PubMed Health⌕ Search

Biomedical subjects

A J Cutler

Publications and source records attributed to A J Cutler.

At least 19 recordsLinked to original sources
PubMed2003

Sexual dysfunction and antipsychotic treatment.

Human sexual function is complex and affected in many different ways by schizophrenia and the antipsychotic drugs used in its treatment. The evaluation of the effects of antipsychotics on sexual function in patients with schizophrenia is also complex because the deleterious effects of conventional antipsychotics are superimposed on the effects of the disease itself. Although not extensively researched, sexual dysfunction seems to be frequent in patients with schizophrenia, especially in men. Sexual dysfunction appears, in significant part, to be a direct consequence of dopamine antagonism, combined with indirect effects due to increased serum prolactin concentration. Atypical antipsychotics have a number of potential advantages over standard agents with regard to their impact on sexual function. Clinical reports indicate that atypical antipsychotics are associated with a lower incidence of sexual adverse events than conventional antipsychotics and that there may also be important differences between them in this regard. For example, dose-related increases in prolactin concentrations occur with risperidone whereas olanzapine is associated with mild and transient increases in long-term treatment. Treatment with clozapine does not result in prolactin elevation and, like olanzapine, only transient increases occur with ziprasidone therapy, but the risk of agranulocytosis with clozapine restricts its use. Quetiapine has no more effect on serum prolactin than placebo across its full dose range. Together with its low frequency of reproductive or hormonal side effects and a low incidence of extrapyramidal symptoms, the tolerability profile of quetiapine may be particularly beneficial for many patients. Sexual dysfunction can be an important source of distress to patients and adversely affects compliance, and is one of the factors that must be taken into account when selecting treatment.

Antipsychotic Agents↗
PubMed2001

Intact B cell tolerance in the absence of the first component of the classical complement pathway.

A critical role for complement in the regulation of self tolerance has been proposed to explain the strong association between complement deficiency and autoimmunity. To elucidate the role of the classical pathway of complement in the maintenance of B cell tolerance, C1q-deficient (C1qa-/-) mice were bred with anti-hen egg lysozyme (HEL) immunoglobulin (Ig(HEL)) and soluble HEL (sHEL) transgenic mice. B cell tolerance was intact in C1qa-/- mice. In vivo, double-transgenic (Ig(HEL)/sHEL) C1qa-/- and wild-type control mice down-regulated surface immunoglobulin expression on splenocytes and equivalent numbers of HEL-binding B cells accumulated in the periphery. Maturation of B cells, evidenced by CD21 expression, was retarded to the same extent and at a similar time point. The frequency of anti-HEL-producing plasma cells and serum levels of anti-HEL immunoglobulin were comparably reduced in control and C1qa-/- double-transgenic mice compared to control Ig(HEL) and C1qa-/- Ig(HEL) mice. Furthermore, splenocytes from double-transgenic C1qa-/- or wild-type mice did not modulate intracellular calcium levels after stimulation with HEL in vitro. These data demonstrate that a stable form of B cell anergy persists in the periphery of C1qa-/- mice, suggesting that activation of the classical pathway by C1q is not essential for the maintenance of B cell tolerance in this transgenic model.

Animals↗
PubMed2000

Inhibitors of abscisic acid 8'-hydroxylase.

Structural analogues of the phytohormone (+)-abscisic acid (ABA) have been synthesized and tested as inhibitors of the catabolic enzyme (+)-ABA 8'-hydroxylase. Assays employed microsomes from suspension-cultured corn cells. Four of the analogues [(+)-8'-acetylene-ABA, (+)-9'-propargyl-ABA, (-)-9'-propargyl-ABA, and (+)-9'-allyl-ABA] proved to be suicide substrates of ABA 8'-hydroxylase. For each suicide substrate, inactivation required NADPH, increased with time, and was blocked by addition of the natural substrate, (+)-ABA. The most effective suicide substrate was (+)-9'-propargyl-ABA (K(I) = 0.27 microM). Several analogues were competitive inhibitors of ABA 8'-hydroxylase, of which the most effective was (+)-8'-propargyl-ABA (K(i) = 1.1 microM). Enzymes in the microsomal extracts also hydroxylated (-)-ABA at the 7'-position at a low rate. This activity was not inhibited by the suicide substrates, showing that the 7'-hydroxylation of (-)-ABA was catalyzed by a different enzyme from that which catalyzed 8'-hydroxylation of (+)-ABA. Based on the results described, a simple model for the positioning of substrates in the active site of ABA 8'-hydroxylase is proposed. In a representative physiological assay, inhibition of Arabidopsis thaliana seed germination, (+)-9'-propargyl-ABA and (+)-8'-acetylene-ABA exhibited substantially stronger hormonal activity than (+)-ABA itself.

