Pertussis: should we vaccinate post transplant?
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
C F Craddock
Publications and source records attributed to C F Craddock.
Stem cell transplantation after salvage therapy with high-dose cytarabine and amsacrine in adults with high-risk leukaemia.
Stem cell transplantation (SCT) may be the only curative option for patients with relapsed or refractory leukaemia, that is, high-risk (HR) leukaemia. Several salvage regimens have been used to cytoreduce disease before SCT, but disease progression or treatment toxicity limits numbers of patients receiving SCT. Here, we report our experience with high-dose cytarabine and amsacrine (Ara-amsa) to salvage patients with HR-leukaemia in the context of SCT. A total of 34 patients with HR-leukaemia (20 AML, 12 ALL, two advanced CML) received 3 g/m(2)/day cytarabine for 5 days and amsacrine 200 mg/m(2)/day for 3 days. Disease response was observed in 62% of patients. Toxicity was limited to neutropenic fever, one patient developed cerebellar toxicity and there was one treatment-related death. A total of 17 patients proceeded to SCT (12 allografts and five autografts). Median survival (OS) of all patients was 10.8 months (95% CI 7.8-21). Patients who were consolidated with SCT after salvage therapy had a superior median OS of 29.4 months (95% CI 12.5-upper limit not reached, n=17) than those who did not receive SCT (6.7 months, CI 1.5-8.6, P<0.0001). Median disease-free survival with SCT (23 months) was higher than after treatment with salvage chemotherapy alone (6.7 months, P=0.0002). Thus Ara-amsa can be used effectively to salvage HR-leukaemia, enabling further consolidation with SCT.
Adolescent↗
Allogeneic stem-cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH (+/- fludarabine) conditioning combined with post-transplant donor-lymphocyte infusion.
BACKGROUND: We report our updated experience of allogeneic transplantation in lympho-proliferative disorders using a reduced-intensity conditioning regimen combining BEAM (plus fludarabine in three cases) with pre-transplant CAMPATH. Post-transplant donor lymphocytes have been infused for persisting disease or relapse, and both chimerism and minimal residual disease have been monitored utilizing molecular techniques. METHODS: Thirty patients with median age 47.6 years underwent allogeneic transplantation for relapsed or high-risk lymphoproliferative disease using HLA-identical (sibling n = 25, unrelated n = 2) or one antigen mismatched sibling donors (n = 3). Twenty-one had NHL, three had HD and six had CLL/PLL. Stem-cell source was PBSC (n = 24), BM (n = 5) or both (n = 1) with a median CD34 dose of 4.5 x 10(6)/kg. GvHD prophylaxis was with CYA and MTX. RESULTS: Engraftment was prompt in the majority of patients, with a median of 15 days to both ANC > 0.5 and platelets > 20. There have been three transplant-related deaths secondary to viral pneumonitis or bacterial pneumonia. Seven patients developed Grade I-II acute GvHD post-transplant. Of 28 evaluable patients, 18 achieved a CR at assessment 2-3 months post-transplant and a further patient converted from PR to CR following DLI, to give an overall CR rate of 68%. Three patients had early progressive disease and six have relapsed from CR or progressed from PR (two of whom have achieved CR following DLI therapy). Overall survival is 67% and event-free survival 48% at 3 years. With a median follow-up of 1.3 years 57% of patients are currently alive and lymphoma-free. A molecular remission has been achieved in nine of 12 informative patients. DISCUSSION: These encouraging results show that this reduced-intensity conditioning regimen is effective, with a low-toxicity profile compared with conventional TBI-based conditioning, and certainly merits further evaluation in this setting.
Adolescent↗
Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice.
