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Biomedical subjects

M Christian

Publications and source records attributed to M Christian.

At least 19 recordsLinked to original sources
PubMed2006

The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks.

NRs (nuclear receptors) regulate the expression of specific gene networks in target cells by recruiting cofactor complexes involved in chromatin remodelling and in the assembly of transcription complexes. The importance of activating gene expression, in metabolic tissues, is well established, but the contribution of transcriptional inhibition is less well defined. In this review, we highlight a crucial role for RIP140 (receptor-interacting protein 140), a transcriptional co-repressor for NR, in the regulation of metabolic gene expression. Many genes involved in lipid and carbohydrate metabolism are repressed by RIP140 in adipose and muscle. The repressive function of RIP140 results from its ability to bridge NRs to repressive enzyme complexes that modify DNA and histones. In the absence of RIP140, expression from many metabolic genes is increased so that mice exhibit a lean phenotype and resistance to high-fat-diet-induced obesity and display increased glucose tolerance and insulin sensitivity. We propose that a functional interplay between transcriptional activators and the co-repressor RIP140 is an essential process in metabolic regulation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

How does auxin enhance cell elongation? Roles of auxin-binding proteins and potassium channels in growth control.

Elongation growth and a several other phenomena in plant development are controlled by the plant hormone auxin. A number of recent discoveries shed light on one of the classical problems of plant physiology: the perception of the auxin signal. Two types of auxin receptors are currently known: the AFB/TIR family of F box proteins and ABP1. ABP1 appears to control membrane transport processes (H+ secretion, osmotic adjustment) while the TIR/AFBs have a role in auxin-induced gene expression. Models are proposed to explain how membrane transport (e.g., K+ and H+ fluxes) can act as a cross-linker for the control of more complex auxin responses such as the classical stimulation of cell elongation.

Arabidopsis Proteins↗
PubMed2003

Effectiveness of multidrug therapy in multibacillary leprosy: a long-term follow-up of 34 multibacillary leprosy patients treated with multidrug regimens till skin smear negativity.

The World Health Organization (WHO) Field Trials of multidrug therapy (MDT) started at Schieffelin Leprosy Research and Training Centre (SLR & IC), Karigiri, India in December 1981. The patients were treated with two MDT regimens. The first (regimen A) consisted of 600mg rifampicin and 300mg of clofazimine given under supervision on 2 consecutive days monthly, 225mg injection of acedapsone bimonthly and dapsone 100mg daily. The second regimen (regimen B) was the conventional MDT (WHO/MDT), rifampicin 600mg and clofazimine 300mg supervised once a month, dapsone 100mg and clofazimine 50mg daily, unsupervised. Both the regimens were administered for a minimum period of 2 years or until skin smear negativity, whichever occurred later. Thirty-four newly detected previously untreated MB patients, 16 of whom received regimen A and 18 regimen B, were reassessed. Both regimens were well accepted and well tolerated by the patients. Clofazimine discolouration was the only adverse effect of MDT seen in these patients. After completion of treatment with MDT, the patients were followed up for a total duration of 466 person-years with a mean of 13.7 +/- 1.4 years per patient. No relapse was seen.

Acedapsone↗
PubMed2002

Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro.

Differentiation of human endometrium during the secretory phase of the menstrual cycle is characterized by expression of a variety of genes implicated in the establishment and maintenance of pregnancy. An increased abundance of signal transducers and activators of transcription (Stats) in the secretory phase suggests Stat5 as a component of the differentiation of endometrium in response to ovarian hormone stimulation in vivo. Decidualization is initiated in a subset of endometrial stromal cells (ESC) in vivo during the secretory phase, but it is unclear whether regulated expression of Stat5 is a feature of these cells. Here, therefore, the abundance and subcellular distribution of Stat5 in ESC after a decidualization stimulus of cAMP plus medroxyprogesterone acetate (MPA) has been investigated in vitro. Western blotting revealed an increase in the apparent abundance of Stat5a and Stat5b, in the cytosolic and nuclear fractions, at 2, 3, and 4 d after stimulation. The potential functional relevance of this increase in Stat5 is suggested by the ability of transiently transfected Stat5a or Stat5b to significantly enhance the response of the decidual PRL promoter to cAMP/MPA and attenuation of the response to cAMP/MPA by dominant negative Stat5. Recent evidence suggests endometrial differentiation, including PRL production, as a possible target of antiphospholipid antibodies (aPL) prevalent in recurrent miscarriage. Monoclonal antibody, ID2, which has similar reactivity as human aPL, significantly decreased the apparent abundance of nuclear Stat5b in response to cAMP/MPA and was associated with decreased decidual PRL promoter activation and PRL secretion. Regulated expression of Stat5 is therefore a component of decidual differentiation of human ESC and contributes significantly to activation of the decidual PRL promoter. Alteration of this process by an aPL component suggests decidual differentiation as a potential clinical target in recurrent early miscarriages.

