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Biomedical subjects

J A Holmes

Publications and source records attributed to J A Holmes.

At least 19 recordsLinked to original sources
PubMed2004

Hypermethylation of 5'-region of the human calcitonin gene in leukemias: structural features and diagnostic significance.

Methylation of the 5'-region of the calcitonin gene was investigated in bone marrow and peripheral blood cells of 27 healthy volunteers and 25 leukemic patients. In all patients suffering from various forms of myeloid and lymphoid leukemia, hypermethylation of CpG sequences was observed in this region of the calcitonin gene. Cytosine hypermethylation in the CpG sequence did not involve cytosines of adjacent CpNpG sequences (where N is any nucleoside). The 5'-region of the calcitonin gene lacked CpNpG methylation both in healthy controls and in leukemic patients; this apparently represents specific "non-alternative" type of CpG methylation in the extended DNA sequence. Methylation of the calcitonin gene was monitored in 18 leukemic patients during malignant progression and medical treatment. Hypermethylation of the calcitonin gene was not observed on long-term clinical hematological remission. In ten patients characterized by unstable (or incomplete) remission hypermethylation of the calcitonin gene persisted through the whole period of observation. In relapses, hypermethylation of the calcitonin gene appeared again and in six patients, this "molecular relapse" being registered 1-8 months before onset of clinical and laboratory signs of disease progression. The leukemia-specific hypermethylation of CpG sequences of the 5'-region of the calcitonin gene is a promising prognostic and diagnostic marker of leukemias and might be useful for monitoring of this disease.

5' Flanking Region↗
PubMed2001

Variable effects of goitrogens in inducing precocious metamorphosis in sea lampreys (Petromyzon marinus).

The ability of different goitrogens (anti-thyroid agents) to induce precocious metamorphosis in larval sea lampreys (Petromyzon marinus) was assessed in four separate experiments. Two of these goitrogens (propylthiouracil [PTU] and methimazole [MMI]) are inhibitors of thyroid peroxidase-catalyzed iodination, and three (potassium perchlorate [KClO(4)], potassium thiocyanate [KSCN], and sodium perchlorate [NaClO(4)]) are anionic competitors of iodide uptake. Because, theoretically, all of these goitrogens prevent thyroid hormone (TH) synthesis, we also measured their influence on serum concentrations of thyroxine and triiodothyronine. All goitrogens except PTU significantly lowered serum TH concentrations and induced metamorphosis in some larvae. The incidence of metamorphosis appeared to be correlated with these lowered TH concentrations in that KClO(4), NaClO(4), and MMI treatments resulted in the lowest serum TH concentrations and the highest incidence of metamorphosis in sea lampreys. Moreover, fewer larvae metamorphosed in the KSCN and low-KClO(4) treatment groups and their serum TH concentrations tended to be greater than the values in the aforementioned groups. MMI treatment at the concentrations used (0.087 and 0.87 mM) was toxic to 55% of the exposed sea lampreys within 6 weeks. The potassium ion administered as KCl did not alter serum TH concentrations or induce metamorphosis. On the basis of the results of these experiments, we have made the following conclusions: (i) In general, most goitrogens other than PTU can induce metamorphosis in larval sea lampreys, and this induction is coincident with a decline in serum TH concentrations. (ii) The method by which a goitrogen prevents TH synthesis is not directly relevant to the induction of metamorphosis. (iii) PTU has variable effects on TH synthesis and metamorphosis among lamprey species. (iv) Unlike in protochordates, potassium ions do not induce metamorphosis in sea lampreys and are not a factor in the stimulation of this event.

Animals↗
PubMed2001

Basement membrane pores in human bronchial epithelium: a conduit for infiltrating cells?

This study reports the presence of oval-shaped pores in the basement membrane of the human bronchial airway that may be used as conduits for immune cells to traffic between the epithelial and mesenchymal compartments. Human bronchial mucosa collected after surgery was stripped of epithelial cells without damaging the basement membrane. Both scanning and transmission electron microscopy showed oval-shaped pores 0.75 to 3.85 microm in diameter in the bronchial basement membrane at a density of 863 pores/mm2. Transmission electron microscopy showed that the pores spanned the full depth of the basement membrane, with a concentration of collagen-like fibers at the lateral edges of the pore. Infiltrating cells apparently moved through the pores, both in the presence and absence of the epithelium. Taken together, these results suggest that immune cells use basement membrane pores as predefined routes to move between the epithelial and mesenchymal compartments without disruption of the basement membrane. As a persistent feature of the basement membrane, pores could facilitate inflammatory cell access to the epithelium and greatly increase the frequency of intercellular contact between trafficking cells.