Although the use of cytokine-mobilized peripheral blood stem cells has gained a significant momentum in clinical transplantation, the mobilization schemes practiced are guided by a great deal of empiricism. The mechanism(s) by which cytokines or chemokines, alone or in combination, bring about redistribution of stem/progenitor cells from bone marrow to peripheral blood are poorly understood. Likewise the fate of mobilized stem/progenitor cells and their biological properties are incompletely defined. One of the leading hypotheses to explain the mechanism of cytokine-induced mobilization encompasses the view that cytokines disrupt, directly or indirectly, cytoadhesive interactions of stem/progenitor cells with their bone marrow stroma. Compatible with this view are changes in the expression and/or function of several cytoadhesion molecules, especially integrins, postmobilization, and extensive in vitro experimentation supporting the concept of cytokine/integrin interactions. To provide a further insight on the cytokine/integrin interplay in vivo, we have combined cytokine treatments with anti-integrin treatments for mobilization in primates and mice. We found that anti-VLA4 treatment combined with either granulocyte colony-stimulating factor (G-CSF ) treatment or kit ligand treatment leads to significant enhancement of mobilization efficiency (fivefold to eightfold) well above the levels produced by either cytokine alone or anti-VLA4 treatment alone. Similar enhancement was seen when combinations of cytokines, ie, G-CSF plus kit ligand or G-CSF plus Flt3-ligand were used with anti-VLA4 in primates and mice. Furthermore, when anti-VLA4 was given in 5-Fluorouracil-treated primates, significant numbers of progenitor cells were circulating for several days during the recovery period only in the anti-VLA4 treated animals. These data suggest that (1) the effect of anti-VLA4 on mobilization, when used alone, is unlikely to be mediated by secondary cytokine elaboration in vivo; (2) three different cytokines and their combinations do not appear to influence the in vivo responsiveness to anti-VLA4 in coadministration schemes; (3) even if cytokine treatments on their own exert downmodulation of VLA4 function, the target progenitor cells influenced by anti-VLA4 or by cytokines may not necessarily overlap; and (4) augmentation of mobilization in cytokine/anti-VLA4 treatments is most likely caused by an amplification of the pool of target cells on which anti-VLA4 exerts its effects. Because cytokines or anti-VLA4 are each capable of mobilizing long-term repopulating cells and because we show with the present studies that anti-VLA4 in an autologous bone marrow cell transplantation setting does not cause any delay in engraftment, the combination of cytokine/anti-integrin treatment enhancing mobilization may have a clinical use.
Animals↗
The role of CS1 moiety of fibronectin in VLA mediated haemopoietic progenitor trafficking.
In vitro the integrin VLA4 mediates the adhesion of haemopoietic progenitors to bone marrow stroma through an interaction with its ligands VCAM-1 and the CS1 moiety of fibronectin. The VLA4/VCAM-1 pathway has been implicated in haemopoietic trafficking in vivo since antibodies to both VLA4 and VCAM-1 decrease the homing (lodgement) of transplanted progenitors and mobilize progenitors. However, the role of the CS1 domain of fibronectin in progenitor trafficking in vivo has not been explored. We studied the effect of competitive inhibition of the VLA4/CS1 pathway on progenitor homing and mobilization in mice. Pre-incubation of bone marrow cells with a CS1 inhibitor did not alter the number of CFU-C or CFU-S12 lodged to the bone marrow of lethally irradiated mice 3 h after transplantation. In addition, continuous administration of a CS1 inhibitor did not increase the number of CFU-C in the peripheral blood. In order to study the role of the VLA4/CS1 pathway in trafficking of more primitive progenitors we studied whether administration of a CS1 inhibitor mobilized radioprotective cells. In contrast to the effect of anti-VCAM-1 which mobilized cells capable of rescuing 100% of lethally irradiated mice, administration of a CS1 inhibitor did not increase the number of radioprotective cells in the peripheral blood. Haemopoietic progenitors also bind to the RGD motif of fibronectin through an interaction with VLA5 and we therefore also studied the effect of antibodies to VLA5 on progenitor homing and mobilization. Antibody to VLA5 did not alter bone marrow lodgement at 3 h or increase the number of circulating haemopoietic progenitors. These studies therefore imply that, in contrast to VCAM-1, the CS1 moiety of fibronectin is not a significant ligand in VLA4 mediated progenitor trafficking in vivo.
Animals↗
Chromosomal stabilisation by a subtelomeric rearrangement involving two closely related Alu elements.
We have characterised a subtelomeric rearrangement involving the short arm of chromosome 16 that gives rise to alpha-thalassaemia by deleting the major, remote regulatory element controlling alpha-globin expression. The chromosomal breakpoint lies in an Alu family repeat located only approximately 105 kb from the 16p subtelomeric region. The broken chromosome has been stabilised with a newly positioned telomere acquired by recombination between this 16p Alu element and a closely related subtelomeric Alu element of the Sx subfamily. It seems most likely that this abnormal chromosome has been rescued by the mechanism of telomere capture which may reflect a more general process by which subtelomeric sequences are normally dispersed between chromosomal ends.
Adolescent↗
Contrasting effects of alpha and beta globin regulatory elements on chromatin structure may be related to their different chromosomal environments.
