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Biomedical subjects

J Kirk

Publications and source records attributed to J Kirk.

At least 73 records · Page 4Linked to original sources
PubMed1997

Cancer in the family. Guidelines for general practice.

In the past 2 years the major genes for inherited breast-ovarian cancer, bowel cancer and melanoma have been identified. Relatives of cancer patients frequently perceive themselves to be at high risk of cancer. Appropriate assessment of the family history permits the identification of those at particularly high risk who may benefit from special programs of prevention, screening and surveillance. In certain cases, genetic testing and prophylactic surgery may be indicated. This article looks at the general issues involved. A follow-up article next month will look at specific diseases.

Genetic Testing↗
PubMed1996

Glucose uptake in Plasmodium falciparum-infected erythrocytes is an equilibrative not an active process.

The uptake of glucose into human erythrocytes infected with Plasmodium falciparum was investigated using a number of different glucose analogues. In short time-courses with cells suspended in media containing 5 mM glucose, 2-deoxy-D-glucose equilibrated rapidly between the intracellular and extracellular compartments. Its transport into the infected cell was primarily via the host cell (cytochalasin B-sensitive) transporter. 2-Deoxy-D-glucose did permeate the broad-specificity pathway that is induced in infected cells by the intracellular parasite. However, this pathway made little contribution to the total uptake of 2-deoxy-D-glucose under physiological conditions. In parasitised cells incubated with [14C]2-deoxy-D-glucose for prolonged periods the intracellular concentration of radiolabel increased to values higher than that in the external medium; it reached a maximum value three to six times higher than the extracellular concentration before falling back to a concentration similar to that outside the cells. This transient intracellular accumulation of radiolabel was due entirely to the phosphorylation of the [14C]2-deoxy-D-glucose and its consequent trapping within the cell. The specific characteristics of the 2-deoxy-D-glucose uptake time courses measured under different conditions were accounted for by the kinetics of the phosphorylation process and the energy status of the cell. The data indicate that 2-deoxy-D-glucose (as well as the non-phosphorylated compounds 3-O-methyl-D-glucose and L-glucose) enter the intracellular parasite via a passive (i.e. equilibrative) rather than an active (i.e. concentrative) transport process.

3-O-Methylglucose↗
PubMed1996

Volume-regulatory amino acid release from the protozoan parasite Crithidia luciliae.

The unicellular protozoan parasite, Crithidia luciliae, responded to osmotic swelling by undergoing a regulatory volume decrease. This process was accompanied by the efflux of amino acids (predominantly alanine, proline and glycine). The relative loss of the electroneutral amino acids proline, valine, alanine and glycine was greater than that for the anionic amino acid, glutamate; there was negligible loss of the cationic amino acids, lysine, arginine and ornithine. The characteristics of amino acid release were investigated using a radiolabeled form of the nonmetabolized alanine analogue alpha-aminoisobutyrate. alpha-Aminoisobutyrate efflux was activated within a few seconds of a reduction of the osmolality, and inactivated rapidly (again within a few seconds) on restoration of isotonicity. The initial rate of efflux of alpha-aminoisobutyrate from cells in hypotonic medium was unaffected by the extracellular amino acid concentration. Hypotonically activated alpha-aminoisobutyrate efflux (as well as the associated regulatory volume decrease) was inhibited by the sulfhydryl reagent N-ethylmaleimide but was not inhibited by a range of anion transport blockers. As in the efflux experiments, unidirectional influx rates for alpha-aminoisobutyrate increased markedly following reduction of the osmolality, consistent with the swelling-activated amino acid release mechanism allowing the flux of solutes in both directions. Hypotonically activated alpha-aminoisobutyrate influx showed no tendency to saturate up to an extracellular concentration of 50 mM. The functional characteristics of the amino acid release mechanism are those of a channel, with a preference for electroneutral and anionic amino acids over cationic amino acids. However, the pharmacology of the system differs from that of the anion-selective channels that are thought to mediate the volume-regulatory efflux of organic osmolytes from vertebrate cells.

Amino Acids↗
PubMed1996

Large, virus-like sinuous tubules in the endoplasmic reticulum of human neurons: report from a case of encephalopathy and brief critical review.

We report a case of a rapidly progressive, fatal non-inflammatory demyelinating disease, distinct from multiple sclerosis and lysosomal disorders, in a patient with progressive dementia. Electron microscopy of stereotactic brain biopsy samples revealed the presence in neurons of sinuous, double-walled cylindrical membranous structures within the cisterns of the endoplasmic reticulum. These structures were 75-80 nm in overall diameter, up to 1.5 mm long and had a 40- to 45-nm diameter core. The possibility that they might be viruses of the Filoviridae or Paramyxoviridae families was considered, but the inclusions differed in key morphological aspects from members of both virus families and there were no supporting clinical or pathological data. Neither was it possible to assign the structures to any other known virus family on the basis of their morphology. Such inclusions have been the subject of only three published reports over the past 20 years. Evidence suggests that they may be confined to human central nervous system neurons, but occur in unrelated disorders (Alzheimer's disease, amyotrophic lateral sclerosis, meningoencephalitis, low-pressure hydrocephalus, demyelination). The possibility that they are formed in certain neurons by an abnormal internal budding process, as a response to a variety of pathological insults, is considered most likely, although an infectious origin (such as an unrecognised virus with variable clinical effect) cannot be ruled out.

