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Biomedical subjects

A Miller

Publications and source records attributed to A Miller.

At least 73 records · Page 4Linked to original sources
PubMed2001

When symptoms persist: clozapine augmentation strategies.

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.

Antipsychotic Agents↗
PubMed2001

Nuclear transfer protocol affects messenger RNA expression patterns in cloned bovine blastocysts.

The successful production of embryos by nuclear transfer (NT) employing cultured somatic donor cells depends upon a variety of factors. The objective of the present study was to investigate the effects 1) of two different activation protocols, 2) the use of quiescent or nonquiescent donor cells (G(0) or G(1) of the cell cycle), and 3) passage number of donor cells on the relative abundance (RA) of eight specific mRNAs (DNA methyltransferase, DNMT; mammalian achaete-scute homologue, Mash2; glucose transporter-1, Glut-1; heat shock protein 70.1, Hsp; desmocollin II, Dc II; E-cadherin, E-cad; interferon tau, IF; insulin-like growth factor 2 receptor, Igf2r) in single blastocysts employing a semiquantitative reverse transcription-polymerase chain reaction assay. The results were compared with those for their in vitro (IVP)- and in vivo-generated noncloned counterparts. In experiment 1, employing either FBA (fusion before activation) or AFS (fusion and activation simultaneously) to generate NT blastocysts, Hsp mRNAs were not found in NT embryos from either protocol, whereas Hsp transcripts were detectable in IVP embryos. The relative abundance (RA) of IF transcripts was significantly increased in the AFS and IVP groups compared to the FBA treatment. In experiment 2, the use of either G(0) or G(1) donor cells to produce cloned embryos both significantly reduced the relative amount of DNMT transcripts and significantly increased the RA of Mash2 compared to the IVP embryos. In addition, IF transcript levels were significantly elevated in NT blastocysts employing G(1) donor cells for NT compared to IVP embryos and those generated using G(0) cells. In experiment 3, donor cells, either from passsage 5/6 or 8, were employed for NT. DNMT transcripts were significantly decreased, whereas Mash2 transcripts were significantly increased in both NT groups compared to their IVP counterparts. The amount of IF mRNA was significantly higher in P8-derived than in P5/6 and IVP embryos. In experiment 4, the RA of DNMT transcripts was decreased in in vivo-derived blastocysts compared to those produced in vitro. Mash2 expression was increased in in vivo embryos and those IVP embryos produced in medium containing Sigma BSA. The RA of Hsp was higher in IVP embryos produced in serum containing medium than in those produced in Sigma BSA or in vivo. In vivo embryos and those produced in Life Technologies BSA had the lowest expression of IF transcripts. Expression of all other genes was not affected by variation in NT methodology or IVP culture systems throughout experiments 1-4. In conclusion, depending on steps of the cloning procedure NT-derived embryos display marked differences from their IVP- and in vivo-derived counterparts. An aberrant expression pattern in NT embryos was found with respect to genes thought to be involved in stress adaptation, trophoblastic function, and DNA methylation during preimplantation development.

Animals↗
PubMed2001

Immuno-EM localization of GFP-tagged yolk proteins in C. elegans using microwave fixation.

Because of the presence of a low-permeability cuticle covering the animal, fixation of C. elegans tissue for immunoelectron microscopy has proved very difficult. Here we applied a microwave fixation protocol to improve penetration of fixatives before postembedding immunogold labeling. Using this technique, we were able to successfully localize several components of yolk (YP170) trafficking in both wild-type and transgenic strains expressing a vitellogenin::green fluorescent protein fusion (YP170::GFP). Green fluorescent protein (GFP) and its variants are commonly used as markers to localize proteins in transgenic C. elegans using fluorescence microscopy. We have developed a robust method to localize GFP at the EM level. This procedure is applicable to the characterization of transgenic strains in which GFP is used to mark particular proteins or cell types and will undoubtedly be very useful for high-resolution analysis of marked structures.

Animals↗
PubMed2001

Childhood outcome after early high-frequency oscillatory ventilation for neonatal respiratory distress syndrome.