Abscisic Acid↗
PubMed2000

Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII.

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.

Animals↗
PubMed2000

Anthracenone ABA analogue as a potential photoaffinity reagent for ABA-binding proteins.

An anthracenone analogue of abscisic acid (ABA) was synthesized as a potential photoaffinity reagent and tested for biological activity. Reaction between 10,10'-dimethoxy-9-anthrone with two equivalents of the lithiated dianion of cis-3-methylpent-2-en-4-yn-1-ol afforded an acetylenic alcohol key intermediate. Subsequent reduction of the triple bond, functional group manipulation of the side chain alcohol and deprotection of the dimethoxy protected anthrone provided anthracenone ABA analogue 7 as a potential photoaffinity reagent for ABA-binding proteins. The effect of natural ABA and the potential photoaffinity anthracenone ABA 7 on corn cell growth was determined at various concentrations. The results show that anthracenone ABA 7 is perceived as ABA-like, although producing less inhibition than ABA itself. For example, 7 at 33 microM produces approximately the same inhibition as ABA at 10 microM.

Abscisic Acid↗
PubMed1998

T cell-dependent immune response in C1q-deficient mice: defective interferon gamma production by antigen-specific T cells.

The role of the classical complement pathway in humoral immune responses was investigated in gene-targeted C1q-deficient mice (C1qA-/-). Production of antigen-specific immunoglobulin (Ig)G2a and IgG3 in primary and secondary responses to T cell-dependent antigen was significantly reduced, whereas IgM, IgG1, and IgG2b responses were similar in control and C1qA-/- mice. Despite abnormal humoral responses, B cells from C1qA-/- mice proliferated normally to a number of stimuli in vitro. Immune complex localization to follicular dendritic cells within splenic follicles was lacking in C1qA-/- mice. The precursor frequency of antigen-specific T cells was similar in C1qA-/- and wild-type mice. However, analysis of cytokine production by primed T cells in response to keyhole limpet hemocyanin revealed a significant reduction in interferon-gamma production in C1qA-/- mice compared with control mice, whereas interleukin 4 secretion was equivalent. These data suggest that the classical pathway of complement may influence the cytokine profile of antigen-specific T lymphocytes and the subsequent immune response.

Animals↗
PubMed1998

ICK1, a cyclin-dependent protein kinase inhibitor from Arabidopsis thaliana interacts with both Cdc2a and CycD3, and its expression is induced by abscisic acid.

Cyclin-dependent kinase (CDK) inhibitor genes encode low molecular weight proteins which have important functions in cell cycle regulation, development and perhaps also in tumorigenesis. The first plant CDK inhibitor gene ICK1 was recently identified from Arabidopsis thaliana. Although the C-terminal domain of ICK1 contained an important consensus sequence with the mammalian CDK inhibitor p27Kip1, the remainder of the deduced ICK1 sequence showed little similarity to any known CDK inhibitors. In vitro assays showed that recombinant ICK1 exhibited unique kinase inhibitory properties. In the present study we characterized ICK1 in terms of its gene structure, its interaction with both A. thaliana Cdc2a and CycD3, and its induction by the plant growth regulator, abscisic acid (ABA). ICK1 was expressed at a relatively low level in the tissues surveyed. However, ICK1 was induced by ABA, and along with ICK1 induction there was a decrease in Cdc2-like histone H1 kinase activity. These results suggest a molecular mechanism by which plant cell division might be inhibited by ABA. ICK1 clones were also identified from independent yeast two-hybrid screens using the CycD3 construct. The implication that ICK1 protein could interact with both Cdc2a and CycD3 was confirmed by in vitro binding assays. Furthermore, deletion analysis indicated that different regions of ICK1 are required for the interactions with Cdc2a and CycD3. These results provide a mechanistic basis for understanding the role of CDK inhibitors in cell cycle regulation in plant cells.

Abscisic Acid↗
PubMed1996

Neonatally tolerant rats actively eliminate donor-specific lymphocytes despite persistent chimerism.