Basement Membrane↗
PubMed2000

Changes in intestinal and hepatic thyroid hormone deiodination during spontaneous metamorphosis of the sea lamprey, Petromyzon marinus.

We measured microsomal low-K(m) outer-ring deiodination (ORD) and inner-ring deiodination (IRD) activities for thyroxine (T(4)) and 3, 5,3'-triiodothyronine (T(3)) in intestine and liver in nonmetamorphosing (undersized) larvae, immediately premetamorphic larvae, animals in stages 1-7 of metamorphosis, and immediately postmetamorphic sea lampreys (Petromyzon marinus). For intestine: T(4)ORD activity was relatively low in nonmetamorphosing larvae, increased in premetamorphic individuals, was highest in stages 1 and 2 and was very low during stages 3-7; T(4)IRD activity was negligible until stage 3 but increased 4.7-fold through stages 3 to 7 such that T(4)IRD activity was 14 times T(4)ORD activity at stage 6; T(3)ORD activity was undetectable; T(3)IRD activity was not measured through stages 3-7 but correlated with T(4)IRD activity at other stages. For liver: deiodination was only measured up to stage 2 and in postmetamorphic animals; in contrast to intestine, T(4)ORD activity fell to low levels at stage 2 and was low during postmetamorphosis; T(4)IRD and T(3)IRD activities were very low and uninfluenced by developmental stage; T(3)ORD activity was undetectable. We conclude that (1) deiodination activity is usually much higher in intestine than in liver, (2) intestinal ORD and IRD activities change reciprocally so that ORD predominates in early metamorphosis but IRD predominates in mid and late metamorphosis, and (3) changes in intestinal deiodination may contribute to the characteristic depression of plasma T(4) and T(3) levels during spontaneous metamorphosis. J. Exp. Zool. 286:305-312, 2000.

Animals↗
PubMed2000

The relationship between type of antidepressant and neurovegetative symptoms in adult unipolar nonpsychotic depression: an opinion survey.

The bi-directional nature of the neurovegetative symptoms of depression, as well as the differential response to antidepressant medications, underscore the existence of possible subtypes of this disorder. This study surveyed 56 physicians practicing psychiatry in Hawaii for opinions regarding the most effective antidepressant medication for the following symptoms: hypersomnia vs. insomnia, psychomotor agitation vs. retardation, and gain vs. loss of appetite or weight. Fluoxetine was found to be the drug of choice for weight and appetite gain, hypersomnia, and psychomotor retardation. Mirtazapine was viewed as most effective for weight and appetite loss. Trazodone was found most effective for insomnia and nefazodone for psychomotor agitation. It is concluded that subtyping of depression should be investigated at the symptom level and the generalizability of the effects of each specific compound should be tested.

Antidepressive Agents↗
PubMed1999

Effects of insulin on lipid metabolism of larvae and metamorphosing landlocked sea lamprey, Petromyzon marinus.

This study was designed to examine the role of insulin (INS) in regulating changes in lipid metabolism of larval and metamorphosing landlocked lamprey, Petromyzon marinus. Larvae and stage 6 metamorphosing individuals were injected intraperitoneally once per day for 2 days with either saline (0.6%), bovine INS (100 ng/g body weight), or alloxan (0.2 mg/g body weight). Insulin administration resulted in depressed plasma fatty acid (FA) levels, whereas alloxan injection elevated plasma FA levels at both life cycle intervals. In larvae, INS-induced hypolipidemia was attended by increased lipid concentration in kidney and muscle, reduced rates of lipolysis in kidney, liver, and muscle (as indicated by decreased triacylglycerol lipase activity), and, to a lesser extent, by higher rates of lipogenesis in kidney and muscle (as evidenced by higher acetyl-CoA carboxylase and/or diacylglycerol acyltransferase activities). In general, the effects of alloxan were opposite of those of INS. The alloxan-induced increase in plasma FA was supported by an enhanced rate of lipolysis in the kidney, a relatively lower rate of fatty acid synthesis in kidney, liver, and muscle, and a relatively lower renal rate of TG synthesis. In stage 6 metamorphosing lamprey, the INS-induced decline in plasma FA was attended by reduced renal and hepatic rates of lipolysis and by enhanced lipogenesis, as indicated by increased renal and hepatic rates of de novo fatty acid synthesis and hepatic and muscular rates of TG synthesis. In contrast, the increase in plasma FA induced by alloxan in stage 6 animals was supported by reduced TG synthesis in liver. Immunocytochemistry revealed that alloxan was not cytotoxic to pancreatic beta cells, suggesting that the effects of alloxan were extrapancreatic in the time frame of our study. Because insulin-induced lipogenesis and antilipolysis is similar to the pattern of lipid metabolism (phase I) displayed by lamprey during their spontaneous metamorphosis, INS may play a role, possibly in concert with other factors, in coordinating metamorphosis-associated changes in lipid metabolism.