OBJECTIVE: In a previous multicenter controlled clinical trial, we randomly assigned surfactant-treated premature newborns with moderate to severe respiratory distress syndrome to early treatment with high-frequency oscillatory ventilation (HFOV) or to conventional ventilation (CV). Compared with control infants who were treated with CV, neonates who were treated with HFOV using a strategy designed to recruit and maintain lung volume and minimize oxygen exposure had clinical evidence of improved pulmonary outcome and less lung injury. We report a follow-up study designed to determine whether clinical differences persisted between these study groups. METHODS: Patients were recruited from 81 survivors at 1 center (Provo, Utah) and evaluated for sociodemographic and health history, growth, mental development, motor proficiency, and pulmonary function. RESULTS: Eighty-seven percent of the cohort who originally were assigned to treatment with HFOV (n = 36) or CV (n = 33) were seen in follow-up at a mean age of 77 months (6.4 years). There were no differences in the frequency of hospitalization, pulmonary illness, asthma, or disabilities. Growth, verbal IQ, and motor development were appropriate for age and not different between groups. Patients who initially were randomized to treatment with CV showed pulmonary function evidence of decreased peak expiratory flow, increased residual lung volume, and maldistribution of ventilation. CONCLUSION: Neurodevelopmental childhood outcome after early intervention HFOV was normal and not different compared with patients who were treated with CV. Surfactant replacement combined with early HFOV using a lung recruitment strategy ameliorates the acute lung injury in respiratory distress syndrome that predisposes some preterm infants to develop chronic lung disease.

Child↗
PubMed2001

The development of functional response units: the role of demarcating stimuli.

An experiment with rats examined the roles of demarcating stimuli and differential reinforcement probability on the development of functional response units. It examined the development of units in a probabilistic, free-operant situation in which the presence of demarcating stimuli was manipulated. In all conditions, behavior became organized into two-response sequences framed by changes in local reinforcement probability. A tone demarcating the beginning and end of contingent response sequences facilitated the development of functional response units, as in chunking, but the same units developed slowly in the absence of the tone. Complex functional response units developed even though reinforcement contigencies remained constant. These findings demonstrate that models of operant learning must include a mechanism for changing the response unit as a function of reinforcement history. Markov models may seem to be a natural technique for modeling response sequences because of their ability to predict individual responses as a function of reinforcement history; however, no class of Markov chain can incorporate changing response units in their predictions.

Animals↗
PubMed2001

Task-dependent changes in frontal brain asymmetry: effects of incentive cues, outcome expectancies, and motor responses.

The current study was designed to clarify the psychological functions most closely associated with frontal brain asymmetry. Electroencephalography (EEG) was recorded from 60 participants while they performed a delayed reaction time (RT) task that included manipulations of incentive, expectancy, and response. Significant alpha asymmetry effects were reflected in topographic differences across anterior EEG sites. Variations in monetary incentives resulted in parametric changes in anterior frontal alpha asymmetry. Manipulations of outcome expectancies were related to mid-frontal EEG changes that differed for men and women. Varied response requirements were related to central asymmetry patterns. Taken together, the findings suggest that regionally specific patterns of frontal asymmetry are functionally related to particular aspects of approach-withdrawal tendencies involved in the temporal guidance and regulation of goal-directed behavior.

Adult↗
PubMed2001

[Albumin--biological functions and clinical significance].

Albumin is a simple protein present both in animal and plant physiological fluids and tissues. It plays many important roles including maintenance of appropriate osmotic pressure, binding and transport of various substances like hormones, drugs etc. in blood, and neutralisation of free radicals. Both acute and chronic disorders lead to hypoalbuminemia, oedema and many other disturbances. Albumin preparations obtained by separation of human plasma are used clinically for more than 50 years to reverse hypoalbuminemia and to allow for reversal of abnormalities in substance transport. These problems are discussed through out this paper.

Albumins↗
PubMed2001

[Hospital-at-home as a solution for the treatment requirements of acute exacerbation in multiple sclerosis].

Cooperation between the Multiple Sclerosis center at the Carmel medical center and the Hospital-at-Home (H.H) department of the continuing care unit in the Haifa and Western Galilee district of the Clalit Health Services has made it possible to give methylprednisolone intravenously to Multiple Sclerosis (M.S) patients during an acute exacerbation of the disease, in their home. In this study, we describe the joint work of the two centers. We have summarized 30 treatment courses given to 26 patients in their homes, following referral by the M.S. center, in the year 1999. The aims of the study included assessing satisfaction, safety and cost-effectiveness in a treatment course in the HH framework, as compared to the same treatment being conducted in the framework of hospitalization in various neurological departments, as was done in the past in the same group of patients. The expenses involved in HH for this group of patients were only 14% of the parallel treatment in the hospital (a savings of 86%). The treatment has proven to be extremely safe. There were no side-effects that required returning patients to the hospital, and the treatment was given in conditions of maximum comfort for the patient and his family. A telephone survey was conducted, which compared the satisfaction with the HH treatment, and the burden caused the patient's family to prior hospitalization for the same treatment. For all of the parameters examined, greater satisfaction was distinctly proven in the HH treatment. In light of these findings, we can conclude that giving methylprednisolone intravenously to M.S patients during an acute exacerbation, in the HH framework, is a safe and cost effective treatment, preferred by the patient and his family.