Rats from the allotype-marked PVG-RT7b and PVG-RT1u-RT7b strains were injected at birth with semi-allogenic F1 bone marrow (BM) cells from athymic nude rats (PVG-rnu/rnu x PVG-RT1u-rnu/rnu) to induce neonatal tolerance. As adults, 97% of the animals accepted donor-specific allogeneic skin grafts and a majority (65%) of rats were chimeric, expressing the major histocompatibility complex class I and allotype marker of the donor strain. Similar results were obtained when PVG-RT1u-RT7b rats were injected at birth with fully allogeneic PVG-rnu/rnu nude BM cells: as adults, 94% accepted donor-specific skin allografts and 76% of recipients were chimeric. Donor derived CD4 T cells, CD8 T cells and B cells were found in low numbers (less than 2%) in peripheral blood of rats made tolerant by F1 BM cells. A large proportion of T cells bore the phenotype of recent thymic emigrants, suggesting that they were newly produced. All the evidence was consistent with clonal deletion tolerance, induced centrally within the thymus. The thymus was chimeric and thymocytes failed to respond in vitro to alloantigens of the donor-specific haplotype; donor-specific skin allografts survived indefinitely on athymic nude recipients reconstituted with CD4+CD8- thymocytes or peripheral CD4 T cells from tolerant animals. The chimeric state was interesting, since the PVG and PVG-RT1u rat strains contain a natural killer (NK) cell system that rapidly eliminates (within 24 h) intravenously injected allogeneic or semi-allogeneic lymphocytes--a phenomenon known as allogeneic lymphocyte cytotoxicity or ALC. When neonatal tolerant rats were tested, the ALC index (a measure of cell killing) was unchanged in nonchimeric tolerant rats and significantly altered (reduced killing), but not abolished in chimeric animals. Hence, the injection of allogeneic BM cells which induced specific tolerance in the T cell population failed to tolerize the NK cell system, allowing the constant killing of newly produced donor-derived lymphocytes and putting at risk the very survival of the allogenic BM cells. This has interesting implications for clinical transplantation.

Animals↗
PubMed1995

Promoters from kin1 and cor6.6, two homologous Arabidopsis thaliana genes: transcriptional regulation and gene expression induced by low temperature, ABA, osmoticum and dehydration.

The Arabidopsis thaliana genes kin1 and cor6.6 belong to the same family and were expressed at higher levels following low temperature and ABA treatments. In an attempt to elucidate the mechanism of gene regulation by low temperature, the relationship between low-temperature- and abscisic acid (ABA)-induced gene expression and possible differential expression of the two genes, we have cloned a 5.3 kb genomic fragment harboring kin1 and cor6.6 and their respective 5' sequences. The putative promoters of both genes were fused to the beta-glucuronidase (GUS) coding sequence and GUS expression was analysed in transgenic tobacco and Arabidopsis plants. The cor6.6 promoter produced a higher basal level of expression than the kin1 promoter in transgenic tobacco. Enzyme assays of inducible GUS activity in transgenic Arabidopsis and tobacco plants showed that GUS activity directed by both kin1 and cor6.6 promoters was significantly induced by ABA, dehydration and osmoticum, but not by low temperature. Northern analysis revealed, in contrast, that GUS mRNA was significantly induced in these transgenic plants by low temperature. Further analysis showed that, at low temperature, GUS protein synthesis from the induced GUS mRNA was inhibited. Together these results reveal induction of kin1 and cor6.6 transcription by low temperature, exogenous ABA and dehydration. However, low-temperature expression is dramatically reduced at the translational level.

Abscisic Acid↗
PubMed1995

Promoters from kin1 and cor6.6, two Arabidopsis thaliana low-temperature- and ABA-inducible genes, direct strong beta-glucuronidase expression in guard cells, pollen and young developing seeds.

The ability of most higher plants to withstand freezing can be enhanced by cold acclimation, although the freezing tolerance of plant tissues is also affected by their developmental stage. In addition, low temperature has pleiotropic effects on many plant developmental processes such as vernalization. The interaction between plant development and low temperature implies that some genes are regulated by both environmental factors and developmental cues. Although a number of cold-inducible genes from plants have been identified, information concerning their regulation during plant development is limited. In order to understand their developmental regulation and obtain possible clues as to function, the promoters of kin1 and cor6.6, two cold- and abscisic acid (ABA)-regulated genes from Arabidopsis thaliana, were fused to the beta-glucuronidase (GUS)-coding sequence and the resulting constructs were used to transform tobacco and A. thaliana. Transgenic plants with either the kin1 or cor6.6 promoter showed strong GUS expression in pollen, developing seeds, trichomes and, most interestingly, in guard cells. During pollen development, maximum GUS activity was found in mature pollen. In contrast, the maximum GUS activity during seed development was during early embryogenesis. These patterns of expression distinguish kin1 and cor6.6 from related lea genes which are strongly expressed during late embryogenesis. There was no major qualitative difference in patterns of GUS expression between kin1 and cor6.6 promoters and the results were similar for transgenic tobacco and Arabidopsis. Considering the results described, as well as those in an accompanying paper (Wang et al., 1995, Plant Mol Biol 28: 605-617 (this issue), we suggest that osmotic potential might be a major factor in regulating the expression of kin1 and cor6.6 during several developmental processes. The implication of the results for possible function of the gene products is discussed.

