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Biomedical subjects

C Allen

Publications and source records attributed to C Allen.

At least 37 records · Page 2Linked to original sources
PubMed2003

Novel protection strategy for pulmonary transplantation.

BACKGROUND: Ischemia-reperfusion injury continues to represent a significant challenge to successful lung transplantation. Traditional pulmonary ischemic protection is performed using hypothermic hyperkalemic depolarizing solutions to reduce the metabolic demands of the ischemic organ. Measures to further reduce the effects of ischemic injury have focused on the reperfusion period. We tested the hypothesis that novel physiologic hyperpolarizing solutions-using ATP-dependent potassium channel (K(ATP)) openers-given at the induction of ischemia, will reduce cellular injury and provide superior graft function even after prolonged periods of ischemia. METHODS: An isolated blood-perfused ventilated rabbit lung model was used to study lung injury. Airway, left atrial, and pulmonary artery pressures were measured continuously during the 2-h reperfusion period. Oxygenation, as a surrogate of graft function, was measured using intermittent blood gas analysis of paired left atrial and pulmonary artery blood samples. Graft function was measured by oxygen challenge technique (F(i)O(2) = 1.0). Wet-to-dry ratio was measured at the conclusion of the 2-h reperfusion period. Control (Group I) lungs were perfused with modified Euro-Collins solution (depolarizing) and reperfused immediately (no ischemia). Traditional protection lungs were perfused with modified Euro-Collins flush solution and stored for 4 h (Group II) or 18 h (Group III) at 4 degrees C before reperfusion. Novel protection (Group IV) lungs were protected with a hyperpolarizing solution containing 100 nM Aprikalim, a specific K(ATP) channel opener, added to the modified Euro-Collins flush solution and underwent 18 h of ischemic storage at 4 degrees C before reperfusion. RESULTS: Profound graft failure was measured after 18 h of ischemic storage with traditional protection strategies (Group III). Graft function was preserved by protection with hyperpolarizing solutions even for prolonged ischemic periods (Group IV). Wet-to-dry weight ratio, airway, left atrial, and pulmonary artery pressures were not significantly different between the groups. CONCLUSIONS: We have created a model of predictable lung injury. Membrane hyperpolarization with a K(ATP) channel opener (PCO) provides superior prolonged protection from ischemia-reperfusion injury in an in vitro model of pulmonary transplantation.

Animals↗
PubMed2003

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease-substrate interaction.

Fusogenic membrane glycoproteins (FMG) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. FMG expression constructs caused massive syncytia formation followed by cytotoxic cell death in glioma cell lines, and antitumor activity has been shown in glioma xenografts. FMG-induced fusion in glioma cells can involve heterologous cell lines including normal astrocytes and fibroblasts, therefore making targeting important. Here we report on the use of matrix metalloproteinase (MMP) cleavable linkers to target cytotoxicity of FMGs against gliomas. Expression constructs were made expressing the hyperfusogenic version of the Gibbon Ape Leukemia Virus envelope glycoprotein (GALV) linked to a blocking ligand (the C-terminal extracellular domain of CD40 ligand) via either an MMP cleavable linker (GALV M40), a factor Xa protease cleavable linker (GALV X40), or a noncleavable linker (GALV N40). Unmodified GALV expressing constructs were used as positive controls. The glioma cell lines U87, U118, and U251 previously characterized by zymography and MMP-2 activity assay as high, medium, and low MMP expressors, respectively; normal human astrocytes and the MMP-poor cell line TE671 were transfected with the GALV, GALV N40, GALV X40, and GALV M40 constructs. In contrast to unmodified GALV constructs, transfection with GALV X40 and GALV N40 constructs blocked fusion and cytotoxic cell death. Fusion occurred, however, after transfection with constructs containing MMP cleavable linkers to an extent dependent on MMP expression in the specific cell line. Use of the broad-spectrum MMP inhibitors, 1,10-phenanthroline and N-hydroxy-piperazine-carboxamide completely abolished the ability of MMP constructs to induce fusion. In cell mixing experiments, mixing of MMP-poor cell lines transfected with GALV M40 constructs with the MMP overexpressing untransfected U87 glioma cells led to partial restoration of fusion. Use of U87 supernatant did result in a similar effect. Establishment of stable tranfectants expressing the membrane-type MMPs, MT-1 MMP and MT-2 MMP did restore fusion in the MMP-poor cell line TE671 after transfection with GALV M40, thus indicating that both membrane-type MMPs and soluble MMPs activate the MMP cleavable constructs. In addition, the GALV M40 construct retained its cytotoxic activity against U87 cells in vivo, although less effectively as compared to unmodified GALV. Our data indicate that GALV-induced cytotoxicity in glioma cell lines can be blocked by display of the CD40 ligand. Incorporation of an MMP cleavable linker can selectively restore cytotoxicity in MMP expressing glioma cell lines both in vitro and in vivo, while sparing normal human astrocytes. Given the high frequency of MMP overexpression in gliomas, this represents a promising targeting strategy.