Antibodies, Antiphospholipid↗
PubMed2001

Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10(-7.5) M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10(-4) M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity.

Animals↗
PubMed2001

Retrotransposons of the Tnt1B family are mobile in Nicotiana plumbaginifolia and can induce alternative splicing of the host gene upon insertion.

Active retrotransposons have been identified in Nicotiana plumbaginifolia by their ability to disrupt the nitrate reductase gene in chlorate-resistant mutants selected from protoplast-derived cultures. In mutants E23 and F97, two independent insertions of Tnp2, a new retrotransposon closely related to the tobacco Tnt1 elements, were detected in the nitrate reductase gene. These two Tnp2 elements are members of the Tnt1B subfamily which shows that Tnt1B elements can be active and mutagenic in the N. plumbaginifolia genome. Furthermore, these results suggest that Tnt1B is the most active family of Tntl elements in N. plumbaginifolia, whereas in tobacco only members of the Tnt1A subfamily were found inserted in the nitrate reductase gene. The transcriptional regulations of Tnp2 and Tnt1A elements are most probably different due to non-conserved U3 regions. Our results thus support the hypothesis that different Nicotiana species contain different active Tntl subfamilies and that only one active Tntl subfamily might be maintained in each of these species. The Tnp2 insertion found in the F97 mutant was found to be spliced out of the nitrate reductase mRNA by activation of cryptic donor and acceptor sites in the nitrate reductase and the Tnp2 sequences respectively.

Alternative Splicing↗
PubMed2001

The auxin signal for protoplast swelling is perceived by extracellular ABP1.

Protoplasts of corn coleoptiles and Arabidopsis hypocotyls respond to the plant hormone auxin with a rapid change in volume. We checked the effect of antibodies directed against epitopes of auxin-binding protein 1 from Arabidopsis thaliana (AtERabp1) and Zea mays (ZmERabp1), respectively. Antibodies raised against the C-terminus of AtERabp1 inhibited the response to auxin, while antibodies raised against a part of box a, the putative auxin-binding domain, induced a swelling response similar to that caused by auxin treatment. Synthetic C-terminal oligopeptides of ZmERabp1 also caused a swelling response. These effects occurred regardless of whether the experiments were carried out with homologous (anti-AtERabp1 antibodies on Arabidopsis protoplasts or anti-ZmERabp1 antibodies in maize protoplasts) or heterologous immunological tools. The results indicate that the auxin signal for protoplast swelling is perceived by extracellular ABP1.

Amino Acid Sequence↗
PubMed2001

Interferon-gamma modulates prolactin and tissue factor expression in differentiating human endometrial stromal cells.

Cytokines such as interferon-gamma (IFNgamma) released by resident uterine immune cells are thought to influence the expression of differentiated function in the human endometrium. Decidualization of the stromal cell compartment is confined to the superficial endometrial layer in the nonpregnant uterus. To explore the molecular mechanism underlying the spatial expression of the decidual phenotype, the effect of IFNgamma on the induction of two well characterized markers of endometrial stromal (ES) cell differentiation, PRL and tissue factor (TF), has been investigated. IFNgamma antagonizes cAMP-mediated PRL protein and messenger RNA expression in primary ES cell cultures through inhibition of decidual PRL promoter activity. In parallel, IFNgamma stimulates Stat-1 (signal transducer and activator of transcription-1) expression, phosphorylation, and translocation to the nucleus. Exogenously expressed Stat-1 potently represses decidual PRL promoter activation, indicating the potential for the inhibitory effects of IFNgamma to be mediated by Stat-1. We demonstrate that although the coactivator CREB-binding protein/p300 is essential for decidual PRL transcription, this coactivator does not appear to be the target for IFNgamma-mediated repression. By contrast, IFNgamma has little effect on cAMP-mediated TF expression, but induces TF in ES cells not exposed to a decidualizing stimulus. This suggested that in vivo TF expression may not be restricted to decidualizing cells of the superficial layer and was confirmed by immunohistochemical analysis demonstrating intense TF staining in the basal stromal compartment during the regeneration phase of the cycle. The differential sensitivity of decidualization-associated genes to IFNgamma illustrates its potential role as a selective biological response modifier that influences regional function within the endometrium.