Adult↗
PubMed1996

The significance of measles virus antigen and genome distribution in the CNS in SSPE for mechanisms of viral spread and demyelination.

The distribution of measles virus (MV) antigen and genomic RNA in the central nervous system (CNS) in 10 cases of subacute sclerosing panencephalitis (SSPE) was determined using optimized immunocytochemistry and in situ hybridization techniques. As in previous reports neurons and oligodendrocytes were found to be the most frequently infected cells. It was confirmed that MV infection in neuronal processes was predominantly dendritic but there was also some evidence suggestive of occasional axonal involvement, a finding confirmed by electron microscopy. In addition MV genomic RNA was detected in neuronal processes, in some cases in the absence of demonstrable MV antigen. The relationship between myelin destruction and oligodendrocytic infection suggested that the demyelination may be solely the result of virus infection. A possible correlation between viral distribution and form and the clinical duration of disease was examined. Viral antigen and genome were equally abundant in the cerebral cortex in most short duration cases (<6 months). However, in two of these cases viral RNA but not antigen was detected in the spinal cord. In long duration cases (>36 months) viral RNA was abundant in all areas of the CNS examined, frequently in the absence of demonstrable antigen. These findings may suggest viral spread in a cephalo-caudal direction, probably by transneuronal spread.

Child↗
PubMed1996

Anion channel blockers inhibit swelling-activated anion, cation, and nonelectrolyte transport in HeLa cells.

The effect of osmotic cell swelling on the permeability of HeLa cells to a range of structurally unrelated solutes including taurine, sorbitol, thymidine, choline, and K+ (96Rb+) was investigated. For each solute tested, reduction in the osmolality of the medium from 300 to 200 mosmol/kgH2O caused a significant increase in the unidirectional influx rate. In each case, the osmotically activated transport component was nonsaturable up to external substrate concentrations of 50 mM. Inhibitors of the swelling-activated anion channel of HeLa cells [quinine, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, niflumate, 1,9-dideoxyforskolin, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and tamoxifen] blocked the osmotically activated influx of each of the different substrates tested, as well as the osmotically activated efflux of taurine and I-. Tamoxifen and NPPB were similarly effective at blocking the osmotically activated efflux of 96Rb+. The simplest of several hypotheses consistent with the data is that the osmotically activated transport of the different solutes tested here is via a swelling-activated anion-selective channel that has a significant cation permeability and a minimum pore diameter of 8-9 A.

Anions↗
PubMed1996

Enuresis nocturna can be provoked in normal healthy children by increasing the nocturnal urine output.

In a large proportion of enuretics, the enuresis episodes are accompanied by high urine output at night. At this study we provoked a high urine output in normal non-enuretic children in order to investigate whether volume provocation per se could cause enuresis. In six of ten children it was possible to provoke nine enuresis-like episodes. The enuresis volumes were small with no relation to functional bladder capacity. It is concluded, that increased urine output at night may produce enuresis-like episodes even in normal children.

Child↗
PubMed1996

Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study.

At present, allogeneic bone marrow transplantation (BMT) seems to be the only curative treatment for patients with chronic myeloid leukemia (CML). The mechanisms of this therapeutic approach probably include anti-leukemic immune response or "graft-versus-leukemia" (GVL) reaction against leukemic cell clones, since even aggressive chemotherapy is not sufficient per se to cure this type of disease. In many patients, allogeneic BMT results in the disappearance of the Ph chromosome; this negativity does not exclude the presence of residual leukemic cells since sensitivity of cytogenetic analysis is low. The chimeric BCR-ABL gene in CML is a tumor-specific marker that is well suited to allowing detection of low numbers of residual leukemic cells through the extremely sensitive detection method of polymerase chain reaction (PCR). Using this method, 1 leukemic cell in 10(5) or 10(6) normal cells can be detected. Many studies have evaluated the clinical significance and predictive value of BCR-ABL gene rearrangement detected by PCR assay after BMT, most often on heterogeneous populations. Results from such studies have been conflicting. We have conducted a review of the literature, focussing on long-term survivors (> 3 years from BMT) of CML to determine the value of PCR in such patients (n = 183). With the consideration that such a population is obviously heterogenous, long-term PCR negativity strongly correlated with achieving a cure since no patient relapsed in this population (n = 117). Among the PCR positive patients (n = 66), only 5 (8%) relapsed, suggesting a poor prognostic value for a PCR+ test > 36 months post-transplant. Besides the potential clinical value of these data, they contribute to the understanding of the biology of the disease and may suggest a crucial role for the long term GVL effect of marrow transplantation.