Animals↗
PubMed2003

Echis time, under-carboxylated prothrombin and vitamin K status in intensive care patients.

Vitamin K deficiency is a known cause of coagulopathy in hospitalized patients, but the extent of the problem has not been well assessed. This noninterventional, prospective observational study of 35 adults was undertaken in the intensive care unit (ICU) and examined the incidence of and the methods for diagnosing vitamin K deficiency. Measurements of prothrombin time, Echis time and plasma concentrations of under-carboxylated prothrombin (proteins induced in vitamin K absence or antagonism, PIVKA-II), vitamin K1 and ferritin were made during the 48 h after admission to the unit and repeated if coagulopathy developed later. Plasma vitamin K1 was low in 15 admissions (43%), in 11 cases of patients with coagulopathy and in four cases without coagulopathy. PIVKA-II was present in 12 cases (34%), of whom four had low vitamin K1 levels. All of the eight patients with raised PIVKA-II but normal vitamin K concentration were hyperferritinaemic. We conclude that low plasma vitamin K levels, suggestive of low tissue stores, are common in intensive care patients with or without coagulopathy. As 34% of patients had a raised PIVKA-II, this suggests that vitamin K stores may be insufficient to maintain full gamma-carboxylation of prothrombin and emphasize the need to anticipate vitamin K deficiency in the ICU setting by appropriate supplementation.

Adolescent↗
PubMed2003

A survey of Irish consultants regarding awareness of sperm freezing and assisted reproduction.

Chemotherapy and radiotherapy decrease male fertility. Pretreatment semen cryopreservation offers a chance for future fatherhood. However many eligible patients are not referred. One potential reason for the reduced uptake is lack of awareness by referring consultants. We sent a questionnaire to all 41 consultant oncologists, haematologists and urologists listed in the Irish Medical Directory. The questionnaire surveyed the current knowledge, opinions and clinical practices of this key group regarding semen cryopreservation for male cancer patients. 63% responded. 73% routinely discuss semen freezing with their male cancer patients (mostly testicular carcinomas and lymphomas). 100% believe semen cryopreservation helps the patient psychologically. 12% do not know where facilities exist. 92% will only refer men aged between 20 and 40 years. 92% are unaware that semen freezing does not delay cancer treatment. 54% have heard of intracytoplasmic sperm injection (ICSI) but 88% are unaware of its benefits for patients with low sperm counts. Consultants dealing with male cancer patients do not prioritise future fertility. Most of the consultants surveyed were unaware of the advances in reproductive technology and this may be contributing to underutilization of sperm cryopreservation by male cancer patients. Units offering this service need to increase awareness of its potential benefits.

Awareness↗
PubMed2002

Controlling the physical behavior and biological performance of liposome formulations through use of surface grafted poly(ethylene glycol).

The presence of poly(ethylene glycol) (PEG) at the surface of a liposomal carrier has been clearly shown to extend the circulation lifetime of the vehicle. To this point, the extended circulation lifetime that the polymer affords has been attributed to the reduction or prevention of protein adsorption. However, there is little evidence that the presence of PEG at the surface of a vehicle actually reduces total serum protein binding. In this review we examine all aspects of PEG in order to gain a better understanding of how the polymer fulfills its biological role. The physical and chemical properties of the polymer are explored and compared to properties of other hydrophilic polymers. An evidence based assessment of several in vitro protein binding studies as well as in vivo pharmacokinetics studies involving PEG is included. The ability of PEG to prevent the self-aggregation of liposomes is considered as a possible means by which it extends circulation longevity. Also, a "dysopsonization" phenomenon where PEG actually promotes binding of certain proteins that then mask the vehicle is discussed.

Adsorption↗
PubMed2002

Determinants of migraine-specific quality of life.

This paper reports an analysis of two randomized controlled trials of rizatriptan, in which the 24-h Migraine Quality of Life QuestionnaireCopyright was used to assess migraine-specific quality of life in patients receiving acute treatment. The objective of the analysis was to determine which clinical effects of a migraine medication, as measured by traditional clinical trial endpoints, contribute to a better short-term health-related quality of life. The results demonstrate that patients who experience complete pain relief and are able to function at their normal ability within 2 h and experience no headache recurrence have the highest migraine-specific quality of life scores. Patients who were satisfied with medication at 2 h had higher migraine-specific quality of life scores than those who were not satisfied. In conclusion, migraine therapy that provides rapid, complete, and sustained pain relief, with restoration of functional ability, has the most beneficial impact on short-term health-related quality of life for migraineurs.

Adult↗
PubMed2002

Case report: retrocaval ureter: MR appearances.

We present a case of retrocaval ureter and its MR appearances. This is the first case in reported literature. The findings on i.v. urography are correlated with the MRI findings. So far CT has been the procedure of choice to confirm the diagnosis of retrocaval ureter. However, we believe MRI is likely to replace CT in the diagnosis of retrocaval ureter.

Adult↗
PubMed2001

Overexpression of human RAD51 and RAD52 reduces double-strand break-induced homologous recombination in mammalian cells.