Caregivers↗
PubMed2001

Cognitive-behavioral therapy to reduce weight concerns improves smoking cessation outcome in weight-concerned women.

Women smokers concerned about weight gain (N = 219) were randomly assigned to 1 of 3 adjunct treatments accompanying group smoking cessation counseling: (a) behavioral weight control to prevent weight gain (weight control); (b) cognitive-behavioral therapy (CBT) to directly reduce weight concern, in which dieting was discouraged; and (c) standard counseling alone (standard), in which weight gain was not explicitly addressed. Ten sessions were conducted over 7 weeks, and no medication was provided. Continuous abstinence was significantly higher at posttreatment and at 6 and 12 months of follow-up for CBT (56%, 28%, and 21%, respectively), but not for weight control (44%, 18%, and 13%, respectively), relative to standard (31%, 12%, and 9%, respectively). However, weight control, and to a lesser extent CBT, was associated with attenuation of negative mood after quitting. Prequit body mass index, but not change in weight or in weight concerns postquit, predicted cessation outcome at 1 year. In sum, CBT to reduce weight concerns, but not behavioral weight control counseling to prevent weight gain, improves smoking cessation outcome in weight-concerned women.

Adolescent↗
PubMed2000

Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization.

The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle. Biochemical and genetic studies have demonstrated overlapping as well as distinct functions for the three proteins in cell cycle control and mouse development. However, the role of the pRB family as a whole in the regulation of cell proliferation, cell death, or cell differentiation is not known. We generated embryonic stem (ES) cells and other cell types mutant for all three genes. Triple knock-out mouse embryonic fibroblasts (TKO MEFs) had a shorter cell cycle than wild-type, single, or double knock-out control cells. TKO cells were resistant to G(1) arrest following DNA damage, despite retaining functional p53 activity. They were also insensitive to G(1) arrest signals following contact inhibition or serum starvation. Finally, TKO MEFs did not undergo senescence in culture and do possess some characteristics of transformed cells. Our results confirm the essential role of the Rb family in the control of the G(1)/S transition, place the three Rb family members downstream of multiple cell cycle control pathways, and further the link between loss of cell cycle control and tumorigenesis.

Animals↗
PubMed2000

Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity.

Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.

3T3 Cells↗
PubMed2000

A role for CD40-CD40 ligand interactions in the generation of type 1 cytokine responses in human leprosy.

The interaction of CD40 ligand (CD40L) expressed by activated T cells with CD40 on macrophages has been shown to be a potent stimulus for the production of IL-12, an obligate signal for generation of Th1 cytokine responses. The expression and interaction of CD40 and CD40L were investigated in human infectious disease using leprosy as a model. CD40 and CD40L mRNA and surface protein expression were predominant in skin lesions of resistant tuberculoid patients compared with the highly susceptible lepromatous group. IL-12 release from PBMC of tuberculoid patients stimulated with Mycobacterium leprae was partially inhibited by mAbs to CD40 or CD40L, correlating with Ag-induced up-regulation of CD40L on T cells. Cognate recognition of M. leprae Ag by a T cell clone derived from a tuberculoid lesion in the context of monocyte APC resulted in CD40L-CD40-dependent production of IL-12. In contrast, M. leprae-induced IL-12 production by PBMC from lepromatous patients was not dependent on CD40L-CD40 ligation, nor was CD40L up-regulated by M. leprae. Furthermore, IL-10, a cytokine predominant in lepromatous lesions, blocked the IFN-gamma up-regulation of CD40 on monocytes. These data suggest that T cell activation in situ by M. leprae in tuberculoid leprosy leads to local up-regulation of CD40L, which stimulates CD40-dependent induction of IL-12 in monocytes. The CD40-CD40L interaction, which is not evident in lepromatous leprosy, probably participates in the cell-mediated immune response to microbial pathogens.

CD40 Antigens↗
PubMed2000

Virulence gene regulation inside and outside.