Bone Marrow Transplantation↗
PubMed1996

Provoked enuresis-like episodes in healthy children 7 to 12 years old.

PURPOSE: We evaluated whether a water load before bedtime provoked enuresis episodes in healthy children with no previous enuresis. We also studied pelvic floor activity during an enuresis episode and the completeness of bladder emptying, attempted to identify a possible trigger mechanism for nocturnal enuresis, and investigated any age and sex differences regarding the frequency of provoked enuresis episodes. MATERIALS AND METHODS: We evaluated 55 healthy volunteers (22 girls and 33 boys) 7 to 12 years old who were dry from age 5 years and had no urological or other complaints. Subjects were admitted to the hospital for 4 consecutive nights. Night 1 was for adaptation without a water load. On nights 2 to 4, 25 ml./kg. body weight of water were given orally half an hour before bedtime. During the night pelvic floor activity was monitored, and the time and volume of enuresis and nocturia episodes were noted. RESULTS: In 17 subjects 28 enuresis-like episodes were provoked, generally comprising incomplete voidings with large residual volumes mostly in younger children and in boys. Enuresis and nocturia episodes were provoked at a volume specific for each individual without a relation to the bladder filling rate. CONCLUSIONS: Our results support the hypotheses that nocturnal polyuria is an important pathogenetic factor in enuresis and that arousal failure can be provoked in nonenuretic subjects.

Adolescent↗
PubMed1996

Viral infection at the blood-brain barrier in multiple sclerosis:--an ultrastructural study of tissues from a UK Regional Brain Bank.

Although viral infections are often invoked as environmental factors in the aetiology and pathogenesis of multiple sclerosis (MS) it is only recently that a specific, indirect, cytokine-mediated mechanism for triggering of relapses during viral infections has been demonstrated. It is not yet clear however whether this indirect mechanism can account for all reported viral associations with the aetiopathogenesis of MS. A direct causal role of central nervous system (CNS) viral infection in MS has largely been discounted following repeated failures to demonstrate virus within the oligodendrocyte-myelin unit. In the light of increasing evidence of blood-brain barrier (BBB) dysfunction in MS and to further explore the issue of possible viral involvement in MS, an ultrastructural search for viruses was undertaken in the CNS microvasculature, in autopsy and biopsy tissue from human CNS primary demyelinating diseases, including MS (20 cases), idiopathic monophasic CNS demyelinating disease (Mdemy, four cases) and metabolic or immunopathological demyelinating disease (two cases). For comparison, tissues from CNS viral disease in which demyelination is a major feature (nine cases) were examined in the same way. Control CNS tissues (nine cases) from a range of other neurological and non-neurological diseases were also examined. Outside the MS and Mdemy groups, morphological evidence of virus associations with the BBB were found only in the acute and subacute viral encephalitides (three cases subacute sclerosing panencephalitis, one case of Herpes encephalitis) and in one case of disseminated Cytomegalovirus infection. In a small proportion of MS and Mdemy cases, particles resembling either adenovirus (one case of MS) or paramyxovirus (one case of MS, one case of Mdemy) were found in the vicinity of microvessels. In each case a different cell type or extracellular compartment was involved and an exact correlation between the virus particles and the demyelinating lesions could not be demonstrated. Furthermore, corroborative clinical or laboratory evidence of current CNS infection in these primary demyelinating disease cases was available only from the single positive Mdemy case and not from the two cases of MS. This and other previously published evidence from MS (which implicated a Coronavirus) and other diseases highlights the potential vulnerability to viral infection of cells associated with the BBB. Furthermore it is concluded that the detection rate of such infections in pathological tissue could underestimate their true frequency. A possible role of transient virus-BBB interactions in triggering focal inflammation, BBB breakdown and demyelination in some cases of MS and parainfectious demyelinating disease cannot be discounted.

Acute Disease↗
PubMed1995

Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients.