Expression of the human alpha and beta globin gene clusters is regulated by remote sequences, referred to as HS -40 and the beta-locus control region (beta-LCR) that lie 5-40 kb upstream of the genes they activate. Because of their common ancestry, similar organization and coordinate expression it has often been assumed that regulation of the globin gene clusters by HS -40 and the beta-LCR occurs via similar mechanisms. Using interspecific hybrids containing chromosomes with naturally occurring deletions of HS -40 we have shown that, in contrast to the beta-LCR, this element exerts no discernible effect on long-range chromatin structure and in addition does not influence formation of DNase I hypersensitive sites at the alpha globin promoters. These differences in the behaviour of HS -40 and the beta-LCR may reflect their contrasting influence on gene expression in transgenic mice and may result from the differing requirements of these elements in their radically different, natural chromosomal environments; the alpha cluster lying within a region of constitutively 'open' chromatin and the beta cluster in a segment of chromatin which opens in a tissue-specific manner. Differences in the hierarchical control of the alpha and beta globin clusters may exemplify more general differences in the regulation of eukaryotic genes which lie in similar open or closed chromosomal regions.
Animals↗
Healing of broken human chromosomes by the addition of telomeric repeats.
We have characterized and compared a series of naturally occurring chromosomal truncations involving the terminal region of the short arm of human chromosome 16 (16p13.3). All six broken chromosomes appear to have been stabilized by the direct addition of telomeric repeats (TTAGGG)n to nontelomeric DNA. In five of the six chromosomes, sequence analysis shows that the three of four nucleotides preceding the point of telomere addition are complementary to and in phase with the putative RNA template of human telomerase. Otherwise we have found no common structural features around the breakpoint regions. These findings, together with previously reported in vitro data, suggest that chromosome-healing events in man can be mediated by telomerase and that a small region of complementarity to the RNA template of telomerase at the end of a broken chromosome may be sufficient to prime healing in vivo.
Base Sequence↗
Circulating stem cells in mice treated with cyclophosphamide.
Chemotherapy has been used clinically to mobilize hematopoietic progenitor cells into the peripheral blood so that they can be harvested for autologous transplantation. In humans, this is demonstrated by the presence of circulating granulocyte-macrophage colony-forming cells (CFU-GM) and CD34-positive cells, but it has not been possible to confirm the presence of marrow-repopulating stem cells. In this study, we treated mice with 200 mg/kg cyclophosphamide (CY) and measured the numbers of white blood cells, day 12 CFU-S (CFU-S12), and CFU-GM in the peripheral blood. There was a peak in the numbers of CFU-S12 and CFU-GM 8 days after treatment with cyclophosphamide. Peripheral blood cells taken at this time rescued lethally irradiated mice and engraftment of donor cells was confirmed after 140 days in sex mismatched recipients using a Y chromosome-specific probe. In vitro culture of the blood cells harvested after cyclophosphamide showed that they proliferated in suspension cultures for at least a year in the presence of interleukin-3. The cultured cells rapidly lost their abilities to rescue irradiated mice and to form colonies in vitro, but they did not become leukemic. Also, CY-treated mice were irradiated with a leukemogenic dose of x-rays to coincide with peak circulating cell numbers but these animals did not develop an excess of leukemias over mice given irradiation alone.
Animals↗
Cis-acting sequences regulating expression of the human alpha-globin cluster lie within constitutively open chromatin.
Current models suggest that tissue-specific genes are arranged in discrete, independently controlled segments of chromatin referred to as regulatory domains. Transition from a closed to open chromatin structure may be an important step in the regulation of gene expression. To determine whether the human alpha-globin cluster, like the beta-globin cluster, lies within a discrete, erythroid-specific domain, we have examined the long-range genomic organization and chromatin structure around this region. The alpha genes lie adjacent to at least four widely expressed genes. The major alpha-globin regulatory element lies 40 kb away from the cluster within an intron of one of these genes. Therefore, unlike the beta cluster, cis-acting sequences controlling alpha gene expression are dispersed within a region of chromatin that is open in both erythroid and nonerythroid cells. This implies a difference in the hierarchical control of alpha- and beta-globin expression.
Animals↗
Diurnal variation in serum cortisol concentrations in asthmatic subjects after allergen inhalation.