Double-strand breaks (DSBs) can be repaired by homologous recombination (HR) in mammalian cells, often resulting in gene conversion. RAD51 functions with RAD52 and other proteins to effect strand exchange during HR, forming heteroduplex DNA (hDNA) that is resolved by mismatch repair to yield a gene conversion tract. In mammalian cells RAD51 and RAD52 overexpression increase the frequency of spontaneous HR, and one study indicated that overexpression of mouse RAD51 enhances DSB-induced HR in Chinese hamster ovary (CHO) cells. We tested the effects of transient and stable overexpression of human RAD51 and/or human RAD52 on DSB-induced HR in CHO cells and in human cells. DSBs were targeted to chromosomal recombination substrates with I-SceI nuclease. In all cases, excess RAD51 and/or RAD52 reduced DSB-induced HR, contrasting with prior studies. These distinct results may reflect differences in recombination substrate structures or different levels of overexpression. Excess RAD51/RAD52 did not increase conversion tract lengths, nor were product spectra otherwise altered, indicating that excess HR proteins can have dominant negative effects on HR initiation, but do not affect later steps such as hDNA formation, mismatch repair or the resolution of intermediates.

Animals↗
PubMed2001

Human resources. Lean on me.

Appointing a full-time staff support co-ordinator in a community trust has reduced absence and been welcomed by staff. The pilot, which has been operating for two years, offers staff confidential interviews. Most of those using the service do not need more than two sessions. The co-ordinator has also acted as mediator where there is conflict between staff.

Absenteeism↗
PubMed2001

Detailed molecular analysis of 1p36 in neuroblastoma.

BACKGROUND: Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor. PROCEDURE: We analyzed the status of 1p36 in primary neuroblastomas and cell lines to define the region of consistent rearrangement. RESULTS: Loss of heterozygosity (LOH) studies of primary neuro blastomas identified allelic loss in 135 of 503 tumors (27%), with the smallest region of overlap (SRO) defined distal to D15214 (1p36.3). No homozygous deletions were detected at 120 loci mapping to 1p36.1-p36.3 in a panel of 46 neuroblastoma cell lines. A recently identified patient with neuroblastoma was found to have a constitutional deletion within 1p36.2-p36.3, and this deletion, when combined with the LOH results, defined a smaller SRO of one megabase within 1p36.3. We constructed a comprehensive integrated map of chromosome 1 containing 11,000 markers and large-insert clones, a high-resolution radiation hybrid (RH) map of 1p36, and a P1-artificial chromosome (PAC) contig spanning the SRO, to further characterize the region of interest. Over 768 kb (75%) of the SRO has been sequenced to completion. Further analysis of distal 1p identified 113 transcripts localizing to 1p36, 21 of which were mapped within the SRO. CONCLUSION: This analysis will identify suitable positional candidate transcripts for mutational screening and subsequent identification of the 1p36.3 neuroblastoma suppressor gene.

Alleles↗
PubMed2001

Back to the old house? 'Sick role' and biographical narratives of the housing needs of short-stay hospital patients.

This paper examines how decisions are made about the housing needs of short-stay hospital patients. Two narrative types of patients' housing needs are identified. The 'sick role' narrative emphasised patients' ongoing medical needs and tended to prescribe 'sick role' placements in residential care or nursing homes instead of a return home. Conversely, the biographical narrative emphasised the importance of home as an integral element of 'elective biography' (Beck and Beck-Gernsheim, in: Heelas, Lash and Morris (Eds.), Detraditionalization, Blackwell, Oxford, 1996) and thus a highly emotional 'psychic warehouse' (Gurney, Ph.D. Thesis, Bristol, 1996) that was integral to post-discharge recovery and well being.

Aftercare↗
PubMed2001

Oral lesions indicative of plasminogen deficiency (hypoplasminogenemia).

BACKGROUND: Gingival overgrowth with ulceration has recently been recorded in 4 reports: (1) our report of a British patient with ligneous conjunctivitis in whom the gingival lesions appeared to be related to tranexamic acid-an antifibrinolytic agent; (2) a report of 2 Turkish patients and an Italian patient with mainly gingival lesions; (3) our report of 5 Turkish patients with mainly gingival lesions; and (4) a report of 3 new Turkish cases, which also were associated with gingival lesions and alveolar bone loss. These patients all had gingival swellings, and a minority had conjunctival involvement similar to ligneous conjunctivitis, although the etiology was unclear in all. Nevertheless, fibrin exudation was fundamental because the hyaline or amyloidaceous material seen on the gingival biopsy stained for fibrin but failed to stain for amyloid. METHODS: We have examined 6 more patients who exhibited gingival swelling caused by amyloidaceous deposits that stained only for fibrin, and we assayed their plasminogen levels. RESULTS: The plasminogen functional activity assayed in these 6 additional patients, and in 2 of the 5 patients previously reported by us, was significantly reduced. CONCLUSIONS: Gingival overgrowth with ulceration appears to be a new complication caused by plasminogen deficiency; it also appears to be related to ligneous conjunctivitis in some cases.

Adolescent↗