clinical disease in malaria. Serum cytokine (TNF) levels and killing effects on blood stage malaria parasites were lower in patients who were exposed to endemic P. vivax malaria who had partial clinical immunity, than in non-immune patients. Evidence suggest that individuals acquire natural immunity to the disease by avoiding the induction of high levels of cytokines and complementary factors.
Animals↗
Commitment of the malaria parasite Plasmodium falciparum to sexual and asexual development.
Blood-stage malaria parasites in the vertebrate host can develop either into the asexual, multiplying forms, called schizonts, or into gametocytes, the sexual stages of the parasite. In the present work we studied the differentiation into asexual parasites or gametocytes of the progeny of single, isolated schizonts of the clone 3D7A of Plasmodium falciparum, using monoclonal antibodies specific for the sexual or asexual stages of the parasite. We observed that schizonts obtained from a continuous culture undergoing serial cycles of growth and dilution with fresh red blood cells produced either only gametocytes or only asexual parasites, showing a high degree of commitment to one or the other developmental pathway. The relative proportion of schizonts which produced gametocytes was very low at low parasite densities in culture, while at high parasite densities a much greater proportion of schizonts produced gametocytes. Nevertheless, at both low and high parasite densities individual schizonts were almost always fully committed to producing only gametocytes or only asexual parasites.
Animals↗
The prevalence of hyperlipidemia in renal transplant recipients. Associations with immunosuppressive and antihypertensive therapy.
To determine the extent of persisting hyperlipidemia in renal transplant recipients receiving modern maintenance immunosuppressive and antihypertensive therapy we compared plasma levels of total and high-density lipoprotein and triglyceride in 275 renal transplant recipients with stable graft function with age- and sex-matched groups from the local general population (n = 4055). Total cholesterol and triglyceride were higher in transplanted patients in all age groups, but the difference was much more striking in women. Plasma levels of HDL cholesterol were similar or slightly lower in transplanted patients. Association with parameters of graft function, immunosuppressive therapy, and antihypertensive therapy were studied within the transplanted population using multiple regression. Total cholesterol was significantly and independently associated with age, sex, diuretic therapy, and urinary protein. In 127/134 (95%) of patients the diuretic was a loop diuretic. None of the other classes of antihypertensive drug was independently associated with serum cholesterol. The only variables significantly associated with HDL cholesterol were sex and the plasma creatinine. Plasma triglyceride was significantly and independently associated with both diuretic therapy and beta-blocker therapy and with age, urinary protein excretion, and plasma albumin. Plasma cholesterol, HDL cholesterol, and triglyceride levels were almost identical in patients receiving triple therapy (cyclosporine 3-5 mg/kg; prednisolone 7-10 mg o.d.; azathioprine 1-1.5 mg/kg) to those in patients receiving conventional immunosuppression (prednisolone 7-10 mg o.d.; azathioprine 2-2.5 mg/kg). Thus these results do not support the existence of a persisting long-term effect of cyclosporine on plasma cholesterol and triglyceride at these doses of the drug. The more striking abnormality of plasma cholesterol and triglyceride in females is unexplained but might be connected with greater sensitivity to low doses of corticosteroids.
Adult↗
Clinical and pharmacological study of a novel controlled release preparation of salbutamol.
This study compared the efficacy of 8 mg controlled release (CR) salbutamol tablets twice daily with standard 4 mg salbutamol tablets four times daily in patients with chronic obstructive airways disease. There was significant bronchodilation in both treatment groups as measured by standard spirometry (P less than 0.05). With the CR preparation there was significantly less wheeze (P less than 0.05) and significantly reduced requirement for rescue bronchodilator (P less than 0.05). Salbutamol levels measured hourly on the final day of each treatment period showed that the drug profile in the CR group was smoother, without the troughs and peaks seen with standard tablets.
Adult↗
Properties of epitopes of Pfs 48/45, a target of transmission blocking monoclonal antibodies, on gametes of different isolates of Plasmodium falciparum.
We have studied the properties of epitopes on Plasmodium falciparum gamete surface protein Pfs 48/45, a target antigen of malaria transmission blocking antibodies. Using a two site immunoradiometric assay we have defined three spacially separate, non-repeated, epitope regions on the peptides representing this antigen. Epitope region I is a target of monoclonal antibodies (MoAbs) which strongly suppress infectivity of gametocytes of P. falciparum to mosquitoes; the effect is complement independent and is mediated as effectively by the monovalent Fab fragments as by intact MoAb. Epitope region II consists of two spacially close subregions, IIa and IIb; variant forms of epitopes IIa and IIb occurred in different isolates of P. falciparum. Epitope region III also showed slight structural modification between isolates. MoAbs against regions II or III were relatively ineffective in suppressing gametocyte infectivity compared to MoAbs against region I. However, certain combinations of MoAbs against regions II and III together acted synergistically to suppress infectivity to mosquitoes. All these epitopes failed to react with MoAb when the antigen was presented in reduced form. A fourth epitope, however, was identified which reacted strongly with MoAb when the antigen was presented in reduced form. The MoAb against this epitope had no effect on the infectivity of gametocytes of P. falciparum to mosquitoes.
Animals↗
Is the penile brachial index a reproducible and useful measurement?
The intra- and inter-observer variation in the measurement of the penile brachial index (PBI) was prospectively assessed in 30 patients. An appreciable error was discovered that cast doubt on the reliability of the measurements. Up to 20% of patients deemed normal by one observer would be deemed abnormal by a second. The PBI appears to be an inaccurate and poorly reproducible test of penile blood flow which can lead to a false diagnosis and subsequent management of impotent patients. There would appear no justification for the continued use of the penile brachial index in the assessment of erectile dysfunction.
Adult↗
Nephroblastoma presenting with acute hepatic encephalopathy.
A 3 year old girl presented with Budd-Chiari syndrome of acute onset, and hepatic encephalopathy secondary to intravascular extension of a Wilms' tumour shown on echocardiography. After a period of intensive medical treatment the tumour was removed, cardiopulmonary bypass with hypothermic circulatory arrest being necessary. Her hepatic failure resolved and she made a complete neurological recovery.
Acute Disease↗
Sexual differentiation in malaria parasites.
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Animals↗