Churchill Hospital

About: Churchill Hospital is a healthcare organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Transplantation. The organization has 3548 authors who have published 5357 publications receiving 304275 citations.

Ambulatory blood pressure and left ventricular hypertrophy in subjects with untreated obstructive sleep apnoea and snoring, compared with matched control subjects, and their response to treatment.

Abstract: 1. Obstructive sleep apnoea and snoring are associated with daytime hypertension. It is uncertain whether this association is directly due to the disturbed sleeping respiration or the result of confounding variables, particularly obesity, smoking and alcohol intake. 2. Ambulatory blood pressure and echocardiographic left ventricular muscle mass were measured in 19 patients with obstructive sleep apnoea, 19 men who snore without apnoea and 38 control subjects matched for age, sex, body mass index, smoking and alcohol intake. Ambulatory blood pressure was also measured before and after treatment in 11 patients with obstructive sleep apnoea and their matched control subjects. 3. Compared with matched control subjects, untreated obstructive sleep apnoea and snoring were not associated with an increase in daytime blood pressure. A daytime elevation of either systolic or diastolic blood pressure of > 3.8 mmHg due to obstructive sleep apnoea or snoring was excluded with 95% confidence in each of the study groups. Daytime blood pressure was also unchanged when obstructive sleep apnoea was treated with nasal continuous positive airway pressure. Night-time blood pressure was not significantly different in the patients with obstructive sleep apnoea or the snorers when compared with their matched control subjects. However, a fall in night-time systolic blood pressure was seen in the patients with obstructive sleep apnoea after treatment [fall in systolic blood pressure -6.3 (SD 8.2) mmHg, P < 0.02]. 4. Left ventricular diameter, wall thickness and calculated mass were similar in each of the study groups and their matched control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasmodium vivax Adherence to Placental Glycosaminoglycans

Abstract: Background Plasmodium vivax infections seldom kill directly but do cause indirect mortality by reducing birth weight and causing abortion. Cytoadherence and sequestration in the microvasculature are central to the pathogenesis of severe Plasmodium falciparum malaria, but the contribution of cytoadherence to pathology in other human malarias is less clear. Methodology The adherence properties of P. vivax infected red blood cells (PvIRBC) were evaluated under static and flow conditions. Principal Findings P. vivax isolates from 33 patients were studied. None adhered to immobilized CD36, ICAM-1, or thrombospondin, putative ligands for P. falciparum vascular cytoadherence, or umbilical vein endothelial cells, but all adhered to immobilized chondroitin sulphate A (CSA) and hyaluronic acid (HA), the receptors for adhesion of P. falciparum in the placenta. PvIRBC also adhered to fresh placental cells (N = 5). Pre-incubation with chondroitinase prevented PvIRBC adherence to CSA, and reduced binding to HA, whereas preincubation with hyaluronidase prevented adherence to HA, but did not reduce binding to CSA significantly. Pre-incubation of PvIRBC with soluble CSA and HA reduced binding to the immobilized receptors and prevented placental binding. PvIRBC adhesion was prevented by pre-incubation with trypsin, inhibited by heparin, and reduced by EGTA. Under laminar flow conditions the mean (SD) shear stress reducing maximum attachment by 50% was 0.06 (0.02) Pa but, having adhered, the PvIRBC could then resist detachment by stresses up to 5 Pa. At 37°C adherence began approximately 16 hours after red cell invasion with maximal adherence at 30 hours. At 39°C adherence began earlier and peaked at 24 hours. Significance Adherence of P. vivax-infected erythrocytes to glycosaminoglycans may contribute to the pathogenesis of vivax malaria and lead to intrauterine growth retardation.

Fetal-maternal HLA compatibility confers susceptibility to systemic sclerosis

Abstract: Systemic sclerosis (SSc) is a disease of unknown origin, which occurs predominantly in women after childbearing years. There are prominent clinical and histopathologic similarities between SSc and chronic graft-versus-host disease (GVHD). GVHD can occur after blood transfusions or after transplantation with HLA-compatible bone marrow. Here we examined the hypothesis that SSc may be caused by fetal cells crossing the placenta into the maternal circulation and providing donor lymphocytes which recognize disparate HLA antigens, resulting in a reaction similar to chronic GVHD. To test the hypothesis we analyzed the inheritance of HLA class I and class II haplotypes in the families of 37 SSc patients and 42 control individuals. Twenty-six (70.2%) SSc patients had HLA class II alleles compatible either for their offspring or mother, compared with only nine (21%) control individuals. The four patients with juvenile onset SSc we analyzed had alleles compatible with their mothers. These results suggest that in some patients, SSc may, indeed, be a form of chronic GVHD caused by fetal or maternal cells which have crossed the placenta during pregnancy and have remained unrecognized by the host due to class II HLA compatibility, and that subsequent activation of these cells by as yet unknown stimuli result in the development of the disease.

Selective permeabilization of the blood-brain barrier at sites of metastasis.