Abscisic Acid↗
PubMed1994

Coverage of mental health and substance abuse services under a single-payer health care system.

Health care reform proposals based on a single-payer system of health care insurance were introduced in the U.S. Congress in 1992 and 1993 but were superseded by the Clinton Administration's health care reform proposal, which was based on managed competition. In a single-payer system, the government collects all health care funding and pays private- and public-sector providers; similar providers are paid the same rate. Other features include consumer choice of providers, distribution of risk of high utilization over the entire nation, and control of health care expenses via an annual national health care budget. Such proposals cover outpatient, inpatient, and long-term care and case management services for mental illness and substance abuse disorders, call for periodic utilization review of continuing mental health care, and eliminate the distinction between public and private services based on limits of coverage. The last provision particularly affects severely or chronically mentally ill persons who are likely to exhaust their private insurance coverage.

Health Care Reform↗
PubMed1991

Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis.

The postnatal development of dopamine (DA) D1 receptors in the medial prefrontal cortex (mPFC), striatum (STR) and nucleus accumbens (NAC) of control and perinatally 6-hydroxydopamine (6-OHDA) lesioned rats was examined using quantitative autoradiography of 3H-SCH 23390 binding. D1 receptors are present at one week and increase only slightly to a stable level by 2 weeks in the STR and NAC. Their ontogeny is not altered by intracisternal injection of 6-OHDA 5 days after birth. A biphasic pattern of appearance of D1 receptors was found in the mPFC. D1 receptors are present in the mPFC at 1 week, increase 3-fold by 2-3 weeks, and then decline at 4 and 6 weeks. 6-OHDA lesions do not significantly alter this pattern. At all postnatal ages. D1 receptor binding in the mPFC exhibits a laminar distribution with increased receptor density in deep cortical layers (V, VI) compared to more superficial cortical layers (I, II). Both superficial and deep layers of D1 receptors in the mPFC show similar postnatal developmental patterns. DA turnover rates are consistently about 10-fold higher in frontal pole compared to remainder of forebrain at all postnatal ages. Early 6-OHDA lesions increase DA turnover in forebrain, but lead to a persistent reduction in DA turnover in frontal pole by 2 weeks of age.

Animals↗
PubMed1990

Design and cloning of a synthetic gene for the flounder antifreeze protein and its expression in plant cells.

A synthetic gene coding for the winter flounder antifreeze protein (AFP) has been constructed. A new strategy for the synthesis has been employed such that one strand of the duplex was chemically synthesized and the other was produced enzymatically by chain extension. The chemically synthesized blocks were constructed so that the second strand was self-priming. The resulting DNA fragment was incorporated into the vector, pGCS1, which contained a translational fusion of the sequence encoding AFP and the N terminus of cat (encoding chloramphenicol acetyltransferase, CAT), under the control of the cauliflower mosaic virus 35S promoter. This plasmid was introduced into protoplasts of corn (var. Black Mexican Sweet) by electroporation. Production of the fusion peptide was monitored by CAT assay and Western blotting with antisera to AFP and CAT.

Animals↗
PubMed1989

A N and N Nuclear Magnetic Resonance Study of Nitrogen Metabolism in Shoot-Forming Cultures of White Spruce (Picea glauca) Buds.

Nitrogen-14 and nitrogen-15 nuclear magnetic resonance (NMR) spectra were recorded for freshly dissected buds of Picea glauca and for buds grown for 3, 6 and 9 weeks on shoot-forming medium. Resonances for Glu (and other alphaNH(2) groups), Pro, Ala, and the side chain groups in Gln, Arg, Orn, and gamma-aminobutyric acid could be detected in in vivo(15)N NMR spectra. Peaks for alpha-amino groups, Pro, NO(3) (-) and NH(4) (+) could also be identified in (14)N NMR spectra. Perfusion experiments performed for up to 20 hours in the NMR spectrometer showed that (15)N-labeled NH(4) (+) and NO(3) (-) are first incorporated into the amide group of Gln and then in the alphaNH(2) pool. Subsequently, it also emerges in Ala and Arg. These data suggest that the glutamine synthetase/ glutamate synthase pathway functions under these conditions. The assimilation of NH(4) (+) is much faster than that of NO(3) (-). Consequently after 10 days of growth more than 70% of the newly synthesized internal free amino acid pool derives its nitrogen from NH(4) (+) rather than NO(3) (-). If NH(4) (+) is omitted from the medium, no NO(3) (-) is taken up during 9 weeks and the buds support limited growth by utilizing their endogenous amino acid pools. It is concluded that NH(4) (+) and NO(3) (-) are both required for the induction of nitrate- and nitrite reductase.

Journal Article↗