Alloxan↗
PubMed1999

Effects of resonances on halo formation in high-intensity storage rings.

Numerical calculations for the Spallation Neutron Source accumulator ring indicate that lattice resonances excited by the space-charge potential can increase a mismatch significantly by deforming the beam distribution in phase space. Hence increased mismatch leads to enhanced envelope oscillations that are driving the 2:1 parametric resonance leading to halo formation, even for initially matched beams. We have observed this behavior for the 2 nu(x) - 2 nu(y) = 0 resonance and for the 4 nu(y) = 23 resonance. This mechanism for halo formation peculiar to rings through resonance driven mismatch is very sensitive to the tunes, which emphasizes the importance of a careful choice of operating point in tune space.

Journal Article↗
PubMed1998

Flow cytometric apoptosis assays indicate different types of endonuclease activity in haematopoietic cells and suggest a cautionary approach to their quantitative use.

Two flow cytometric apoptosis assays, the terminal deoxynucleotidyl transferase (TdT) assay and in situ nick translation (ISNT) assay, were assessed for their ability to quantitate drug-induced apoptosis in CLL lymphocytes. In contrast to HL60 cells, biotinylated dUTP could not be effectively incorporated into apoptotic CLL lymphocytes using exogenous TdT. This suggested that CLL lymphocytes possess a different type of endonuclease that cleaves DNA, leaving blunt or 3' recessed DNA breaks, which are poor substrates for TdT. This possibility was tested using lambda exonuclease, which can convert a blunt or 3' recessed DNA break into a 3' overhang. Apoptotic CLL lymphocytes pre-treated with lambda exonuclease demonstrated increased nucleotide incorporation with TdT. Single-strand DNA breaks are also present in apoptotic CLL lymphocytes, as labelled nucleotides could be incorporated using the in situ nick translation assay. This study suggests that the efficiency of tailing reactions may be limited by the nature of the endonuclease activity in certain cell types and that validation with other parameters is an essential prerequisite to their quantitative use.

Apoptosis↗
PubMed1998

Effects of somatostatin on lipid metabolism of larvae and metamorphosing landlocked sea lamprey, Petromyzon marinus.

This study was designed to examine the role of somatostatin in regulating changes in lipid metabolism of larvae and metamorphosing landlocked sea lamprey, Petromyzon marinus. Larvae and animals in late metamorphosis (stage 6 on a 7-stage scale) were injected intraperitoneally once per day for 2 days with either saline (0.6%) or somatostatin-14 (SS-14; 500 ng/g body wt). Injection of SS-14 into larval and stage 6 metamorphosing animals resulted in elevated plasma fatty acids levels. In larvae, SS-14-induced hyperlipidemia was supported by enhanced lipolysis, as indicated by increased triacylglycerol lipase (TGL) activity in the liver and kidney. Mobilization of larval renal lipid was accompanied by reduced TG synthesis, as indicated by decreased diacylglycerol acyltransferase (DGAT) activity. In stage 6 metamorphosing lamprey, SS-14 did not significantly affect TGL activity; however, SS-14 significantly reduced fatty acid synthesis, as measured by acetyl-CoA carboxylase activity, in kidney, liver, and muscle, as well as muscular TG synthesis. SS-14-stimulated lipid depletion is reminiscent of the pattern of lipid metabolism displayed by P. marinus during their spontaneous metamorphosis-an observation which suggests that somatostatin may play a role in metamorphosis-associated changes in lipid metabolism in this species.

Acyltransferases↗
PubMed1998

Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative.