We studied 346 patients after bone marrow transplantation (BMT) for chronic myeloid leukemia (CML) for the presence of the bcr-abl transcript detected by the polymerase chain reaction (PCR) to understand the frequency and implication of a positive test. A total of 634 samples of BM and/or peripheral blood were obtained for PCR analysis between 3 and 192 months after BMT. A positive PCR test at 3 months post-BMT was not statistically significantly associated with an increased risk of relapse compared with PCR-negative patients. However, a positive PCR assay at 6 months and beyond was highly associated with subsequent relapse. The Kaplan-Meier estimate of relapse for patients testing PCR-positive at 6 to 12 months was 42% versus 3% for PCR-negative patients (P < .0001). The Kaplan-Meier estimate of survival at 4 years for the PCR-positive patients was 74% compared with 83% for the PCR-negative group (P = .002). Multivariable analysis indicated that a PCR-positive result at 6 to 12 months post-BMT, the type of BMT donor (allogeneic matched donor v mismatched or unrelated), and the presence of acute GVHD were independent risk factors for subsequent relapse. The relative risk (RR) for relapse for patients PCR-positive at 6 to 12 months post-BMT was 26.1 (95% confidence interval, 8.9 to 76.1, P < .0001). The outcome of long-term patients (> 36 months post-BMT) who tested PCR-positive was much better, as 15 of 59 (25%) tested positive for bcr-abl, but only one patient relapsed. There was a 91% concordance between PCR tests of simultaneously obtained BM and peripheral blood. These analyses show that the PCR assay of the bcr-abl fusion transcript 6 to 12 months post-BMT is an independent predictor of subsequent relapse which provides an opportunity for early therapeutic intervention.

Adolescent↗
PubMed1995

Multiplex PCR of bcr-abl fusion transcripts in Philadelphia positive acute lymphoblastic leukemia.

We describe a multiplex PCR assay for the detection of bcr-abl fusion mRNA in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). The assay provides a quick method for screening p190 (e1:a2) and p210 (b2:a2 or b3:a2) bcr-abl mRNAs simultaneously. The assay proves to be highly sensitive with detection of as little as one positive bcr-abl-expressing cell in a background of 10(5) negative bcr-abl cells. Bone marrow and peripheral blood specimens from six patients were in total accordance when run by multiplex PCR and by the single primer PCR approach. The multiplex bcr-abl assay may prove to be highly useful for screening newly diagnosed patients with ALL for the bcr-abl fusion transcript and in following the course of disease during therapy.

Base Sequence↗
PubMed1994

Inhibition of volume-activated I- and taurine efflux from HeLa cells by P-glycoprotein blockers correlates with calmodulin inhibition.

P-glycoprotein, an active transporter that pumps a diverse range of hydrophobic compounds out of cells, has recently been proposed to function as, or regulate, a volume-activated, anion-selective channel (Valverde, M.A., Diaz, M., Sepulveda, F. V., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992) Nature 355, 830-833). In this study a number of compounds known to inhibit P-glycoprotein-mediated drug pumping were tested for their effect on the osmotically activated release from HeLa cells of I-, a known substrate of volume-activated anion channels, and taurine, a sulfonic amino acid that serves as an important organic osmolyte in many cell-types. Tamoxifen, 4-iodotamoxifen, and pyrrolidino-4-iodotamoxifen (idoxifene) were potent blockers of osmotically activated I- and taurine efflux. Other known P-glycoprotein inhibitors (verapamil, cyclosporin A, pimozide, trifluoperazine, ICI 164, and ICI 182) were less effective. For all compounds tested the effect on taurine release was the same as that on I- release, consistent with the hypothesis that swelling-activated taurine release is via anion-selective channels. There was no positive correlation between the effect of the inhibitors on osmotically activated solute release and their effect on P-glycoprotein-mediated drug transport. In contrast, there was a strong positive correlation between the IC50 values for the effect of the inhibitors on volume-activated solute release and those for their effect on calmodulin. These data raise doubts as to whether the effect of P-glycoprotein inhibitors on volume-activated channels is a consequence of their interaction with P-glycoprotein and indicate a possible role for calmodulin, or a cell component having at least some physical similarities, in controlling channel activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Reversal of P-glycoprotein-mediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives.

In this study the ability of five novel anti-oestrogens [4-iodotamoxifen, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 164,384 (ICI 164) and ICI 182,780] to alter drug toxicity to multidrug resistant cell lines have been compared. The effect of these compounds on ATP-dependent vinblastine (VBL) transport was also tested using inside-out vesicles (IOV) prepared from highly P-glycoprotein (Pgp)-expressing CCRF-CEM/VBL1000 cells. The pure anti-oestrogen ICI 164 was most effective, enhancing doxorubicin and VBL toxicity to MCF-7Adr cells 25- and 35-fold, respectively, and was also the best inhibitor of ATP-dependent [3H]VBL accumulation by IOV. Pure anti-oestrogens, tamoxifen and iodotamoxifens completely reversed VBL resistance in the mdr1 transfected lung cancer cell line, S1/1.1, where resistance relative to wild-type cells was mediated solely by Pgp. The membrane impermeant tamoxifen derivative EBTx did not modify drug resistance, yet was as effective an inhibitor of VBL accumulation by inside-out Pgp-positive vesicles as tamoxifen. This indicates an intracellular role for tamoxifen and its derivatives in the modulation of Pgp-mediated drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