Abstract: Brain metastases pose a substantial challenge for chemotherapeutic treatment because of the impermeable nature of the blood–brain barrier (BBB), which limits access of drugs and thus prevents accumulation of clinically effective doses at tumor sites. Substances with good penetration of the BBB have limited activity against breast cancer, one of the most common cancers metastasizing to the brain, whereas the most active therapeutics for breast cancer (including doxorubicin and trastuzumab) appear not to reach the central nervous system (CNS) (1) because of their hydrophilic nature. At the same time, the impermeable BBB also prevents early diagnosis of small brain metastases by the current clinical gold-standard method of gadolinium-enhanced magnetic resonance imaging (MRI). This diagnostic approach enables detection of large cerebral metastases and primary brain tumors but only when gross structural abnormalities have developed. Moreover, although BBB compromise may allow limited access of drugs to the tumor in later stages, this BBB permeability is frequently inhomogenous and generally poor around the tumor margin (2). Thus, the late stage of BBB disruption and inhomogeneity across the tumor mean treatment is largely ineffective. Smaller metastases possessing an intact BBB evade both detection and treatment and will inevitably develop into symptomatic tumors. A number of approaches to transiently circumvent the BBB have been investigated for the delivery of chemotherapeutics to brain tumors [for a review see (3)]. Bradykinin B2 receptor activation by cereport (RPM-7) was the first pharmacological treatment to be shown to transiently modify the BBB in a receptor-mediated manner (4,5) and to increase drug transport into rat and human gliomas. This approach, however, did not improve the efficacy of carboplatin in a phase II trial in glioma patients at the dose used because of the dose-limiting side effect of hypotension (6). The efficacy of RMP-7 in brain metastases has not been investigated. Alternatively, intravenous infusion of the hyperosmotic agent mannitol has been shown to globally induce endothelial cell shrinkage and tight junction separation and has been proposed as a means of transiently providing access to cerebral tumors (7). This approach has been performed in humans and has been shown to cause BBB disruption. However, the lack of specificity for tumor sites is a serious confounder with regard to healthy brain tissue, whereas the short working window limits therapeutic efficacy (8). Alternatively, ultrasound-mediated focused BBB disruption is a promising technique but relies on prior knowledge of metastatic sites (9). Thus, further work in this area is critical if brain metastases are to be detected and treated effectively. Preclinical studies aimed at increasing drug delivery to systemic tumors have demonstrated the ability of an intravenous bolus dose of recombinant human tumor necrosis factor (TNF), a proinflammatory cytokine, to disrupt endothelial tight junctions in the tumor vasculature through the RhoA/Rho kinase pathway (10). This approach was shown to enhance the permeability of tumor vasculature and to facilitate virus particle delivery to a solid subcutaneous xenograft EL4 lymphoma model in mice. TNF has two endogenous receptors (TNFR1 and TNFR2), which mediate endothelial cytoskeletal reorganization and destabilization of interendothelial adhesion complexes (11). Although their activation is generally associated with pathophysiological processes, the effect of TNF receptor activation in controlled low-dose administration may be beneficial. However, the normal adult brain microvasculature, unlike peripheral blood vessels, is known to be resistant to the permeabilizing effects of cytokines (12). This resistance can be modified by a number of factors, and in previous work we have shown that microinjection of TNF into the rat brain can cause focal, but delayed, disruption of the BBB in association with a focal inflammatory response (13). Our recent work has shown that the early phases of metastasis development in the brain are associated with a strong inflammatory response and activation of the cerebral endothelium (14,15). Based on the above findings, we hypothesized that cerebral metastases may provide a unique environment for TNF receptor activation on the associated vasculature and that this might yield a target for specific and local opening of the tumor-associated BBB. The primary aims of this study, therefore, were to determine whether TNFR1 and TNFR2 are expressed on metastasis-associated vasculature, and to determine whether intravenous administration of TNF, or its endogenous analogue lymphotoxin (LT), can permeabilize the BBB specifically at sites of cerebral metastasis throughout the brain to an extent that allows entry of 1) diagnostic imaging agents and 2) a clinically relevant anticancer drug.

Recommendations for a standard UK approach to incorporating umbilical cord blood into clinical transplantation practice: an update on cord blood unit selection, donor selection algorithms and conditioning protocols

Abstract: Allogeneic haemopoietic stem cell transplantation offers a potentially curative treatment option for a wide range of life-threatening malignant and non-malignant disorders of the bone marrow and immune system in patients of all ages. With rapidly emerging advances in the use of alternative donors, such as mismatched unrelated, cord blood and haploidentical donors, it is now possible to find a potential donor for almost all patients in whom an allograft is indicated. Therefore, for any specific patient, the transplant physician may be faced with a myriad of potential choices, including decisions concerning which donor to prioritize where there is more than one, the optimal selection of specific umbilical cord blood units and which conditioning and graft-versus-host disease prophylactic schedule to use. Donor choice may be further complicated by other important factors, such as urgency of transplant, the presence of alloantibodies, the disease status (homozygosity or heterozygosity) of sibling donors affected by inherited disorders and the cytomegalovirus serostatus of patient and donor. We report UK consensus guidelines on the selection of umbilical cord blood units, the hierarchy of donor selection and the preferred conditioning regimens for umbilical cord blood transplantation, with a summary of rationale supporting these recommendations.