XR9051 (N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene) methylbenzamide) was identified as a potent modulator of P-glycoprotein-mediated multidrug resistance (MDR) following a synthetic chemistry programme based on a natural product lead compound. The activity of XR9051 was determined using a panel of human and murine drug-resistant cell lines (H69/LX4, 2780AD, EMT6/AR 1.0, MC26 and P388/DX Johnson). XR9051 was able to reverse resistance to a variety of cytotoxic drugs, including doxorubicin, etoposide and vincristine, which are associated with classical MDR. At a concentration of 0.3-0.5 microM, XR9051 was able to fully sensitize resistant cells to cytotoxics, whereas little or no effect was observed on the corresponding parental cell lines. No effect of XR9051 was observed on the response of cells to non-MDR cytotoxics such as methotrexate and 5-fluorouracil. XR9051 was consistently more potent than cyclosporin A (CsA) and verapamil (Vpm) in all assays used. XR9051 inhibited the efflux of [3H]daunorubicin from preloaded cells and, unlike CsA and Vpm, remained active for several hours after removal of resistance-modifying agent. In photoaffinity labelling experiments employing [3H]azidopine, XR9051 was able to displace binding to P-glycoprotein. In binding studies using [3H]vinblastine, XR9051 was shown to be a potent inhibitor of the binding of the cytotoxic to P-glycoprotein (EC50 = 1.4 +/- 0.5 nM). Taken together, the results indicate that XR9051 reverses the MDR phenotype through direct interaction with P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Effects of exogenous thyroxine (T4) and triiodothyronine (T3) on spontaneous metamorphosis and serum T4 and T3 levels in immediately premetamorphic sea lampreys, Petromyzon marinus.

The effect of exogenous thyroid hormones (TH), thyroxine (T4) or triiodothyronine (T3), on spontaneous metamorphosis and serum T4 and T3 levels was examined in immediately premetamorphic sea lampreys (Petromyzon marinus) from two populations. Size (> or = 120 mm in length and 3.0 g in weight) and a condition factor (CF) of > or = 1.50 were used to predict the number of larvae that were expected to metamorphose. The smallest size and lowest CF found in metamorphosing animals of each population (i.e., the minimum length, weight, and CF) were also used in our assessment. Untreated larvae from Putnam Creek metamorphosed at a larger size (minimums; 134 mm, 4.12 g) than anticipated, out the minimum CF (1.59) and the incidence of metamorphosis (4/5 based on minimums) were consistent with results from the Salmon River population (minimums: 121 mm, 3.15 g, 1.54 CF, 8/9 metamorphosing). In the two experiments, T4-treated animals showed the predicted incidence of metamorphosis (2/2, 10/10), but significantly fewer larvae metamorphosed in the T3-treated groups (1/5, 5/11) than predicted. It was concluded that exogenous T3 administration affected the incidence of metamorphosis. In the treatment groups, serum TH levels in most nonmetamorphosing and metamorphosing animals were significantly higher than controls. Metamorphosing animals exposed to either TH had lower serum TH concentrations than nonmetamorphosing animals. A decline in serum TH levels is an early feature of metamorphosis in lampreys, but the artificial maintenance of elevated serum levels of TH cannot inhibit the decline in spontaneous metamorphosis. If the depression of serum TH levels contributes to the initiation of metamorphic change, the magnitude of the decline is not a contributing factor.

Animals↗
PubMed1997

Thyroid hormone deiodination in various tissues of larval and upstream-migrant sea lampreys, Petromyzon marinus.

Properties and activities of four potential thyroid hormone (TH) monodeiodinating pathways (T4ORD, L-thyroxine (T4) outer-ring (5') deiodination to 3,5,3'-triiodo-L-thyronine (T3); T4IRD, T4 inner-ring (5) deiodination to 3,3',5'-triiodo-L-thyronine (reverse T3); T3ORD, T3 outer-ring deiodination to 3,5-diiodo-L-thyronine; T3IRD, T3 inner-ring deiodination to 3,3'-diiodo-L-thyronine) were studied in microsomes of liver, kidney, muscle, and intestine of unmetamorphosed larvae and nontrophic upstream-migrant (spawning-phase) sea lampreys, Petromyzon marinus. T4ORD properties (pH optimum, dithiothreitrol cofactor requirement, apparent K(m), substrate preference and potency of potential inhibitors) were similar in most respects to those described previously for teleosts. T4ORD activity was detected in all larval tissues examined and was highest in intestine. In upstream migrants, T4ORD was also greatest in intestine, but low in muscle and kidney and undetectable in liver. T3ORD activity was not found in any tissue of either developmental stage. T4IRD and T3IRD activities were negligible in larval tissues, but present in kidney and particularly intestine of upstream migrants. We conclude that depending on developmental/physiological state, sea lampreys possess low-K(m) outer-ring and inner-ring monodeiodinases, which in most respects correspond functionally with those of teleosts. However, in contrast to teleosts, deiodination is particularly active in larval intestine, perhaps reflecting the release from the endostyle of TH into the lumen of the alimentary canal.