To assess whether differences in the adrenal response to allergen are important in determining the magnitude of the allergen induced late responses in asthmatic subjects, we measured serum cortisol concentrations after inhalation challenge with allergen or control solution (phosphate buffered saline). The two challenges were performed in random order with an interval of 14 days. A normal diurnal decrease in serum cortisol concentrations was observed on both days. Mean blood cortisol concentrations three hours after inhalation of allergen (before the late response), nine hours afterwards (at the time of the late response), and 24 hours afterwards were virtually identical to those observed after inhalation of phosphate buffered saline. Serum cortisol concentrations before challenge and three, nine, and 24 hours after challenge were not related to the diurnal increase in blood eosinophils on the control day, or to the size of the late asthmatic response or accompanying changes in blood eosinophils after allergen challenge. It is concluded that serum cortisol concentrations show normal diurnal variation after allergen challenge and are unrelated to the size of the late response or associated changes in blood eosinophil counts.
Adult↗
Falls in peripheral eosinophil counts parallel the late asthmatic response.
Peripheral eosinophil counts were measured at intervals before and after control and allergen inhalation in 14 asthmatic subjects. A relative fall in eosinophil counts was noted 9 h after allergen challenge, in contrast to the diurnal increase seen on the control day (p = 0.005). This fall in eosinophil count correlated strongly with the magnitude of the late asthmatic response (r = -0.72, p = 0.003) and with the changes in bronchial responsiveness to histamine at 3 and 24 h after allergen was given (r = 0.54, p = 0.044 and r = 0.82, p less than 0.001, respectively). The findings demonstrate eosinophil kinetics are related to the occurrence of late-phase reactions and to the associated worsening of bronchial hyperreactivity.
Adult↗
Increases in airway responsiveness to histamine precede allergen-induced late asthmatic responses.
Changes in airway responsiveness to histamine after allergen inhalation challenge were studied in 14 nonsmoking atopic adult subjects with asthma. Inhalation challenges with allergen and with phosphate-buffered saline (control challenge) were performed single blind in random order, with an interval of 14 days. The development of a late asthmatic response was accompanied by an increase in airway histamine responsiveness that was significant when it was compared with the airway histamine responsiveness after the control challenge at 3 hours (p less than 0.01), 24 hours (p less than 0.01), and 48 hours (p less than 0.02), with recovery at 2 weeks after allergen inhalation. The 3-hour changes in airway responsiveness occurred independently of changes in airway caliber and correlated with the magnitude of the subsequent late response (r = 0.86; p less than 0.001). These results suggest that the tissue events (possibly airway inflammation) that underlie the late asthmatic response may occur before this response becomes clinically apparent.
Adult↗
Pseudomonas peritonitis in continuous ambulatory peritoneal dialysis: laboratory predictors of treatment failure.
Five episodes of pseudomonas peritonitis complicating continuous ambulatory peritoneal dialysis (CAPD) which were not cured by intraperitoneal antibiotics were studied to assess causes for treatment failure. The activity of gentamicin and ceftazidime against these strains was decreased in the presence of sterile used dialysate compared with nutrient broth. Likewise, kinetic studies showed that in dialysate therapeutically used concentrations of antibiotics failed to kill the isolates over 24 h. All five pseudomonas strains were adherent to silicone rubber Tenckoff catheter segments. An in vitro model of CAPD peritonitis demonstrated that persistence of viable adherent bacteria, after exposure to therapeutic concentrations of gentamicin and ceftazidime, contributes to the failure of antibiotics to cure pseudomonas CAPD peritonitis.
Adult↗
Novel C3 nephritic factor activity in the glomerulonephritis of staphylococcal endocarditis.
A case of glomerulonephritis complicating staphylococcal endocarditis is presented. Hypocomplementaemia and a C3-activating factor in the serum suggested that the patient might have mesangiocapillary glomerulonephritis in association with C3-nephritic factor. Renal biopsy showed that this was not so and further examination of the serum factor showed that it differed from classical C3-nephritic factor because it was not an immunoglobulin. It is postulated that complement activation and glomerulonephritis in staphylococcal endocarditis may be the direct result of a bacterial product. A substance in the serum which activates C3 should be confirmed to be an immunoglobulin before the presence of classical C3-nephritic factor is assumed.
Complement Activation↗
Influence of bacterial adherence to intravascular catheters on in-vitro antibiotic susceptibility.
Explore the source record for details and available documents.
Adhesiveness↗
Reversible coma in Wernicke's encephalopathy.
Explore the source record for details and available documents.
Adult↗
Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance.
Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.
Acidosis, Lactic↗