Much knowledge about microbial gene regulation and virulence is derived from genetic and biochemical studies done outside of hosts. The aim of this review is to correlate observations made in vitro and in vivo with two different bacterial pathogens in which the nature of regulated gene expression leading to virulence is quite different. The first is Vibrio cholerae, in which the concerted action of a complicated regulatory cascade involving several transcription activators leads ultimately to expression of cholera toxin and the toxin-coregulated pilus. The regulatory cascade is active in vivo and is also required for maintenance of V. cholerae in the intestinal tract during experimental infection. Nevertheless, specific signals predicted to be generated in vivo, such as bile and a temperature of 37 degrees C, have a severe down-modulating effect on activation of toxin and pilus expression. Another unusual aspect of gene regulation in this system is the role played by inner membrane proteins that activate transcription. Although the topology of these proteins suggests an appealing model for signal transduction leading to virulence gene expression, experimental evidence suggests that such a model may be simplistic. In Streptococcus pyogenes, capsule production is critical for virulence in an animal model of necrotizing skin infection. Yet capsule is apparently produced to high levels only from mutation in a two-component regulatory system, CsrR and CsrS. Thus it seems that in V. cholerae a complex regulatory pathway has evolved to control virulence by induction of gene expression in vivo, whereas in S. pyogenes at least one mode of pathogenicity is potentiated by the absence of regulation.

Animals↗
PubMed2000

A review of water quality concerns in livestock farming areas.

Post-war changes in farming systems and especially the move from mixed arable-livestock farming towards greater specialisation, together with the general intensification of food production have had adverse affects on the environment. Livestock systems have largely become separated into pasture-based (cattle and sheep) and indoor systems (pigs and poultry). This paper reviews water quality issues in livestock farming areas of the UK. The increased losses of nutrients, farm effluents (particularly livestock wastes), pesticides such as sheep-dipping chemicals, bacterial and protozoan contamination of soil and water are some of the main concerns regarding water quality degradation. There has been a general uncoupling of nutrient cycles, and problems relating to nutrient loss are either short-term direct losses or long-term, related to accumulated nutrient surpluses. Results from several field studies indicate that a rational use of manure and mineral fertilisers can help reduce the pollution problems arising from livestock farming practices. Several best management practices are suggested for the control of nutrient loss and minimising release of pathogen and sheep-dip chemicals into agricultural runoff.

Agriculture↗
PubMed2000

Signal peptide determinants of SecA binding and stimulation of ATPase activity.

A signal peptide is required for entry of a preprotein into the secretory pathway, but how it functions in concert with the other transport components is unknown. In Escherichia coli, SecA is a key component of the translocation machinery found in the cytoplasm and at membrane translocation sites. Synthetic signal peptides corresponding to the wild type alkaline phosphatase signal sequence and three sets of model signal sequences varying in hydrophobicity and amino-terminal charge were generated. These were used to establish the requirements for interaction with SecA. Binding to SecA, modulation of SecA conformations sensitive to protease, and stimulation of SecA-lipid ATPase activity occur with functional signal sequences but not with transport-incompetent ones. The extent of SecA interaction is directly related to the hydrophobicity of the signal peptide core region. For signal peptides of moderate hydrophobicity, stimulation of the SecA-lipid ATPase activity is also dependent on amino-terminal charge. The results demonstrate unequivocally that the signal peptide, in the absence of the mature protein, interacts with SecA in aqueous solution and in a lipid bilayer. We show a clear parallel between the hierarchy of signal peptide characteristics that promote interaction with SecA in vitro and the hierarchy of those observed for function in vivo.

Adenosine Triphosphatases↗
PubMed2000

Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation.

The death domain kinase, receptor interacting protein (RIP), is one of the major components of the tumor necrosis factor receptor 1 (TNFR1) complex and plays an essential role in tumor necrosis factor (TNF)-mediated nuclear factor kappaB (NF-kappaB) activation. The activation of NF-kappaB protects cells against TNF-induced apoptosis. Heat-shock proteins (Hsps) are chaperone molecules that confer protein stability and help to restore protein native folding following heat shock and other stresses. The most abundant Hsp, Hsp90, is also involved in regulating the stability and function of a number of cell-signaling molecules. Here we report that RIP is a novel Hsp90-associated kinase and that disruption of Hsp90 function by its specific inhibitor, geldanamycin (GA), selectively causes RIP degradation and the subsequent inhibition of TNF-mediated IkappaB kinase and NF-kappaB activation. MG-132, a specific proteasome inhibitor, abrogated GA-induced degradation of RIP but failed to restore the activation of IkappaB kinase by TNF, perhaps because, in the presence of GA and MG-132, RIP accumulated in a detergent-insoluble subcellular fraction. Most importantly, the degradation of RIP sensitizes cells to TNF-induced apoptosis. These data indicate that Hsp90 plays an important role in TNF-mediated NF-kappaB activation by modulating the stability and solubility of RIP. Thus, inhibition of NF-kappaB activation by GA may be a critical component of the anti-tumor activity of this drug.

Apoptosis↗