Cell Differentiation↗
PubMed2001

Electrical stimulation for swallowing disorders caused by stroke.

BACKGROUND: An estimated 15 million adults in the United States are affected by dysphagia (difficulty swallowing). Severe dysphagia predisposes to medical complications such as aspiration pneumonia, bronchospasm, dehydration, malnutrition, and asphyxia. These can cause death or increased health care costs from increased severity of illness and prolonged length of stay. Existing modalities for treating dysphagia are generally ineffective, and at best it may take weeks to months to show improvement. One common conventional therapy, application of cold stimulus to the base of the anterior faucial arch, has been reported to be somewhat effective. We describe an alternative treatment consisting of transcutaneous electrical stimulation (ES) applied through electrodes placed on the neck. OBJECTIVE: Compare the effectiveness of ES treatment to thermal-tactile stimulation (TS) treatment in patients with dysphagia caused by stroke and assess the safety of the technique. METHODS: In this controlled study, stroke patients with swallowing disorder were alternately assigned to one of the two treatment groups (TS or ES). Entry criteria included a primary diagnosis of stroke and confirmation of swallowing disorder by modified barium swallow (MBS). TS consisted of touching the base of the anterior faucial arch with a metal probe chilled by immersion in ice. ES was administered with a modified hand-held battery-powered electrical stimulator connected to a pair of electrodes positioned on the neck. Daily treatments of TS or ES lasted 1 hour. Swallow function before and after the treatment regimen was scored from 0 (aspirates own saliva) to 6 (normal swallow) based on substances the patients could swallow during a modified barium swallow. Demographic data were compared with the test and Fisher exact test. Swallow scores were compared with the Mann-Whitney U test and Wilcoxon signed-rank test. RESULTS: The treatment groups were of similar age and gender (p > 0.27), co-morbid conditions (p = 0.0044), and initial swallow score (p = 0.74). Both treatment groups showed improvement in swallow score, but the final swallow scores were higher in the ES group (p > 0.0001). In addition, 98% of ES patients showed some improvement, whereas 27% of TS patients remained at initial swallow score and 11% got worse. These results are based on similar numbers of treatments (average of 5.5 for ES and 6.0 for TS, p = 0.36). CONCLUSIONS: ES appears to be a safe and effective treatment for dysphagia due to stroke and results in better swallow function than conventional TS treatment.

Aged↗
PubMed2000

A comparison of two methods of analog-to-digital medical video conversion.

The purpose of this study was to compare 2 methods of analog-to-digital video conversion in anticipation of improving, refining, and standardizing digital video production for medical education, diagnosis support, and telemedicine. A video workstation was devised containing 2 analog-to-digital video conversion systems: a digital video media converter with fire wire card and a video capture card. A procedure for final digital video production was created that used equivalent compression, pixel resolution, frame rate, and data rate for both systems. A subjective test was performed in which 12 archived analog videotapes, consisting of magnetic resonance angiograms, ultrasounds, neurosurgeries, and telemedicine applications, were converted digitally using the 2 methods. Randomized side by side video comparisons were analyzed and rated by subjective quality. An objective test was performed by videotaping a gray-scale test pattern off a computer monitor, digitally converting it by the 2 methods, and comparing the gray-scale values to the original pattern. There was no significant difference in overall video quality (P = .31) or grayscale reproduction using the 2 methods of analog-to-digital conversion. When performing simple analog-to-digital video conversion, a video capture card is equal in quality and costs less than a digital video (DV) media converter or fire wire card. If a digital video camera is available for use, then a DV media converter or fire wire card is more advantageous because it enables full operation of the digital video camera.

Analog-Digital Conversion↗
PubMed2000

Occlusive dressing versus oxygen mist therapy following CO2 laser resurfacing.