Animals↗
PubMed1996

Abrupt cessation of immunosuppression in a patient with persistent acute lymphoblastic leukaemia following allogeneic transplantation.

A 20-year-old man with acute lymphoblastic leukaemia (ALL) in second complete remission underwent sibling donor transplant. Post-transplant there was haematological and immunophenotypic evidence of persisting disease. Cyclosporine was abruptly discontinued and following this the leukaemic clone disappeared. Discontinuation of immunosuppression may be of benefit in leukaemia which persists following transplant.

Adult↗
PubMed1996

Quality of life in long-term survivors of marrow transplantation: comparison with a matched group receiving maintenance chemotherapy.

A retrospective descriptive study was designed to assess the quality of life (QoL) and psychosocial adjustment in long-term BMT survivors compared with a group of patients with haematological malignancies receiving maintenance chemotherapy (MC), matched for age, post-treatment time, sociodemographic and disease characteristics. The sample consisted of 91 long-term BMT survivors and 73 MC patients from three teaching hospitals in the UK. The results indicated that most of the BMT subjects had a good to excellent quality of life and, in some domains, even better adjustment than the MC patients. However, 20% of the BMT subjects had failed to return to full-time employment at a mean post-BMT time of almost 40 months. A significant number of BMT subjects were also identified with symptoms of anxiety and depression. The physical symptomatology had an association with psychological status. Impotence-related difficulties, decreased sexual satisfaction and altered body image were the main characteristics of psychosexual dysfunction in the BMT group. Poorer quality of life was predicted by the presence of depressive symptoms, low affirmation, and impoverished social adjustment.

Adolescent↗
PubMed1995

The activity of deoxyspergualin in multidrug-resistant cells.

Deoxyspergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic spergualin, has been shown to possess potent in vitro and in vivo anti-tumour activity and is currently in the National Cancer Institute (NCI) decision network. Deoxyspergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multidrug resistance. We therefore decided to examine the comparative activity of deoxyspergualin in parent and multidrug-resistant cells. Deoxyspergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxyspergualin. It appears that in the presence of horse serum, deoxyspergualin may exert its effect by a mechanism other than polyamine oxidation. Deoxyspergualin did not enhance the accumulation of [3H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxyspergualin (1-20 microM) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [3H]-azidopine. Deoxyspergualin did not inhibit this labeling. Although deoxyspergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxyspergualin a promising candidate for development as an anti-cancer agent.

Animals↗
PubMed1995

Loss of spatial control of the mitotic spindle apparatus in a Chlamydomonas reinhardtii mutant strain lacking basal bodies.

The bld2-1 mutation in the green alga Chlamydomonas reinhardtii is the only known mutation that results in the loss of centrioles/basal bodies and the loss of coordination between spindle position and cleavage furrow position during cell division. Based on several different assays, bld2-1 cells lack basal bodies in > 99% of cells. The stereotypical cytoskeletal morphology and precise positioning of the cleavage furrow observed in wild-type cells is disrupted in bld2-1 cells. The positions of the mitotic spindle and of the cleavage furrow are not correlated with respect to each other or with a specific cellular landmark during cell division in bld2-1 cells. Actin has a variable distribution during mitosis in bld2-1 cells, but this aberrant distribution is not correlated with the spindle positioning defect. In both wild-type and bld2-1 cells, the position of the cleavage furrow is coincident with a specialized set of microtubules found in green algae known as the rootlet microtubules. We propose that the rootlet microtubules perform the functions of astral microtubules and that functional centrioles are necessary for the organization of the cytoskeletal superstructure critical for correct spindle and cleavage furrow placement in Chlamydomonas.

Actins↗