BACKGROUND: Oxygen is an essential element for collagen synthesis and reepithelialization. The use of topical oxygen after CO2 laser resurfacing has not been studied. OBJECTIVE: To compare the rate and quality of healing in wounds treated with an oxygen mist to those treated with occlusive dressing following CO2 laser resurfacing. METHODS: Three patients underwent CO2 laser resurfacing to each half of the face 3 weeks apart. Postoperatively, half of the face was treated with an oxygen mist protocol for 5 days, while the other half was treated with occlusive dressing for 4 days. RESULTS: At postoperative day 5, significantly less crusting was observed on the half of the face treated with the oxygen mist protocol (p < 0.05). CONCLUSION: The oxygen mist postoperative protocol may offer patients similar overall healing rates and significantly less crusting compared to occlusive dressing.

Aged↗
PubMed2000

Phase I clinical trial design in cancer drug development.

The past decade has seen the publication of a number of new proposals for the design of phase I trials of anticancer agents. The purpose of these proposals has been to address ethical concerns about treating excessive numbers of patients at subtherapeutic doses of a new agent and to increase the overall efficiency of the process while enhancing the precision of the recommended phase II dose. In early 1998, a workshop of phase I investigators was held under the sponsorship of Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to review the experience to date with novel phase I methodologies, with a particular focus on their efficiency and safety. This report summarizes the material presented. It was concluded that for phase I trials of antineoplastics (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date suggests that the historic approach of using a modified Fibonacci escalation and three patients per dose level is not necessary and is seldom used. One patient per dose level and more rapid escalation schemes, both empirically based and statistically based, are commonly used with apparent safety. There remain questions, however: Which of the dose escalation schemes is optimal? Are there alternatives to toxicity as a phase I end point, and will these end points be reliable in defining active doses? Answering these questions in a reasonable time frame will be important if new anticancer agents are not to suffer undue delays in phase I evaluation.

Animals↗
PubMed2000

Long-term follow up of multibacillary leprosy patients with high BI treated with WHO/MDT regimen for a fixed duration of two years.

Forty-six, newly detected, previously untreated multibacillary (MB) patients with a bacterial index (BI) of > or = 3+ who had received WHO/MDT for 2 years were followed up for a total duration of 424 person-years and a mean duration of 9.26 +/- 2.98 years per patient. The BIs of the patients continued to fall, and all of the patients, except one, reached skin-smear negativity. WHO/MDT was well accepted and well tolerated. Relapse, which was defined as an increase in the BI of 1+ or more with or without clinical evidence of activity, was observed in only one patient, giving a relapse rate of 2.2% or 0.23 per 100 person-years in patients with a BI of > or = 3+ after long-term follow up. This patient was started on a second course of WHO/MDT to which he responded favorably. WHO/MDT for a fixed duration of 2 years for MB patients as recommended by the WHO is vindicated.

Adult↗
PubMed1999

Measuring response in solid tumors: unidimensional versus bidimensional measurement.

BACKGROUND: Tumor shrinkage is a common end point used in screening new cytotoxic agents. The standard World Health Organization criterion for partial response is a 50% or more decrease in the sum of the products of two measurements (the maximum diameter of a tumor and the largest diameter perpendicular to this maximum diameter) of individual tumors. However, theoretically, the simple sum of the maximum diameters of individual tumors is more linearly related to cell kill than is the sum of the bidimensional products. It has been hypothesized that the calculation of bidimensional products is unnecessary, and a 30% decrease in the sum of maximum diameters of individual tumors (assuming spherical shape and equivalence to a 50% reduction in the sum of the bidimensional products) was proposed as a new criterion. We have applied the standard response and the new response criteria to the same data to determine whether the same number of responses in the same patients would result. METHODS: Data from 569 patients included in eight studies of a variety of cancers were reanalyzed. The two response criteria were separately applied, and the results were compared using the kappa statistic. The importance of confirmatory measurements and the frequency of nonspherical tumors were also examined. In addition, for a subset of 128 patients, a unidimensional criterion for disease progression (30% increase in the sum of maximum diameters) was applied and compared with the standard definition of a 25% increase in the sum of the bidimensional products. RESULTS: Agreement between the unidimensional and bidimensional criteria was generally found to be good. The kappa statistic for concordance for overall response was 0.95. CONCLUSION: We conclude that one dimensional measurement of tumor maximum diameter may be sufficient to assess change in solid tumors.

Disease Progression↗